Divergent Strategy in Natural Product Total Synthesis - Chemical

Review Cite This: Chem. Rev. XXXX, XXX, XXX−XXX

pubs.acs.org/CR

Divergent Strategy in Natural Product Total Synthesis Lei Li, Zhuang Chen, Xiwu Zhang, and Yanxing Jia* State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xueyuan Road, Beijing 100191, China ABSTRACT: The divergent total syntheses of complex natural products from a common intermediate have attracted enormous attention in the chemical community in the past few years because it can improve the efficiency of chemical synthesis. A number of powerful and unified strategies have been developed by emulating the natural biosynthesis or through innovative transformations. This review focuses on the total synthesis of natural products by applying divergent strategies and the literature covering from 2013 to June 2017. On the basis of where the diversity comes from, the examples are grouped into three parts and discussed in detail. In each group, the examples that synthesize natural products belonging to the same subfamily are put together to contrast with one another.

CONTENTS 1. Introduction 2. Diversity from Different Redox Process of Common Intermediate 2.1. Alkaloids 2.1.1. Indole Alkaloids 2.1.2. Carbazole Alkaloids 2.1.3. Hydrogenated Isoquinoline Alkaloids 2.1.4. Decahydroquinoline (DHQ) Alkaloids 2.1.5. Lycopodium Alkaloids 2.1.6. The Other Alkaloids 2.2. Terpenes 2.2.1. Sesquiterpenes 2.2.2. Diterpenoids 2.2.3. Sesterterpenoids 2.2.4. Meroterpenoids 2.3. Polyketides 2.4. The Other Natural Products 3. Diversity from Framework Reorganization of Common Intermediate 3.1. Alkaloids 3.1.1. Indole Alkaloids 3.1.2. Lycopodium Alkaloids 3.1.3. The Other Alkaloids 3.2. Terpenes 3.2.1. Sesquiterpene Lactone 3.2.2. Diterpenoids 3.3. Polyketides 4. Diversity from Assembling Different Appendages and Common Intermediate 4.1. Alkaloids 4.1.1. Indole Alkaloids 4.1.2. Carbazole Alkaloids 4.1.3. Terpenoid Alkaloids 4.1.4. The Other Alkaloids 4.2. Terpenoids 4.2.1. Sesquiterpenes 4.2.2. Diterpenoid © XXXX American Chemical Society

4.2.3. Tetraterpenoids 4.2.4. Meroterpenoids 4.3. Polyketides 4.4. The Other Natural Products 5. Summary and Outlook Associated Content Special Issue Paper Author Information Corresponding Author ORCID Notes Biographies Acknowledgments References

A D D D L M O P Q T T X AA AB AD AF

BR BR BT BV BX BX BX BX BX BX BX BX BX BX

1. INTRODUCTION Since Wöhler achieved the synthesis of urea in 1828,1 the field of natural product total synthesis, also known as “targetoriented synthesis” (TOS), has made tremendous advances. With the increasing power of organic synthesis, more and more complex natural products, from acetic acid to glucose to vitamin B12 to palytoxin and so on, have been synthesized.2−6 Danishefsky achieved the total synthesis of a homogeneous, wild-type erythropoietin (EPO) with a relative molecular mass of 17868 in 2013, reaching a new milestone of natural product synthesis.7,8 Today, organic chemists have demonstrated they are capable of synthesizing nearly any molecule with enough effort and time. Despite such enormous achievements, organic chemists are still facing great challenges in natural product synthesis. As we know, natural products are an important source of new drugs.9−14 Unfortunately, many natural products are available only in extremely small quantities from natural sources, especially those from higher plants and marine organisms.

AH AH AH AP AV AX AX AX BA BD BD BD BJ BK BL BN BN BN

Received: October 29, 2017

A

DOI: 10.1021/acs.chemrev.7b00653 Chem. Rev. XXXX, XXX, XXX−XXX

Chemical Reviews

Review

The reliable access and supply have always been the “bottleneck” to translate their biological activities to practical applications. The present state-of-the-art processes for the synthesis of most complex natural products are not efficient enough to generate sufficient quantities for biological studies. Thus, the development of efficient synthetic routes for the scalable synthesis of complex natural products is still a challenging task facing synthetic chemists.15−19 A group of natural products are unusually made biosynthetically from a key common intermediate in a divergent manner.20,21 The logic and simplicity of this divergent approach is striking and, if effectively harnessed, could provide a powerful synthetic strategy to improve the efficiency of chemical synthesis. Furthermore, the synthesis of a number of natural product families and their analogues can dramatically improve our ability to develop these molecules as biological probes and new medicines. In this context, the original definition of divergent total synthesis was proposed and demonstrated by Boger in 1984. It is defined as the synthesis of at least two members of the same class of natural products from a common intermediate, preferably an advanced intermediate.22 As shown in Scheme 1, they achieved the divergent total syntheses of

Scheme 2. MacMillan’s Collective Total Syntheses of Three Families of Indole Alkaloids

Scheme 1. Boger’s Divergent Total Syntheses of Rufescine (3) and Imetuteine (5)

strategy. Second, the most important and also difficult step is the design of a suitable common intermediate that could be easily transformed into the target natural products. In most cases, the target natural products belong to one or several biosynthetic families that share the same biosynthetic intermediate. Although the biosynthetic intermediates could be candidates for the common intermediate, it is usually not the case in practice because of a variety of reasons such as high polarity, instability, lack of chemoselectivity, and so on. Thus, an alternative intermediate, bearing the common scaffold and equipped with versatile functionality, is often designed as the common synthetic intermediate. Third, a more advanced common intermediate should be pursued to improve the overall synthetic efficiency. For example, if A were employed as the common intermediate, it would require 2 + 2n overall steps (Figure 1). In contrast, if B were employed as the common intermediate, it would require 3 + n overall steps (Figure 1). Obviously, it is advantageous to use B as the common

rufescine (3) and imeluteine (5) from the common intermediate 1 by using the inverse electron demand Diels− Alder reaction. However, this novel strategy of divergent total synthesis of natural products did not attract wide attention from synthetic chemists initially. MacMillan introduced the term “collective total synthesis” in 2011 and demonstrated this concept in the synthesis of six structurally diverse Strychnos, Aspidosperma, and Kopsia alkaloids from a common tetracyclic intermediate 6 (Scheme 2). His approach extended the scope of divergent total synthesis and could be applied to the synthesis of different classes of molecules.23 In recent years, the divergent syntheses of natural products from a common intermediate have attracted increasing attention and a large number of reports have been published.24−27 In theory, it would be more challenging to design the route for the total synthesis of two or more natural products through a common intermediate than that for one natural product. First, you should be familiar with the structural features of the interested classes of natural products including oxidative states, substitutions, stereocenters, and skeletal structures, their biosynthetic pathways, and retrosynthetic relationship. This information determines the target selection and synthesis

Figure 1. Parallel total synthesis and divergent total synthesis. B


Chemical Reviews

Review

Figure 2. Three general categories of divergent strategy.

examples. Normally, the common carbon skeleton is synthesized followed by further transformation with precisely designed redox process. For example, Baran’s group accomplished the divergent total synthesis of eudesmanes terpenes by employing the “two phase” approach. In this case, direct C−H oxidations at different sites of the common intermediate achieved the diversity (Figure 2A).38 (2) Diversity from framework reorganization of the common intermediate. Some families of natural products contain a variety of subfamilies with different structure frameworks. Biosynthetically, they are derived from a common biosynthetic precursor and diversified into different subfamilies of structures by skeleton reorganization. A synthetic intermediate is often designed and transformed to different structure frameworks. In Figure 2B, a Heathcock tricycle compound was used for the divergent total synthesis of fawcettimine-type lycopodium alkaloids by William’s group. The diversity of this case came from the different kinds of reorganization of the Heathcock tricycle common intermediate 18.39 (3) Diversity from assembling different appendages on the common intermediate. The same family and even different families of natural products often contain the common substructure or are biosynthetically derived from the same fragment. Thus, the common substructure or fragment is employed as the common intermediate. The divergent total synthesis of these natural products could be achieved through assembling different appendages on the common intermediate. In another example, by adding half, one, or two isoprene moieties as appendages to achieve diversity, Kerr’s group finished the divergent total synthesis of eustifolines and glycomaurrol (Figure 2C).40

intermediate. However, the more advanced the intermediates are, the less variability they have. Therefore, there is a need to balance the diversity and the advanced stage of common intermediates. Moreover, just as in the target-oriented synthesis, a short synthetic route (idea synthesis) for the common intermediate is desirable. In this context, the concepts of step economy and redox economy gain additional importance28−30 as well as green chemistry and atom economy.31−33 In the end, however, the practicality of the individual steps will be of utmost importance. This review aims to highlight recent applications of divergent strategy in natural product synthesis and illustrate its tremendous power and versatility. It covers the literature from 2013 to 2017. The examples presented herein have been collected mostly by searching the term “collective total synthesis”, “divergent total synthesis”, and “common intermediate”, although some authors did not use these terms in the cited literature. Only representative examples of divergent total synthesis are discussed. In addition, the literatures of diversityoriented synthesis (DOS) and diverted total synthesis (DTS), which focus on synthesizing natural product-like compounds, are not included.34−37 We have tried our best to make this review as comprehensive and exhaustive as possible, but that is not possible. Therefore, we would like to apologize in advance to those researchers whose work may have been missed in this review. The divergent total syntheses of natural products can be organized into three general categories based on the strategies employed: (1) Diversity from different redox process of the common intermediate. Structurally, some families of natural products are closely related and possess the common core structure but vary only in the oxidation states, relative stereochemistry, and appendages. The divergent total syntheses of these families of natural products provide the earliest C


Chemical Reviews

Review

2. DIVERSITY FROM DIFFERENT REDOX PROCESS OF COMMON INTERMEDIATE

In the same year, Shao and co-workers achieved the total syntheses of (−)-aspidospermidine (9) and (+)-kopsihainanine A (41) from the common tetracyclic intermediate 36 (Scheme 4).42 Before the synthesis, they first developed an enantiose-

2.1. Alkaloids

2.1.1. Indole Alkaloids. 2.1.1.1. Aspidosperma-Type Alkaloids. The Aspidosperma family, a representative class of the monoterpenoid indole alkaloids, possesses a characteristic pentacyclic skeleton. Because of their diverse and complex skeleton structures together with valuable pharmacological activity, they have attracted wide attention from synthetic chemists. Recently, several elegant approaches for the divergent total syntheses of several members of these natural products have been developed. In 2013, Andrade and co-workers reported the syntheses of (−)-aspidospermidine (9), (−)-tabersonine (33), and (−)-vincadifformine (10) via a pentacyclic intermediate 32 by latestage functional group transformations (FGT) (Scheme 3).41

Scheme 4. Shao’s Divergent Total Syntheses of (−)-Aspidospermidine (9) and (+)-Kopsihainanine A (41)

Scheme 3. Andrade’s Divergent Total Syntheses of (−)-Aspidospermidine (9), (−)-Tabersonine (33), and (−)-Vincadifformine (10)

lective Pd-catalyzed decarboxylative allylation of carbazolones for the synthesis of highly functionalized chiral carbazolones that featured an alpha-quaternary carbon center, which is found in numerous natural products and pharmacologically active compounds. With this novel protocol, decarboxylative allylic alkylation of 34 afforded 35 with high enantioselectivity, which could be converted to 36 over two steps. To access (−)-aspidospermidine (9), the vinyl side chain was transformed to ethyl group to give 37 through an oxidation/mercaptalation/ hydrogenation sequence. (−)-Aspidospermidine (9) could be generated from 37 in five steps. Meanwhile, hydroboration/ oxidation of vinyl side chain and protection of the resulted hydroxyl group with MsCl followed by treatment with NaH afforded cyclization product 39, which could be transformed to (+)-kopsihainanine (41) in three steps. This example demonstrates the remarkable outcome of methodological development on indole alkaloid synthesis. In 2014, Shao’s group further described the catalytic enantioselective and divergent total syntheses of (+)-10oxocylindrocarpidine (53), (+)-cylindrocarpidine (50), (−)-N-acetylcylindrocarpinol (52), and (+)-aspidospermine (51) from a common pentacyclic system 48 (Scheme 5).43 Like the above total synthesis, the key quaternary carbon center was constructed on the basis of their Pd-catalyzed decarboxylative asymmetric allylation. Condensation of 2-methoxyaniline (42) and cyclohexane-1,3-dione (43) provided the corresponding enaminone, which underwent Pd-catalyzed C− H bond activation cyclization to afford carbazolone 44.

Condensation of commercially available 26 and (R)-N-tertbutanesulfinamide 27 afforded N-sulfinylimine 28. Deprotonation of 28 with LiHMDS followed by addition of methyl ethacrylate and anion trapping with allyl bromide furnished 29 via a novel domino Michael addition/Mannich/N-alkylation sequence. Compound 29 could be readily converted to pentacyclic indolenine 32 over seven steps including ringclosing metathesis (RCM) to construct the D-ring and Bosch− Rubiralta spirocyclization to form the C-ring. Catalytic hydrogenation of olefin and imine in 32 with PtO2 afforded (−)-aspidospermidine (9). Meanwhile, treatment of 32 with LDA and Mander’s reagent provided (−)-tabersonine (33), which could be transformed to (−)-vincadifformine (10) by catalytic hydrogenation. The 10-step syntheses of 9 (27% overall yield) and 33 (26% overall yield) as well as the 11-step synthesis of 10 (22% overall yield) may provide viable synthesis routes for the process development to address their short supply. D


Chemical Reviews

Review

Scheme 5. Shao’s Divergent Total Syntheses of Four Aspidosperma Alkaloids

Carbazolone 44 was readily converted to the key Pd-catalyzed decarboxylative allylation precursor 45, which gave the enantioenriched carbazolone 46 with 91% ee. Further elaborations gave tetracyclic lactam 47. Reduction of the amide moiety in 47 and subsequent N-debenzylation followed by Heathcock-type annulation afforded the common precursor 48. The sequence of reduction of the imine in 48, acylation of the corresponding aniline, oxidation of the allyl group with osmate−periodate procedure, and final oxidation of the resulting aldehyde furnished (+)-10-oxocylindrocarpidine (53). In another direction, reduction of the imine and amide groups with LiAlH4 followed by acylation and oxidation of the allyl group afforded aldehyde 49. Reduction of 49 with NaBH4 afforded (−)-N-acetylcylindrocarpinol (52), while oxidation of 49 with I2/KOH/MeOH gave (+)-cylindrocarpidine (50). Finally, (+)-aspidospermine (51) was obtained from 49 through a two-step sequence involving mercaptalation and Raney nickel hydrogenation. In 2014, Movassaghi’s group reported the total synthesis of four Aspidosperma alkaloids (−)-aspidospermidine (9), (−)-mehranine (61), (+)-(6S,7S)-dihydroxy-N-methylaspidospermidine (62) and (−)-methylenbismehranine (63) from a common pentacyclic precursor 60, which was efficiently and high stereoselectively constructed based on a transannular cyclization (Scheme 6).44 Alkylation of (−)-54 with iodide 55 afforded tertiary amide 56, which underwent a few steps of conventional transformation to give amino acid 58. Intramolecular amide condensation of 58 followed by ring-closing metathesis provided lactam 59, which was converted to the common synthetic precursor 60 through Tf2O-mediated cyclization and subsequent removal of the PMB group. Hydrogenation of 60 furnished (−)-aspidospermidine (9). While N-formylation of 60, epoxidationm and the following reduction of the formamide yielded (−)-mehranine (61). Stereoselective opening of the epoxide in 61 with TFA in water afforded (+)-(6S,7S)-dihydroxy-N-methylaspidospermidine (62). Finally, dimerization of 61 was conducted with bis(4methylpiperazin-1-yl)methane as the source of the methylene carbon to produce (−)-methylenbismehranine (63). In 2016, Movassaghi’s group further achieved the total syntheses of limaspermidine (69) and four other hexacyclic

Scheme 6. Movassaghi’s Divergent Total Syntheses of Four Aspidosperma Alkaloids

C19-hemiaminal ether Aspidosperma alkaloids (70, 71, 73, and 74) via the final-stage and highly selective C−H hydroxylation (Scheme 7).45 The common pentacyclic iminium ion 68 was constructed based on the same transannular cyclization. The racemic alcohol 65 was obtained from the known compounds 64 and 55 via six steps. The critical alcohol (−)-65 with an excellent level of enantiomeric excess (>98% ee) was prepared by a highly effective enzymatic resolution with Amano PS lipase and vinyl acetate. Hydrogenation of (−)-65 followed by pnitrobenzoylation of the C21-alcohol gave 67. The electrophilic amide activation of lactam (+)-67 with Tf2O resulted in the E


Chemical Reviews

Review

Scheme 7. Movassaghi’s Divergent Total Syntheses of Limaspermidine (69) and Four Other Aspidosperma Alkaloids

Scheme 8. Dixon’s Divergent Total Syntheses of Five Aspidosperma Alkaloids (10, 85−88)

diastereoselective formation of diiminium ion, which was regioselectively reduced at C2 position with Bu3SnH to afford the key C19-iminium ion 68. Reduction of 68 followed by removal of protection groups afforded (+)-limaspermidine (69). On the other hand, methanolysis of iminium ion 68 followed by spontaneous cyclization and removal of PMB group gave (+)-fendleridine (70). N-Protection of 70 with acetic anhydride or propionic anhydride gave (+)-acetylaspidoalbidine (71) or compound 72, respectively. (+)-Acetylaspidoalbidine (71) could be readily converted to (+)-haplocidine (73) by a Pd-catalyzed amide-directed ortho-acetoxylation of indoline amides, which was developed by this group. Following the same sequence, 72 could also be converted to (+)-haplocine (74). This synthesis demonstrates the critical role of method development in natural product synthesis. In 2016, Dixon and co-workers reported the divergent total syntheses of five Aspidosperma alkaloids (10, 85−88) from a secodine intermediate Int A formed in situ from lactam precursors 79, 80 or 81 (Scheme 8).46 The lactams were formed from compound 75 through seven-step conventional transformations. Exposure of 79 or 80 to IrCl(CO)(PPh3)2/ TMDS resulted in the secodine intermediate Int A via the highly chemoselective iridium(I) catalyzed reduction. Subsequent intramolecular enamine Michael addition/reduction afforded vincaminorine (85) or 83, while a formal Diels−

Alder cycloaddition reaction led to minovine (86) or 82. The two pathways are complementary to each other. Vincaminorine (85), 83, and 82 were converted to N-methylquebrachamine (87), quebrachamine (88), and vincadifformine (10), respectively, by treatment with HCl. Additionally, removal of Boc group in lactam 81 followed by the Ir-catalyzed reduction provided exclusively the formal Diels−Alder product vincadifformine (10). Rhazinilam and rhazinicine belong to Aspidosperma-type alkaloids, which share a nine-membered lactam ring and a quaternary carbon center. In 2013, the Tokuyama group reported the total synthesis of (−)-rhazinilam (98) and (−)-rhazinicine (97) from a common precursor 95, which was constructed by a gold-catalyzed cascade cyclization (Scheme 9).47 The synthesis commenced with construction of the quaternary stereocenter by using the diastereoselective Michael reaction. Michael addition of the chiral enamine intermediate, generated from 2-ethylcyclohexanone (89) and (S)-1-phenethylamine with methyl acrylate followed by removal of the amine, afforded ketoester 90. After conversion of 90 into epoxyketone 91 in three steps, Eschenmoser− Tanabe-type fragmentation followed by oxidative fragmentation F


Chemical Reviews

Review

Scheme 9. Tokuyama’s Divergent Total Syntheses of (−)-Rhazinicine (97), and (−)-Rhazinilam (98)

Scheme 10. Tokuyama’s Divergent Total Syntheses of Leuconodine B (105), Melodinine E (107), and Leuconoxine (108)

2.1.1.2. Lundurine-Type Alkaloids. Lundurines A−C (115, 116, 127), isolated from Kopsia tenuis, share a unique hexacyclic skeleton that includes a cyclopropane-fused indoline. They are the only natural products which have an indoline cyclopropane structure and exhibit different oxidation states on the pyrrole ring. In 2014, Nishida’s group reported the total synthesis of lundurines A (115) and B (116) (Scheme 11).49 Starting from compound 109, they first prepared compound 110, which was

gave an aldehyde with terminal acetylene, which was further oxidized to carboxylic acid 92. Amide coupling of 92 with 93 and subsequent Sonogashira coupling with 2-bromoiodobenzene formed the cyclization precursor ynamide 94. After a series of screening, the crucial gold-catalyzed cascade double cyclization of 94 under microwave condition produced 95 in satisfactory yield. Successive reduction of 95 under Luche conditions and NaBH3CN provided 96, which was converted to (−)-rhazinilam (98) through sequential one-pot coppermediated amination, hydrolysis of the ester, and subsequent lactamization. Alternatively, hydrolysis of ester 95, amidation of the resulting carboxylic acid, and copper-mediated intramolecular amidation resulted in (−)-rhazinicine (97). Of note, the use of protecting groups was avoided during this synthesis. In 2014, Tokuyama and co-workers reported the divergent total syntheses of leuconodine B (105), melodinine E (107), and leuconoxine (108) (Scheme 10).48 Structurally, these alkaloids share a [5.5.6.6] diazafenestrane skeleton possessing a quaternary carbon center and an aminal functionality, and melodinine E (107) and leuconoxine (108) could be derived from leuconodine B (105) by dehydration and deoxygenation, respectively. 1,4-Cyclohexanedione (99) was converted to carboxylic acid 100 over five steps. Treatment of 100 with Boc2O followed by addition of 101 in the presence of DMAP/ NEt3 afforded the desired acylindole 102, which was transformed to leuconodine B (105), mainly through intramolecular Heck reaction, DMDO oxidation, and subsequent aminal cyclization as well as ring-closing metathesis. Sequential exposure of 105 to NaH, CS2, and MeI provided methyl xanthate 106, which underwent Barton−McCombie deoxygenation, afforded leuconoxine (108). Meanwhile, elimination reaction of xanthate 106 with DBU gave melodinine E (107).

Scheme 11. Nishida’s Divergent Total Syntheses of Lundurines A (115) and B (116)

G


Chemical Reviews

Review

were unsuccessful, the intramolecular cyclopropanation of indoles was achieved by formation of a pyrazoline via formal [3 + 2] cycloaddition in the presence of BF3·OEt2 as the Lewis acid. Isomerization and reduction of the C−C double bond of 123 gave the common precursor 125. Different reduction or oxidation reactions were conducted with 125, affording three different alkaloids. Direct reduction of lactam 125 with BH3· SMe2 yielded lundurine C (127). Lundurines A (115) and B (116) were both prepared in three additional steps from compound 125, which was first subjected to Lawesson’s reagent followed by p-toluenesulfinyl chloride/DIPEA to generate thiolundurine A (126). Treatment of 126 with MeI followed by NaBH4 gave (−)-lundurine B (116), while oxidation of 126 with m-CPBA produced (−)-lundurine A (115). Worthy of note is the present synthesis, which was carried out without using protecting groups. The short synthesis is truly impressive for such formidable and challenging targets. 2.1.1.3. Epipolythiodiketopiperazine-Type Alkaloids. (+)-Luteoalbusins A (133) and B (134) belong to the epipolythiodiketopiperazine (ETP) alkaloids, which possess an ETP substructure and a C3-(3′-indolyl) substituent. (+)-Luteoalbusin A (133) contains a disulfide bridge, while (+)-luteoalbusin B (134) has a trisulfide bridge. In 2015, Movassaghi and co-workers reported the first total syntheses of (+)-luteoalbusins A and B (133−134) from a common precursor 132 (Scheme 13).51 Diketopiperazine (+)-129 was

then transformed to the key cyclization precursor 111. The key SmI2-mediated intramolecular radical cyclization of 111 was then conducted smoothly to afford the desired cyclopropane 112, in which the two newly generated stereogenic centers were successfully controlled. Cyclopropane 112 was subjected to an eight-step sequence to produce amine 113. Pd-catalyzed intramolecular amination of 113 resulted in the formation of aza-cycloheptane ring to provide the common synthetic precursor 114. N-Acylation of 114 and subsequent RCM using Grubbs second-generation catalyst completed the total synthesis of lundurine A (115). Similarly, N-allylation of 114 and subsequent RCM gave lundurine B (116). In 2016, Echavarren and co-workers accomplished the concise total syntheses of lundurines A-C (115, 116, 127) in both racemic and enantiopure forms in only 11−13 and 12−14 steps, respectively (Scheme 12).50 The lactam 120 was Scheme 12. Echavarren’s Divergent Total Syntheses of Lundurines A−C (115, 116, 127)

Scheme 13. Movassaghi’s Divergent Total Syntheses of (+)-Luteoalbusins A (133) and B (134)

prepared from L-tryptophan derivative (128) by using the published procedures. Silver-mediated Friedel−Crafts arylation of 129 with 130 followed by treatment with Pd/C and H2 provided diketopiperazine 131. Subjecting 131 to the diketopiperazine dihydroxylation developed by the same group yielded the desired dihydroxylated diketopiperazine, which was converted to the common synthetic precursor 132 through acid-induced C11-sulfidation, subsequent acylation of the C11 thiol and C15 hydroxyl group, and removal of the

synthesized from oxoester (118) and 5-methoxytryptamine (117) by a novel tandem double condensation/Claisen rearrangement and a subsequent Seyferth−Gilbert homologation with the Ohira−Bestmann reagent. The key 8-endo-dig gold(I)-catalyzed hydroarylation of 120 to form the 8membered ring was achieved with AuCl3, affording compound 121, which was routinely converted into tosyl hydrazone 122 in four steps. After various transition-metal catalyzed procedures H


Chemical Reviews

Review

rapid addition of AlH3·NEtMe2 led to selective reduction of the oxindole carbonyl moiety and cyclization. Removal of the Nallyl group of the cyclization product provided 141. Cleavage of the exocyclic methylene group in 141 furnished gliocladin C (144). In addition, 141 was converted into 142 and 143 through N-protection and regioselective hydration followed by subsequent protection, respectively. T988C (145) and gliocladine C (146) could be synthesized from 142 and 143 respectively by using the published procedures. 2.1.1.4. The Other Indole Alkaloids. Iboga-type alkaloids, one type of monoterpene indole alkaloids, feature a characteristic indole and isoquinuclidine unit fused with a sevenmembered azepane ring. Although a number of total synthesis schemes have been reported, they lack the synthetic flexibility to prepare other members of this family. In 2016, She and coworkers described the bioinspired divergent syntheses of seven iboga-type and related alkaloids with skeletal variations, including (±)-tabertinggine (151), (±)-ibogamine (153), (±)-ibogaine (154), (±)-ibogaine hydroxyindolenine (157), (±)-3-oxoibogaine hydroxyindolenine (155), (±)-iboluteine (158), and (±)-ervaoffine D (156) (Scheme 15).53 Biosynthetically, these iboga-type alkaloids can be obtained from ibogamine (153) via related facile skeletal rearrangements and modifications. However, considering that it is difficult to oxidize the benzene ring selectively, ibogaine (154) was selected as the common precursor for these alkaloids. Compounds 151 and 152 were prepared from tryptamine 148 and its methoxysubstituted derivative 117 via a sequence of 10-step reactions. Accordingly, reduction of α, β-unsaturated ketone 151 and 152 with Zn/AcOH followed by structure rearrangement and subsequent Wolff−Kishner reduction provided (±)-ibogamine (153) and (±)-ibogaine (154), respectively. Stereoselective oxidation of 154 with DMDO gave ibogaine hydroxyindolenine (157), which could be further converted into iboluteine (158) by treatment with NaOH/MeOH. Meanwhile, compound 154 could also be oxidized to oxoibogaine hydroxyindolenine (155) by I2/NaHCO3. Additionally, oxidation of 155 by H2O2 afforded ervaoffine D (156). Gelsemium alkaloids belong to a subfamily of the famous monoterpene indole alkaloids, which feature the common spiro-N-methoxyindolinone moiety and the oxabicyclo[3.2.2]nonane core skeleton. These alkaloids pose a formidable challenge due to their highly complex, compact, and strained structures. Although a variety of total syntheses of the gelsemium alkaloids has been achieved, the development of a flexible and unified route to this family of alkaloids has not been reported. In 2016, the Fukuyama group achieved the total syntheses of six gelsedine-type alkaloids (165−170) from a common non-natural intermediate (Scheme 16).54 Biosynthetically, natural product gelsenicine (168) is the biosynthetic precursor of gelsedine (169), gelsedilam (166), 4-hydroxygelsenicine (170), and 14,15-dihydroxygelsenicine (167). Considering that it is difficult to oxidize C14 and C15 of gelsenicine (168) selectively by using the current methods of organic synthesis, they abandoned the biomimetic strategy. Instead, tetracyclic compound 160, equipped with versatile enal functionality, was employed as the common precursor to 166− 170. Compound 160 was already synthesized in 21 steps from furfuryl alcohol (159) and has been used for the total synthesis of gelsemoxonine (165) by the same group.55 The conversion of 160 to gelsedilam (166) was necessary to introduce two hydrogen atoms on the C14−C15 double bond as well as to oxidize the aldehyde moiety. Redox-neutral isomerization

benzenesulfonyl group. Selective hydrazinolysis of the thioisobutyryl group in 132 followed by treatment with triphenylmethanesulfenyl chloride (TrSCl) and Et3N yielded the mixed disulfide, which was transformed to (+)-luteoalbusin A (133) by the sequential BF3·Et2O-induced cyclization of the disulfide and cleavage of the acetate. Alternatively, sequential treatment of 132 with hydrazine and chloro(triphenylmethyl)disulfane (TrSSCl) gave the mixed trisulfide, which underwent in situ acylation followed by the addition of hafnium trifluoromethanesulfonate Hf(OTf)4 and subsequent deacylation delivered (+)-luteoalbusin B (134). In 2017, the Martin group reported a unique approach to formal synthesis of the other two members of ETP alkaloids, T988C (145) and gliocladine C (146), and total synthesis of a related hexahydropyrrolo[2,3-b]indole diketopiperazine (DKP) alkaloid gliocladin C (144) from the common intermediate 141 (Scheme 14).52 The synthesis of 141 features an unpreceScheme 14. Martin’s Divergent Total Syntheses of Gliocladin C (144), T988C (145), and Gliocladine C (146)

dented nucleophilic addition of a diketopiperazine to N-allyl isatin and a Friedel−Crafts alkylation of the resulting tertiary alcohol with indole to install the key quaternary center. Diketopiperazine 137 was prepared from oxazolidine 135 over four steps. Mesylation of 137 and in situ double elimination of the corresponding mesylate followed by addition of N-allyl isatin 138 yielded alcohol 139, which was converted to indole 140 in three steps. Exposure of 140 to BF3·OEt2 followed by I


Chemical Reviews

Review

Scheme 15. She’s Divergent Total Syntheses of Seven Iboga-Type and Related Alkaloids

Scheme 16. Fukuyama’s Divergent Total Syntheses of Six Gelsedine-Type Alkaloids

Scheme 17. Scheidt’s Divergent Total Syntheses of Four Pentacyclic Alkaloids

J


Chemical Reviews

Review

Scheme 18. Jia’s Divergent Total Syntheses of Eight Ergot Alkaloids

trans-bicycliclactone 177 was prepared from 174 by treatment with TsOH. Ajmalicine (178) was obtained from transbicycliclactones (177) through similar transformations. Finally, 178 was converted to β-carbolinium salt serpentine methoxide (179) by treatment with Pd black and maleic acid, followed by treatment with NaOH and MeOH/H2O. The ergot alkaloids are a diverse class of indole natural products. They are among the most important groups of natural products because some of them are important pharmaceuticals and are also recognized as important natural toxins in the human history. Structurally, the ergot alkaloids feature a unique tetracyclic ergoline skeleton containing several chiral centers of various configurations. In 2017, Jia and coworkers reported an efficient and divergent total synthesis tactic to eight ergot alkaloids, which are festuclavine (192), pyroclavine (193), costaclavine (197), epi-costaclavine (198), pibocin A (195), 9-deacetoxyfumigaclavine C (194), fumigaclavine G (196), and dihydrosetoclavine (190) (Scheme 18).57 The key step of this synthesis is the use of a palladium-catalyzed intramolecular Larock annulation to assemble 3,4-fused indoles that was developed by them in 2013. The bromide 182 was converted to chiral N-tert-butylsulfinylimine 183 over five steps. Propargylation of imine 183 with 1-(trimethylsilyl)allenylzinc bromide proceeded smoothly to give the cyclization precursors 184a,b and its C5 diastereoisomer (dr = 1:3.4) in excellent overall yield. Surprisingly, when the intramolecular Pdcatalyzed Larock indole annulation of 184a was performed on gram scales under the optimized catalyst system, an unprecedented Pd-catalyzed intramolecular Larock indole annulation/Tsuji−Trost allylation cascade occurred to form 185. Interestingly, under the same condition, another isomer 184b cannot be transformed to similar tetracyclic product but just underwent Larock annulation affording tricyclic product 188. Removal of the tert-butanesulfinyl group of compound 185 and subsequent protection of the resulting amine with ClCO2Me gave carbamate 187. Sequential reduction of

reaction of 160 using TMSCN−DBU followed by protonation and acylation with methanol gave the desired ester 164. Removal of the Cbz group of 164 followed by cyclization under basic conditions furnished (−)-gelsedilam (166). Other target alkaloids possess two additional carbon atoms on the side chain with different oxidation degrees. Thus, treatment of enal 160 with an ethyl Grignard reagent followed by IBX oxidation provided ethyl ketone intermediate 161, which serves as the common intermediate for 167−170. Ketone 161 was selectively oxidized and cyclized to afford 14-hydroxygelsenicine (170) and 14,15-dihydroxygelsenicine (167). Hydrosilylation and hydrogenolysis of ketone 161 with Pd(OAc)2 and Et3SiH followed by treatment with TBAF afforded (−)-gelsenicine (168) smoothly. Finally, catalytic hydrogenation of 168 furnished (−)-gelsedine (169). Serpentine (179) and alstonine (181) are pentacyclic alkaloids containing a zwitterionic indolo[2,3-a]quinolizidine. Tetrahydroalstonine (180) and ajmalicine (178), the representative natural products of the closely related heteroyohimbine family of alkaloids, are structurally similar to serpentine (179) and alstonine (181), only differing in ring saturation and relative stereochemistry at C3 and C20. In 2015, Scheidt and co-workers reported the divergent total syntheses of 178−181 from the common precursor 174 (Scheme 17).56 The enantioenriched 174 was prepared by a cooperative hydrogen bonding/enamine-catalyzed intramolecular Michael addition of 171 followed by reduction with NaBH4. To obtain the cislactone necessary for the synthesis of alstonine, alcohol 174 underwent a six-step transformation. The sequence of αformylation of 175, subsequent Korte rearrangement, removal of Cbz group, and reductive amination with indole-3acetaldehyde provided 2,3-secoakuammigine (176). Exposure of 176 to mercuric acetate/EDTA furnished tetrahydroalstonine (180) via oxidative iminium ion cyclization. Palladium black mediated dehydrogenation of 180 gave the β-carbolinium salt alstonine hydrogen maleate (181). On the other hand, K


Chemical Reviews

Review

carbamate 187 with LiAlH4 and Raney Ni gave festuclavine (192) and pyroclavine (193) with a ratio of 5:3. Chlorination of 192 and 193 with tBuOCl followed by treatment with prenyl-9-BBN in the presence of Et3N provided 9-deacetoxyfumigaclavine (194) and fumigaclavine G (196), respectively. In the meantime, chemoselective bromination of 192 with NBS provided pibocin A (195). Hydrofunctionalization of 185 with Mn(dpm)3 gave alcohol 186a and its diastereoisomer 186b. A sequence of removal of the tert-butanesulfinyl group, protection with ClCO2Me, and reduction with LiAlH4 yielded dihydrosetoclavine (190) and its diastereoisomer iso-dihydrosetoclavine (191). In addition, intermediate 188 could be transformed to compound 189 over four steps. Hydrogenation of 189 with Crabtree’s catalyst provided costaclavine (197) and epicostaclavin (198). 2.1.2. Carbazole Alkaloids. In 2013, Jia’s group reported the divergent synthesis of dictyodendrins B (208) and E (209) (Scheme 19), and in 2015, Itami, Davies, and co-workers communicated the unified synthesis of dictyodendrins A (219) and F (220) (Scheme 20).58,59 It is worthy of mentioning that the cutting-edge C−H functionalization strategy was employed in both synthesis. Jia’s synthesis commenced with the known compound 199, which was converted to o-iodoaniline 200

Scheme 20. Itami and Davies’ Divergent Total Syntheses of Dictyodendrins A (219) and F (220)

Scheme 19. Jia’s Divergent Total Syntheses of Dictyodendrins B (208) and E (209)

through iodination reaction (Scheme 19).58 Larock indole annulation of 200 with alkyne ketone 201, N-alkylation of the resulting indole, and subsequent chemoselective bromination provided 204. The palladium-catalyzed one-pot consecutive Buchwald−Hartwig amination/C−H activation reaction was subsequently conducted to produce the key carbazole 206. Removal of the benzyl group in 206 by hydrogenolysis followed by a three-step sequence, reported by Fürstner and Tokuyama, furnished dictyodendrin B (208). In addition, reduction of the carbonyl group in 206 and removal of the benzyl group gave compound 207, which was then transformed to dictyodendrin E (209) in four similar steps. Itami, Davies, and co-workers prepared 212 from 210 and 211 through the regioselective β-arylation of pyrroles, which was developed by Itami (Scheme 20).59 The rhodium-catalyzed alkylation of pyrrole 212 with diazoacetate derivative 213 L


Chemical Reviews

Review

converted to (+)-lycorine (230) by using the published procedures. In 2017, Sun and co-workers reported another two structurally related amaryllidaceae isocarbostyril alkaloids (+)-lycoricidine (239) and (+)-7-deoxypancratistatin (240) by using the diastereoselective palladium catalyzed cinnamylation of cinnamyl acetates with N-tert-butanesulfinyl imines, developed by the same group (Scheme 22).61 Heck reaction of

followed by bromination of the remaining C−H bond of the pyrrole in one-pot delivered 214, which was converted to 216 through Suzuki−Miyaura cross-coupling with 215. Exposure of 216 to LDA generated the pyrrolo[2,3-c]carbazole structure 217, likely through a formal 6π-electrocyclization of the dianion intermediate. Methylation of the resulting phenol followed by removal of the Boc group and benzyl group in one pot afforded the known 218, which could be converted to dictyodendrin A (219) over three steps. On the other hand, removal of Boc group in 217, oxidation with PhI(OAc)2, hydrolysis, and deprotection of MeO group led to dictyodendrin F (220). These two examples demonstrate the possibility of developing novel strategies and streamlining total synthesis by using C−H functionalization. 2.1.3. Hydrogenated Isoquinoline Alkaloids. In 2014, the Shao group reported the first catalytic asymmetric approach to octahydroindolones and applied this method for a divergent enantioselective synthesis of (+)-α-lycorane (229) and (+)-lycorine (230) from a common intermediate 227 (Scheme 21).60 Structurally, the lycorine-type Amaryllidaceae alkaloids

Scheme 22. Sun’s Divergent Total Syntheses of (+)-Lycoricidine (239) and (+)-7-Deoxypancratistatin (240)

Scheme 21. Shao’s Divergent Total Syntheses of (+)-αLycorane (229) and (+)-Lycorine (230)

bromide 231 and allyl acetate gave the cinnamyl acetate 232. The (S)-N-tert-butanesulfinyl imine 234 was synthesized from iodoribose derivative 233 through elimination with nBuLi and subsequent condensation with (S)-tert-butanesulfinamide. Compounds 232 and 234 were next subjected to the Pdcatalyzed tandem sequence of cinnamylation and cyclization to afford trans-fused lactam 235 as a single diastereoisomer. After constructing the last ring by ring-closing metathesis of diene 235, removal of the tert-butanesulfinyl group and subsequent stereoselective dihydroxylation yielded diol 236. Exposure of diol 236 to SOCl2 and NEt3 followed by oxidation of the resulting sulfoxide with RuCl3/NaIO4 resulted in the cyclic sulfate 237, which served as the common synthetic precursor. Regioselective opening of the sulfate ring with nBu4NI and subsequent anti-elimination of the resultant iodide and acid hydrolysis furnished (+)-lycoricidine (239). trans-Diaxial attack of the cyclic sulfate 237 with PhCO2Na followed by hydrolysis led to the benzoate 238, which was converted to (+)-7deoxypancratistatin (240) by treatment with MeONa. The erythrina alkaloids share a common tetracyclic core structure featuring diverse peripheral oxidation states. In 2015, Ciufolini and co-workers accomplished the total synthesis of two members of erythrinan alkaloids, (+)-3-demethoxyerythridatinonem (254) and (+)-erysotramidine (255), from a

share a tetracyclic pyrrolo[d,e]phenanthridine framework, possessing a trans B/C-ring junction, mostly. The nitro dienyne 222 was prepared from vinyl bromide 221 over three steps. 1,4Conjugate addition of nitro dienyne 222 with 223 in the presence of the chiral diamine−NiBr2 complex gave enantioenriched 224. Decarboxylation with TsOH and subsequent esterification followed by stereoselective intramolecular Michael addition afforded cyclohexanone 225, which could be converted to 227 through a few conventional transformations. Successive reduction of 227 with Raney Ni/H2 and LiAlH4 delivered (+)-α-lycorane (229). Alternatively, deprotection of 227, selective reduction, mesylation, and elimination of the resultant mesylate delivered compound 228, which could be M


Chemical Reviews

Review

Scheme 23. Ciufolini’s Divergent Total Syntheses of (+)-3-Demethoxyerythridatinone (254) and (+)-Erysotramidine (255)

Scheme 24. Fukuyama’s Divergent Total Syntheses of Four Erythrina Alkaloids

common tetracyclic intermediate 247 (Scheme 23).62 Suzuki coupling of 241 and 242 followed by hydrolysis of the methyl ester afforded carboxylic acid 243, which was converted to oxazoline 244 over three steps. The oxazoline 244 was subjected to oxidative amidation cyclization and subsequent intramolecular O-Michael cyclization, yielding enone 245 as a single diastereomer. Enone 245 was then converted into 247 through six conventional transformations. Swern oxidation of 247 gave ketone 248, which was converted to 251 by silica gel chromatography and the following protection of the corresponding alcohol. Starting from crude 248, (+)-3-demethoxyerythridatinonem (254) was synthesized via the sequence of coupling with (EtO)2P(O)CH2COCl and in situ treatment with aq KOH, reduction of the amide group, and acidic

hydrolysis. Additionally, conjugate reduction of 251 with Li/ NH3 led to a mixture of 252 and 253. Compound 252 could be converted to 253 by treatment with t-BuOK. Finally, coupling of 253 with diethyl phosphonoacetic acid followed by allylic oxidation and subsequent methylation of the ally alcohol furnished (+)-erysotramidine (255). In 2016, Kitamura, Fukuyama, and co-workers developed a divergent synthetic strategy for the erythrina alkaloids by using a two-phase synthetic strategy involving the initial construction of a common core structure and further functionalization of the late-stage pluripotent intermediate, which enabled the total syntheses of 8-oxo-erythrinine (264), crystamidine (265), 8oxo-erythraline (266), and erythraline (267) (Scheme 24).63 The chiral nitro alcohol 256 was readily transformed to the N


Chemical Reviews

Review

Scheme 25. Kim’s Divergent Total Syntheses of (−)-Lepadiformine A (277) and (−)-Fasicularin (278)

Scheme 26. Amat and Bosch’s Divergent Total Syntheses of (−)-Lepadins A−C (291−293) and (+)-Lepadin D (294)

and methylation. Finally, exposure of 266 to LiAlH4 and AlCl3 provided erythraline (267). 2.1.4. Decahydroquinoline (DHQ) Alkaloids. (−)-Lepadiformine A (277) and (−)-fasicularin (278) are two tricyclic marine alkaloids possessing pyrrolo-/pyrido[1,2-j]quinolline framework. In 2014, Kim and co-workers reported a divergent synthesis of these two natural products via a quinoline iminium salt 273 as the common intermediate (Scheme 25).64 The key step of transforming starting material 268 into iminium salt 273 was the ester enolate Claisen rearrangement. Reagent-dependent stereoselective reduction of iminium salt 273 with NaCNBH3 and L-selectride afforded 276 and 274, respectively. Smoothly, (−)-lepadiformine A (277) was generated from 276 in five steps. Similarly, 274 was transformed into 275 in five

nine-membered lactam intermediate 258 over 10 steps. Inspired by their biosynthetic sequence, a bioinspired stereospecific singlet oxygen oxidation of 258 and subsequent transannular aza-Michael reaction yielded tetracyclic compound 260. Elimination of the tertiary hydroxyl group in 260 gave the common intermediate 261, equipped with the common core helical architecture and the necessary functional groups. Diastereoselective Luche reduction of the enone 261 followed by methylation and removal of the TBS-ether furnished 8-oxoerythrinine (264). Subsequent elimination of the hydroxyl group by treatment with TsOH·H2O gave crystamidine (265). Removal of the hydroxyl group in 261 afforded compound 263, which was converted to 8-oxo-erythraline (266) by reduction O


Chemical Reviews

Review

steps. Exposure of 275 to Mitsunobu reaction condition in the presence of NH4SCN yielded (−)-fasicularin (278) through an aziridinium intermediate. In 2015, Amat, Bosch, and co-workers reported the enantioselective total synthesis of decahydroquinoline (DHQ) alkaloids (−)-lepadins A−C (291−293) and (+)-lepadin D (294) from a common cis-decahydroquinoline intermediate (282), containing the trans 2-Me/3-OH structure and a C5 modifiable substituent (Scheme 26).65 Bromination of enone 279 followed by Pd-catalyzed cross-coupling afforded the δketo ester 280, which was converted to tricyclic lactam 281 through cyclocondensation reaction of 280 with (R)-phenylglycinol and subsequent catalytic hydrogenation of the resultant unsaturated lactams. The common synthetic precursor 282 was then obtained from 281 through a nine-step sequence. Inversion of the C3 configuration in 283 by oxidation/ reduction strategy followed by protection of the corresponding hydroxyl group, removal of the TIPS group, and oxidation of the C5 chain provide aldehyde 283, the precursor toward lepadins A−C. Horner−Wadsworth−Emmons (HWE) reaction of 283 with 284 gave compound 285. Removal of the Boc group in 285 produced (−)-lepadin B (292), while esterification of 285 with TBSOCH2CO2H followed by deprotection furnished (−)-lepadin A (291). HWE reaction of 283 with 286, esterification, and subsequent deprotection delivered (−)-lepadin C (293). On the other hand, inversion of the C5 configuration in 282 was accomplished through conventional transformations to provide compound 288. Finally, (+)-lepadin D (294) was obtained through elongation of the C5 chain and deprotection. In 2015, Pandey’s group reported the total synthesis of (+)-cylindricines C−E (305−307) and (−)-lepadiformine A (308) from a common aza-quaternary scaffold generated by selective bond cleavage of bridgehead-substituted 7azabicyclo[2.2.1]heptane (Scheme 27).66 Structurally, these natural products, which belong to the marine ascidian alkaloids, contain a perhydropyrrolo[2,1-j]quinolone framework. Cycloaddition of 295 with 296 and the following four-step sequence gave the azabicyclo[2.2.1]heptane 297. Asymmetric desymmetrization of meso-297 by using the sodium salt of (R,R)hydroanisoin produced compound 298 as a single diastereomer with a dr of 9:1 (endo/exo). Compound 298 was subsequently converted to carbamate 299 through nine steps of conventional transformations. The sequence of 6-endo-trig Tsuji−Trost cyclization of 299, hydrogenation, and desulfonylation followed by treatment with TMSOTf and DIPEA gave compound 300, which could be transformed to the common synthetic precursor 301 over three steps. When exposed to Dess−Martin reagent and TFA, 301 was converted to 302 through an oxidation/ retro-aldol/aza-Michael cascade sequence. Reduction of 302 with NaBH(OAc)3 furnished (+)-cylindricine C (305). Methylation of hydroxyl group in 305 led to (+)-cylindricine D (306), while acylation resulted in (+)-cylindricine E (307). Oxidation of 301 followed by retro-aldol reaction provided 304, which was converted to (−)-lepadiformine A (308) through a six-step sequence. 2.1.5. Lycopodium Alkaloids. In 2014, the Yang group described the collective total synthesis of three tetracyclic diquinane Lycopodium alkaloids, (−)-magellanine (314), (+)-paniculatine (315), and (+)-magellaninone (316) from the common intermediate 312 bearing the basic tetracyclic diquinane skeleton (Scheme 28).67 In fact, compound 312 is a known compound that has been employed by Mukai.68 The

Scheme 27. Pandey’s Divergent Total Syntheses of (+)-Cylindricines C−E (305−307) and (−)-Lepadiformine A (308)

Scheme 28. Yang’s Divergent Total Syntheses of (−)-Magellanine (314), (+)-Paniculatine (315), and (+)-Magellaninone (316)

conversion of the known thioether 309 to the tricyclic alcohol 310 was achieved in 11 steps. Hydroboration−oxidation of P


Chemical Reviews

Review

of a double bond. Oxidation of (−)-magellanine (314) with DMP delivered (+)-magellaninone (316). In 2013, Tsukano and co-workers reported the total syntheses of dimeric alkaloid complanadines A (328) and B (329) by straightforward coupling of two monomeric units (325 and 326) prepared from the same N-protected lycodine (324) (Scheme 30).70 Structurally, the natural products are

alkene 310, further oxidation of the two hydroxyl groups into diketone and aldol cyclization, yielded the tetracycle 311 with the anticipated site- and stereoselectivities. Tetracycle 311 was subsequently converted to 312 in a seven-step sequence. According to Mukai’s protocol, 312 was readily converted to the target natural products. (+)-Paniculatine (315) was obtained via a series of conventional transformations. In addition, oxidation of 312 with N-tert-butylbenzenesulfinimidoyl chloride followed by removal of the MOM group produced 5-epimagellanine (313). Mitsunobu reaction of 313 followed by basic hydrolysis gave (−)-magellanine (314), whereas the oxidation of 313 with DMP produced (+)-magellaninone (316). In 2015, the Yan group also reported the total synthesis of these three tetracyclic diquinane Lycopodium alkaloids (314− 316) from the common intermediate 321 that is structurally similar to compound 312 (Scheme 29).69 Comparing with

Scheme 30. Tsukano’s Divergent Total Syntheses of Complanadines A (328) and B (329)

Scheme 29. Yan’s Divergent Total Syntheses of (−)-Magellanine (314), (+)-Paniculatine (315), and (+)-Magellaninone (316)

dimeric Lycopodium alkaloids with different oxidation levels of the lycodine units. The initial effort was to obtain (+)-323 through resolution of (±)-323, prepared by using the published procedures, with an amylose chiral column. Thioketalization of (+)-323 followed by treatment with Ph3SnH and AIBN afforded N-Cbz lycodine (324), which was converted to NCbz-lycodine N′-oxide (325) and N-Cbz-bromolycodine (326) through oxidation with mCPBA or regioselective Miyaura− Hartwig borylation and subsequent bromination, respectively. Coupling of 325 and 326 provided the common intermediate 327. Reduction of the N-oxide and removal of the Cbz groups with Pd(OH)2 and ammonium formate furnished complanadine A (328). Regioselective benzylic oxidation of (+)-327 by prototropy followed by Claisen-type rearrangement of Oacetylated pyridine N-oxide resulted in an acetate, which was converted to complanadine B (329) through the sequence of methanolysis, subsequent oxidation, and removal of the N-Cbz groups. 2.1.6. The Other Alkaloids. In 2015, Jia and co-workers developed a new strategy for the construction of 3,4-fused benzofurans through a Pd-catalyzed Larock-type cyclization on the basis of their previous studies on the Larock annulation for the synthesis of 3,4-fused indoles. They achieved the concise asymmetric total synthesis of (−)-lycoramine (338) and (−)-galanthamine (339) by employing this new benzofuran synthesis and Sc-catalyzed asymmetric conjugate addition as key reactions (Scheme 31).71 Thus, reductive coupling of aldehyde (330) and amine (331) followed by protection with Boc 2O afforded 332, which underwent a Pd-catalyzed

Yang’s work, the synthesis of 321 is more concise, which required only 10 steps from the inexpensive chiral starting material pulegone. The known chiral enone 317 was readily available from pulegone in four steps. 1,4-Addition of homoenolate to enone 317 provided the ketoester 318, which underwent intramolecular cyclization and an intermolecular alkylation with 319 afforded the bicyclic diketone 320. Diketone 320 was converted to 321 through sequential Pdcatalyzed intramolecular Heck reaction, Wacker oxidation, and hydrogenation. With the common intermediate 321 in hand, chemselective silylation, subsequent reduction, and desilylation afforded (+)-paniculatine (315). In addition, chemselective reduction of the less hindered ketone in 321 followed by reduction of carbamate gave hydroxyketone 322, which was further advanced to (−)-magellanine (314) via the introduction Q


Chemical Reviews

Review

Scheme 31. Jia’s Divergent Total Syntheses of (−)-Lycoramine (338) and (−)-Galanthamine (339)

Scheme 32. Fan’s Divergent Total Syntheses of (±)-Cephalezomine H (347) and (±)-Cephalotaxine (348)

annulation to deliver benzofuran 333 with excellent efficiency. Removal of the TES group and subsequent oxidation with mCPBA yielded the benzofuranone intermediate, which was converted to the common synthetic precursor 334 through the asymmetric Michael addition to MVK by using the chiral metal/N,N′-dioxide complexes and subsequent aldol cyclization. Stereoselective reduction of ketone 334 with L-selectride and BF3·Et2O-promoted cationic reduction of the hemiketal accompanied by deprotection of the Boc group provided amine 335, which was converted to (−)-lycoramine (338) by Eschweiler−Clarke methylation. Additionally, ketone 334 was subjected to a five-step sequence to give enone 337, which was successively reduced with L-selectride and LiAlH4 to provide (−)-galanthamine (339). In 2017, Fan and co-workers developed a novel Au-catalyzed [2 + 3] annulation of enamides with propargyl esters for constructing a highly functionalized 1-azaspiro[4.4]-nonane system, which enabled the divergent total synthesis of (±)-cephalezomine H (347) and (±)-cephalotaxine (348) (Scheme 32).72 Structurally, cephalezomine H (347) and cephalotaxine (348), belonging to cephalotaxus alkaloids, share a 1-azaspiro[4.4]nonane ring system with a crucial azaquaternary carbon center. Annulation of enamide 340 and propargyl ester 341 provided azaspirocycle 342 (dr = 5:1). Reduction of the amide and subsequent one-pot Ndebenzylation/enol-acetate hydrogenation, followed by acetylation of the secondary amine, afforded chloroacetamide 343. Witkop photocyclization of 343 with a high-pressure mercury vapor lamp delivered the pentacyclic product 344, which was converted to olefin 345 in three steps. Dihydroxylation of 345 followed by Swern oxidation of the resulting diol delivered the common synthetic intermediate 346. Diastereoselective reduction of the enolone moiety in 346 with KBH4 and further

reduction of the amide motif with alane furnished cephalezomine H (347). Divergently, regioselective etherification of α-enolone 346 and subsequent reduction with alane yielded cephalotaxine (348). In 2013, Herzon and co-workers disclosed a unified pathway to (−)-acutumine (360) and (−)-dechloroacutumine (361) (Scheme 33).73 Structurally, these alkaloids share a tetracyclic ring system, containing a heavily oxidized spirocyclopentenone ring and a dense array of heteroatom-containing functional groups. The synthesis commenced with preparation of the two synthetic units 351 and 355. The tetracyclic imine 351 was prepared from aryl azide 349 in three steps following the literature procedures. Additionally, Pd-catalyzed 1,4-disilylation of acetonide 353, and subsequent in situ cleavage of the resultant enoxysilane followed by treatment with LiHMDS and Comin’s reagent formed vinyl triflate 354, which was converted to enyne 355 through Stille coupling. Exposure of 351 to methyl triflate to provide N-methyliminium ion 352 followed by addition of lithium acetylide 355-Li, generated by treatment of 355 with nBuLi, delivered amine 356 as a single diastereomer. Thermal extrusion of the silylcyclopentene fragment in 356 and subsequent Pd-catalyzed regio- and stereoselective hydrostannylation afforded vinyl stannane 357. The sequence of Hosomi−Sakurai allylation, Cu-mediated chlorodestannylation, and removal of the acetonide provided diol 358, which was converted to the common precursor 359 through a seven-step sequence. Homogeneous hydrogenation of 359 with [Rh(nbd)(dppb)]BF4 furnished (−)-acutumine (360), while hydrogenation of 359 with Pd/C yielded (−)-dechloroacutumine (361). In 2014, Snyder and co-workers achieved the asymmetric total synthesis of 10 coccinellid alkaloids, including eight monomers (367−374) and two dimers (Scheme 34).74 Structurally, the monomers share a tricyclic architecture differing in ring junction stereochemistry, olefin placement, and oxidation state. The divergent total syntheses of 367−374 R


Chemical Reviews

Review

were achieved through a bioinspired strategy from a common precursor 365. The commercially available N-Boc-(S)-(−)-piperidine-2-ethanol 362 was converted to the trans-disposed intermediate 364 through four steps of conventional transformations. Diastereoselective reduction of the enone to generate the methyl stereocenter followed by removal of the TBDPS group afforded the common synthetic precursor 365. Removal of the Boc group and bromination of the hydroxyl group followed by base-induced isomerization of the enamine and subsequent terminating cyclization gave (−)-propyleine (370) and (−)-isopropyleine (369) as an equilibrating 1:3 mixture. Reduction of the enamine with NaBH(OAc)3 led to a 3.7:1 mixture of precoccinelline (372) and hippodamine (371). Alternatively, α-oxidation of 365 followed by the same general procedures already described provided compound 366. Reduction of the ketone in 366 to methylene delivered hippodamine (371) too, while sequential treatment of 366 with N2H4, TsCl, and t-BuLi delivered hippocasine (367). Finally, hippocasine (367), hippodamine (371), and precoccinelline (372) could be oxidized to the corresponding N-oxide congener hippocasine oxide (368), convergine (373), and coccinelline (374). In 2017, Fukuyama’s group reported the enantiostereoselective total synthesis of (−)-tetrodotoxin [(−)-TTX] (389) and 11-norTTX-6(R)-ol (388), two potent inhibitors of voltage-gated sodium channels, by late-stage modification of the common precursor 387 (Scheme 35).75 These natural products share a polyfunctionalized dioxaadamantane skeleton, possessing a cyclic guanidine with a hemiaminal moiety and nine contiguous stereogenic centers. Diels−Alder reaction of pbenzoquinone (375) and 5-TMS-cyclopentadiene (350) followed by Luche reduction afforded meso diol 376 with an endo-tricyclo[6.2.1.0]undecene system, which enabled stereoand enantioselective functionalization of the cyclohexene. Lipase-mediated desymmetrization of 376 delivered monoacetate 377, which was converted to triol 378 through a fivestep sequence. Triol 378 was then transformed to oxime 382 through a series of conventional transformations. Treatment of 382 with chloramine 383 resulted in intramolecular 1,3-dipolar cycloaddition to yield compound 384, which could be converted to the common synthetic precursor 387. Deprotection of the acetonides in 387 under acidic conditions and the following removal of the Cbz group furnished (−)-tetrodotoxin (389). Additionally, selective removal of the terminal acetonide of 387, oxidative cleavage of the resulting 1,2-diol, followed by reduction of the resulting ketone provided the alcohol, which was converted to 11-norTTX-6(R)-ol (388) in the same manner. Amathaspiramides A−F (395−400) share a densely functionalized aza-spirobicyclic core containing three contiguous stereocenters, including a hemiaminal center and a tertalkylamino carbon center. In 2016, Sun and his group reported the asymmetric total synthesis of amathaspiramides A−F (399, 396, 397, 395, 398, 400) from the common synthetic scaffold 393, possessing the desired two contiguous stereocenters and the basic structural unit of the alkaloids (Scheme 36).76 It is worthy of mentioning that Fukuyama and co-workers achieved the conversion of amathaspiramide D (395) into amathaspiramides A (399), C (397), and E (398) in 2012.77 The key azaBarbier reaction of ketimine 390 and allyl bromide 391 was conducted with Zn powder in N,N-diethylformamide (DEF), resulting in the highly functionalized sulfinamide 392 with high dr (10:1). Removal of the N-tert-butanesulfinyl group in 392

Scheme 33. Herzon’s Divergent Total Syntheses of (−)-Acutumine (360) and (−)-Dechloroacutumine (361)

Scheme 34. Snyder’s Divergent Total Syntheses of Eight Coccinellid Alkaloids

S


Chemical Reviews

Review

Scheme 35. Fukuyama’s Divergent Total Syntheses of (−)-Tetrodotoxin [(−)-TTX] (389) and 11-norTTX-6(R)-ol (388)

transformed to amathaspiramide F (400) via successive reduction with Schwartz’s reagent and NaBH 3CN. As mentioned above, amathaspiramides A (399), C (397), and E (398) were obtained from 395 by use of Fukuyama’s method. Additionally, selective N-methylation of 393 with NaH/MeI, subsequent ozonolysis, and cyclization furnished amathaspiramide B (396). Trichodermamides A, B, and C (408−410) share a unique and highly functionalized 1,2-oxazadecaline core possessing four contiguous stereogenic centers. In 2015, Larionov and coworkers developed a novel and efficient approach to the construction of the 1,2-oxazadecaline ring system and successfully applied this method to the concise total synthesis of trichodermamides A−C (408−410) (Scheme 37).78 Thus, 1,2-addition of the C-lithiated O-silyl ethyl pyruvate oxime (401) to benzoquinone (375) followed by an intramolecular oxa-Michael ring-closure reaction gave 1,2-oxazadecaline 402, which was converted to the common synthetic precursor 403 over three steps. Regio- and stereoselective epoxidation of the distal double bond in 403, subsequent ring-opening of the resulting epoxide with PhSeH and NaHCO3, followed by hydrolysis of the ethyl ester delivered acid 405. Amide coupling of 405 with aminocoumarin 406 followed by oxidation and subsequent [2,3]-sigmatropic rearrangement afforded trichodermamide A (408). Additionally, ethyl ester cleavage in 403 followed by HATU-mediated amide coupling with 406 gave 407, which served as the common intermediate for both trichodermamides B (409) and C (410). The sequence of Nmethylation of 407, Mn(salen)-catalyzed epoxidation of the distal C8−C9 double bond, ring-opening of the intermediate distal allylic epoxide, and oxidatively induced selenoxide rearrangement completed the first synthesis of 410. Finally, trichodermamide B (409) was obtained from 407 by a six-step sequence.

Scheme 36. Sun’s Divergent Total Syntheses of Amathaspiramides A−F (399, 396, 397, 395, 398, 400)

2.2. Terpenes

2.2.1. Sesquiterpenes. The guaiane sesquiterpenes feature a hydroazlene core structure and have attracted considerable attention from synthetic chemists due to their various biological activities. In 2013, Sun, Lin and co-workers reported the collective total synthesis of englerins A (420) and B (421),

followed by two amidation reactions delivered the common intermediate 393. Treatment of 393 with O3 and subsequent quenching with PPh3 produced the kinetically controlled 8Ramathaspiramide D (395) and 8-S-epimer 394, which was T


Chemical Reviews

Review

Scheme 37. Larionov’s Divergent Total Syntheses of Trichodermamides A−C (408−410)

Scheme 38. Sun and Lin’s Divergent Total Syntheses of Five Guaiane Sesquiterpenes

+ 3] cycloaddition, and possess the tetracyclic core of guaianolides (Scheme 39).80 Through this total synthesis, the absolute configurations of hedyosumins A−C are successfully established. Organocatalytic asymmetric [4 + 3] cycloaddition

oxyphyllol (422), orientalols E (423) and F (424), by employing a unified strategy, with the total synthesis of orientalol E and oxyphyllol being achieved for the first time (Scheme 38).79 [4 + 3] Cycloaddition of furan 411 and dienal 412 in the presence of organocatalyst (R,R)-413 successfully gave [3.2.1] bicyclic product 414 with 67% ee, which was converted to the enol triflate 415 in four steps. Intramolecular Heck reaction of 415 followed by selective epoxidation of the more electron-rich double bond and subsequent SN2′-type reduction of the resulting epoxide with DIBAL-H delivered allylic alcohol 416. Inverting the configuration of hydroxyl group in 416 through an oxidation−reduction procedure afforded the common synthetic precursor 417. Selective saturation of the less-hindered bridging double bond in 417 by Pd/C-catalyzed hydrogenation yielded orientalol F (424), while catalytic hydrogenation of 417 by using Crabtree’s catalyst furnished oxyphyllol (422). Acetylation of the hydroxyl group in 422 followed by oxidation and subsequent removal of the acetyl group formed orientalol E (423). Alternatively, hydration of 417 by hydroboration−oxidation procedure and the following catalytic hydrogenation employing Pfaltz’s catalyst led to diol 418. Sequential two-step acetylation of 418 generated englerin A acetate 419, which was converted to englerin A (420) and englerin B (421) by treatment with K2CO3. Hedyosumins A−C (428−430), which belong to the guaianolides, share a tetracyclic core and contain a characteristic 7,10-epoxy bridge. In 2016, Sun and co-workers further reported the first asymmetric total synthesis of hedyosumins A−C (428−430) from the common synthetic precursor 427, which was constructed by similar organocatalytic asymmetric [4

Scheme 39. Sun’s Divergent Total Syntheses of Hedyosumins A−C (428−430)

U


Chemical Reviews

Review

Scheme 40. Stoltz’s Divergent Total Syntheses of Four Daucane Sesquiterpenes

resulting epoxyketone, selective hydrogenation of the terminal alkene, and allylic oxidation with SeO2 yielded epoxydaucenal B (436). Alternatively, methylenation of 435 with Lombardo conditions followed by regioselective hydrogenation of the terminal alkene furnished daucene (437), which was further oxidized to daucenal (438) with SeO2. Finally, 14-paraanisoyloxydauc-4,8-diene (439) was obtained from 438 through sequential Luche reduction and acetylation with para-anisoyl chloride. In 2014, the Echavarren group reported the collective syntheses of (−)-epiglobulol (445), (−)-4β,7α-aromadendranediol (446), and (−)-4α,7α-aromadendranediol (447) through a stereodivergent gold(I)-catalyzed cascade cyclization of a common precursor 441, which formed the tricyclic core in a single step (Scheme 41).82 Structurally, these natural products share a 5/7/3-fused ring system, containing several contiguous chiral centers. The key dienyne (S,E)-441 was prepared from (E,E)-farnesol (440) through four steps of conventional transformations. Exposing (S,E)-441 to the gold(I) complex [(JohnPhos)Au(MeCN)]SbF6 (442) gave compound 443 via the cyclization/1,5-OBn migration/intramolecular cyclopropanation cascade. Epoxidation of 443 with DMDO followed by epoxide opening and benzyl ether cleavage with Li in ethylenediamine delivered (−)-4β,7α-aromadendranediol (446), while debenzylation of 443 and subsequent stereoselective hydrogenation yielded (−)-epiglobulol (445). Alternatively, treatment of 441 with 442 in the presence of allylic alcohol led to compound 444, which was converted to

of dienal 412 and furan 425 gave desired isomer 426 with moderate yield and enatioselectivity. Compound 426 was then converted to the common intermediate 427 via a 10-step procedure. Removal of the TBS group in 427 followed by oxidation of the resulting alcohol afforded hedyosumin A (428). In addition, chemoselective hydrogenation of the enone in 427 followed by removal of the silyl ether furnished hedyosumin C (429). Furthermore, Dess−Martin oxidation of hedyosumin C (429) generated hedyosumin B (430). The daucane sesquiterpenes and sphenolobane diterpenes share a bicyclo[5.3.0]decane core, featuring varied degrees of oxidation with different peripheral functionality. In 2013, Stoltz’s group reported a unified approach to the bicyclo[5.3.0]decane core 435, enabling the enantioselective total synthesis of daucene (437), daucenal (438), epoxydaucenal B (436), and 14-para-anisoyloxydauc-4,8-diene (439) (Scheme 40).81 Sequential acylation of 431 with allyl cyanoformate and methylation followed by Pd-catalyzed enantioselective decarboxylative alkylation reaction afforded vinylogous ester 432. Replacement of the tBu group with TIPS group smoothly provided 433, which was exposed to (3-methylbut-3-en-1-yl) magnesium bromide followed by treatment with sodium phosphate buffer and fluoride quench to yield dione 434. It is worthy of noting that this new approach provides the first example of modifying the standard Stork−Danheiser ketonetransposition process by use of a siloxyenone. Ring-closing metathesis of 434 and subsequent intramolecular aldol condensation generated the common precursor 435. The sequence of epoxidation of 435, Wittig olefination of the V


Chemical Reviews

Review

Reduction of the butenolide in 451 with DIBAL-H furnished microcionin-1 (452), which was further oxidized to (+)-aignopsanoic acid A (453) with m-CPBA. Converting 451 to a silyloxyfuran intermediate followed by oxidation with DMDO provided, after treatment with TBAF, (+)-aignopsanoic acid A (453) with better redox economy. Finally, methylation of 453 with trimethysilyldiazomethane (TMSCHN2) led to (−)-methyl aignopsanoate A (454), while acid-catalyzed isomerization of 453 gave (+)-isoaignopsanoic A (455). Small-molecule neurotrophic agents that have a more favorable pharmacokinetic profile have attracted growing interest in recent years. In 2016, the Micalizio group accomplished an asymmetric total synthesis of neurotrophic seco-prezizaane sesquiterpenes (2S)-hydroxy-3,4-dehydroneomajucin (462), (1R,10S)-2-oxo-3,4-dehydroneomajucin (463) and (−)-jiadifenin (464) from the common precursor 460, equipped with a common tetracyclic lactone skeleton (Scheme 43).84 These three natural products are among the most potent

Scheme 41. Echavarren’s Divergent Total Syntheses of Three Sesquiterpenes

Scheme 43. Micalizio’s Divergent Total Syntheses of Three Neurotrophic seco-Prezizaane sesquiterpenes (−)-4α,7α-aromadendranediol (447) through selective epoxidation and followed epoxide opening and allyl cleavage. In 2015, the Renaud group disclosed a general strategy for the synthesis of aignopsanes (+)-aignopsanoic acid A (453), (−)-methyl aignopsanoate A (454), (+)-isoaignopsanoic A (455), and structurally related furanosesquiterpene (+)-microcionin-1 (452) from a common precursor 451 (Scheme 42).83 Scheme 42. Renaud’s Divergent Total Syntheses of Four Members of Aignopsanes

members of the natural product class. Enyne 457 was prepared from chiral epoxide 456 in five steps. The key alkoxide-directed metallacycle-mediated [2 + 2 + 2] annulative coupling reaction was then conducted. Exposure of stannyl-substituted TMSacetylene 458 to the mixture of n-BuLi and Ti(Oi-Pr)4, followed by addition of the Li-alkoxide of enyne 457, produced hydrindane 459. Subsequently, compound 459 was transformed into the common precursor 460 in nine steps, including a powerful intramolecular radical cascade reaction to construct the sterically congested C5 quaternary center. Removal of the tertiary TMS-ether and α-hydroxylation of the common intermediate 460, accompanied by epimerization at C1, yielded (1R,10S)-2-oxo-3,4-dehydroneomajucin (463). Oxidation of 463 followed by methanolysis successfully delivered (−)-jiadifenin (464). Meanwhile, 460 could be converted into (2S)hydroxy-3,4-dehydroneomajucin (462) by six steps of reactions. This is also the first example that such a metallacyclecentered annulation reaction was applied in natural product synthesis.

Structurally, these natural products embody an all-cis 4,5,10trimethyldecalin backbone. Starting from (+)-Wieland− Miescher ketone (448), the cis-decalin core 449 was constructed through conjugate addition, α-hydroxylation, and subsequent protection with TMSCl. Wittig methylenation followed by removal of the TMS-ether and subsequent acylation with acryloyl chloride afforded the ester 450. The sequential ring-closing metathesis of 450 and stereoselective hydrogenation delivered the common synthetic precursor 451. W


Chemical Reviews

Review

2.2.2. Diterpenoids. Ent-kaurane diterpenoids have similar basic skeleton and are assumed to share the same biogenic precursor. Jungermannenones are new ent-kaurene-type diterpenoids, which share a unique bicyclic-[3,2,1]octene framework containing an endocyclic tetrasubstituted alkene moiety. In 2016, Lei’s group reported the total syntheses of racjungermannenones B (475) and C (476) from the common intermediate 474 (Scheme 44).85 The 1-geranyl-4-methox-

Scheme 45. Ma’s Divergent Total Syntheses of 1α,6αDiacetoxy-ent-kaura-9(11), 16-Dien-12,15-dione (490), and Lungshengenin D (491)

Scheme 44. Lei’s Divergent Total Syntheses of racJungermannenones B (475) and C (476)

by two key strategic connections at the C5/C6 and C9/10 junctures with two relatively simple fragments 480 and 482. The key [3.2.1]bicyclic ring system 480 was assembled by using a Pd-catalyzed cycloalkenylation of a silyl enol ether. The fragment 482 was prepared by reduction of compound 481 under the Corey−Bakshi−Shibata’s conditions followed by Cbz protection. The homoaldol reaction of compound 480 and 482 under Hoppe’s conditions produced an alcohol, which was trapped with acetic anhydride to give the ester 483 (dr = 1.3:1). By screening different Lewis acids, they found that the BF3· OEt2 mediated Mukaiyama−Michael-type reaction proceeded well to provide compound 485, which was transformed to 486 in three steps. To access 490, compound 486 was transformed to ketone 487 over three steps. Installation of the enone according Saegusa’s procedure followed by allylic oxidation were conducted to give 1α,6α-diacetoxy-ent-kaura-9(11),16dien-12,15-dione (490). Additionally, oxidation of 486 afforded alcohol 488 as a single isomer, which was treated with HCl to produce ether 489 directly. Finally, 489 was readily converted to lungshengenin D (491) over eight steps. In 2017, Ding and co-workers reported the first asymmetric total synthesis of the other four members of ent-kaurenoids pharicin A (501), pharicinin B (502), 7-O-acetylpseurata C (503), and pseurata C (504) by using an unprecedented oxidative dearomatization-induced (ODI) [5 + 2] cyclo-

ybenzene (467) was prepared from geraniol (465) over two steps. Intramolecular electrophilic hydroarylation of 467 with RuCl3 followed by benzylic oxidation provided ketone 468, which could be converted to dienyne 469 over four steps. An unprecedented regioselective 1,6-dienyne reductive cyclization of dienyne 469 proceeded smoothly to give 473 through a vinyl radical cyclization/allylic radical isomerization sequence and in situ destannylation. Selective cleavage of the exocyclic double bond in 473 gave the common intermediate 474. Direct installation of exoenone by α-methylation furnished jungermannenone C (476), while Barton−McCombie deoxygenation of 474 followed by α-methylenation delivered jungermannenone B (475). In 2017, Ma’s group communicated a new tactic to synthesize ent-kaurane diterpenoids by establishing the [3.2.1] bicyclic unit at the early stage and completed the first total synthesis of 1α,6α-diacetoxy-ent-kaura-9(11),16-dien-12,15dione (490) and lungshengenin D (491) (Scheme 45).86 In this strategy, pentacyclic compound 486 was chosen as the common intermediate, in which the central B ring was forged X


Chemical Reviews

Review

6,5,6-abeoabietane scaffold with cis or trans A/B ring junction and varied degrees of oxidation. To date, more than 20 members of this diterpenoid family have been identified. In 2013, Li and co-workers reported the divergent syntheses of taiwaniaquinones A (512) and F (515) and taiwaniaquinols B (513) and D (514) from an advanced intermediate 509 with trans A/B ring junction (Scheme 47).88 Inspired by the

addition/pinacol-type 1,2-acyl migration cascade for assembling the bicyclo[3.2.1]-octane core skeleton (Scheme 46).87 The Scheme 46. Ding’s Divergent Total Syntheses of Four entKaurenoids

Scheme 47. Li’s Divergent Total Syntheses of Taiwaniaquinones A (512) and F (515) and Taiwaniaquinols B (513) and D (514)

proposed biopathway, the 6,5,6-tricyclic aldehyde 509 was constructed through a Wolff rearrangement of a 6,6,6-tricyclic precursor 508. Homogeranyl arene 506 was synthesized from the known aldehyde 505 in two steps. Bi(OTf)3-induced cationic cyclization of 506 generated tricyclic compound 507, which was further converted to the α-dizaketone 508 via sequential benzylic oxidation and α-diazotization. Wolff rearrangement of 508 under thermal conditions and subsequent reduction and oxidation procedures delivered the common synthetic precursor 509. Epimerization of aldehyde 509 with K2CO3 provided 510, the precursor toward taiwaniaquinones A and F. Oxidation of 510 with CAN furnished taiwaniaquinone F (515), while global demethylation of 510 and spontaneous aerobic oxidation rendered taiwaniaquinone A (512). In another direction, exposure of 509 to TMSOTf and NEt3 produced silyl enol 511, the precursor toward taiwaniaquinols B (513) and D (514). The sequence of Saegusa−Ito oxidation, demethylation, and one-pot oxidation/ reduction gave taiwaniaquinol D (514). Alternatively, oxidative cleavage of the silyl enol 511 followed by the same sequence used for synthesis of taiwaniaquinol D (514) afforded taiwaniaquinol B (513).

known chiral alcohol 493 was prepared from Wieland− Miescher ketone (492) in three steps. Acetylation of 493 and IBX oxidation followed by epoxidation of the resultant enone afforded epoxide 494, which was then converted to the key precursor 497b. The key cascade reaction was then conducted by treatment of 497b with PhI(TFA)2 and K2CO3 in HFIP to provide the anticipated tetracyclic diketone 498 as a single diastereomer. Epimerization of the hydroxyl group at C7 by oxidation/reduction procedure followed by monoacetylation at C7 and selective oxidation at C12 gave alcohol 499. The C14 hydroxyl group was epimerized through a retro-aldol/aldol process to provide 500, which was converted to pharicin A (501) through the sequence of stereoselective reduction, regioselective singlet oxygen ene reaction, and subsequent one-pot dehydration with trichloroisocyanuric acid (TCCA). Removal of the more labile acetyl group of 501 at C7 furnished pharicinin B (502), while regioselective oxidation of 501 delivered 7-O-acetylpseurata C (503), which was further converted to pseurata C (504) via mild saponification with Me3SnOH. Taiwaniaquinoids, first isolated from Taiwania cryptomerioides, are a class of natural products possessing an unusual Y


Chemical Reviews

Review

Scheme 48. Gademann’s Divergent Total Syntheses of 10 Members of the Icetexane Family

and co-workers reported the total synthesis of cyanthiwigins A (540), C (541), H (542), and G (543) from a common precursor 537, possessing the basic tricyclic skeleton (Scheme 49).90 Michael addition of the lithium enolate of 529 to enone 530 followed by oxonium ion-promoted cyclization and subsequent elimination gave enone 532 through a formal [4 + 2] cyclization. Enone 532 was converted to the key cyclization precursor 536 through a few conventional transformations. RCM of 536 using Grubbs II catalyst afforded the common intermediate 537. Exposure of 537 to KHMDS and PhNTf2 followed by Pd-catalyzed reduction of the resultant vinyl triflate and subsequent deprotection provided compound 538. The synthesis of cyanthiwigin G (542) was completed from 538 through the sequence of Saegusa−Ito oxidation, 1,2addition, and PCC-mediated oxidative rearrangement. Alternatively, 537 was converted to 539 in four steps involving reduction of the ketone and deprotection. Cyanthiwigin A (540) was obtained from 539 through the same sequence used for the synthesis of cyanthiwigin G. Reduction of the ketone in 540 resulted in cyanthiwigin C (541), while selective epoxidation of 540 with mCPBA led to cyanthiwigin H (543). Ryanodane diterpenoids share an extremely complex fused pentacyclic ring system with distinct oxygen-based functionalities at different positions and orientations. In 2014 and 2016, the Inoue group subsequently reported the unified synthesis of ryanodol (554), 3-epi-ryanodol (555), cinnzeylanol (556), cinncassiol A (558), and cinncassiol B (557) from the common synthetic scaffold 547, possessing the fused pentacyclic ring system (Scheme 50).91,92 Different modifications of the C2and C3-substitution patterns in compound 547 could achieve the total synthesis of all the targets. The intermediate 547 was constructed from 2,5-dimethylbenzene-1,4-diol (545) and maleic anhydride via a 28-step procedure. In 2014, the group completed the synthesis of ryanodol (554) from 547 over seven steps. In 2016, they reported the total syntheses of the other four natural products from a more advanced intermediate

Icetexanes include a variety of diterpenoids, which possess a unique 6−7−6 tricyclic core structure. Biosynthetically, they are proposed to be derived from the abietane through ring expansion. Inspired by this hypothesis, in 2017, Gademann and co-workers accomplished the divergent total synthesis of 10 members of the icetexane family of natural products from the naturally abundant and commercially available abietane carnosic acid (516) (Scheme 48).89 Triple methylation of 516 gave dimethoxycarnosate methyl ester 517. Reduction of the ester followed by mesylation of the resulting primary alcohol generated a primary cation through the E1 elimination of the mesylate. The primary cation rearranged to the more stable ring-expanded tertiary carbocation immediately, and subsequent elimination and attack by water from the β-face led to a mixture of isomer olefins 518 and tertiary alcohol 519, respectively. Both 518 and 519 could be converted to salvicanol (520) through selective monodemethylation and successive epoxidation and one-pot hydride-mediated epoxide opening/ demethylation, respectively. Protection of 520 as acetate followed by oxidation with RuCl3/TBHP, deacetylation, and subsequent aromatic oxidation with salcomine in an O2 atmosphere yielded komaroviquinone (521) as the sole tautomer. Subjecting 521 to photolysis formed cyclocoulterone (522) and komarovispirone (523). Additionally, reduction of 521 with Na2S2O3 produced coulterone (524). In another direction, demethylation of 520 followed by treatment with silica gel resulted in brussonol (525) and przewalskin E (526) through acid-catalyzed tautomerization and aerobic oxidation. It is worthy of mentioning that brussonol (525) and przewalskin E (526) could be converted to each other by oxidation or reduction procedure. Finally, Diels−Alder dimerization of przewalskin E (526) delivered obtusinones D (527) and E (528) and the configurations of the two natural products were revealed by X-ray analysis. Cyanthiwigin diterpenoids typically share a 5−6−7 tricyclic ring system with four contiguous stereocenters. In 2013, Gao Z


Chemical Reviews

Review

lective hydroalumination of chloroalkyne 559 and subsequent silver−NHC ligand catalyzed enantioselective conjugate addition of the resulting internal vinylaluminum intermediate to enone 560, followed by cyclization of the chloroketone, generated decalone 561, which was transformed to the (Nacyloxy)phthalimide 562 through a seven-step sequence. Generating the tertiary carbon radical by exposure of 562 to 1 mol % of Ru(bpy)3(BF4)2, Hantzsch ester, and i-Pr2NEt, then coupling the radical with butenolide 563, equilibration of the resulting mixture with DBU, and isomerization with RhCl3 yielded (−)-solidagolactone (566). In another approach to 566, the known trans-decalone 564 was converted to 565 in three steps. Generating the tertiary cuprate from sulfide 565 by sequential reaction with LiDBB and CuBr·SMe2, followed by coupling reaction of the intermediate with butenolide 563 and the equilibration of the resulting mixture with DBU, delivered solidagolactone (566). Sequential treatment of 566 with TBSOTf/NEt3, m-chloroperbenzoic acid, and Amberlyst-15 furnished PL3 (567). Meanwhile, reduction of 566 with DIBAL-H delivered annonene (568). The cladiellins are a group of structurally complex diterpenes that share a rare oxatricyclic ring system containing several consecutive chiral centers and different substituents. In 2014, the Yang and Luo group achieved the collective syntheses of nine members (580−588) of the cladiellin family by using the gold-catalyzed cascade reaction of 1,7-diynes as the key step (Scheme 52).94 Condensation of hex-5-ynoic acid (569) and chiral auxiliary (570) gave amide 571, which was converted to the key cyclization precursor 574 through a few conventional transformations. Subjecting 574 to the key gold-catalyzed cascade reaction to construct the 6−5-bicyclic skeleton yielded compound 575, which could be converted to the common intermediate 578 mainly by ring-closing metathesis. Compound 578 could be readily converted to (−)-sclerophytin A (581), (−)-sclerophytin B (582), (+)-cladiella-6Z,11(17)-dien-3-ol (580), and (+)-vigulariol (583) according to the published procedures. Furthermore, region- and stereoselective double oxymercuration of 580 followed by reduction with NaBH4 furnished (+)-deacetylpolyanthellin A (584), which was further converted to (+)-polyanthellin A (585) by acetylation. Alternatively, precursor 578 was converted to hemiketal 579 in five steps. Addition of methylmagnesium chloride to the hemiketal in 579 provided (−)-cladiellinsin (586), which was finally converted to (−)-pachycladin D (588) and (−)-pachycladin C (587) by oxidation and acetylation of the hydroxyl group, respectively. 2.2.3. Sesterterpenoids. Leucosceptroids and norleucosceptroids, isolated from Leucosceptrum canum, are members of families of sesterterpenoids and pentanorsesterterpenoids, respectively. All members of the leucosceptroid family of natural products share a 5−6−5 tricyclic framework with a fully functionalized tetrahydrofuran ring and are different in the oxidation state at C11 and the substitution of the C14 ethyl linkage. In the two papers published by the Magauer group in 2014 and 2015, they reported the asymmetric total synthesis of 16 leucosceptroid natural products from the common precursor 594, comprising the core 5−6−5 tricyclic framework (Scheme 53).95,96 Butenolide 591 and lactone 592 were prepared from 589 and 590, respectively. Exposure of 591 and 592 to LiHMDS and followed by hydrogenation afforded 593 through a Hauser−Kraus-type annulation. The common precursor 594 was then synthesized from 593 through an eight-step sequence. Cleavage of the p-methoxyphenyl ether in 594, regioselective

Scheme 49. Gao’s Divergent Total Syntheses of Cyanthiwigins A (540), C (541), H (542), and G (543)

549, which could be readily synthesized from 547 via the sequence of protection with C10 hydroxyl group with MOMCl, reduction of the C3 ketone accompanied by migration of TMS group, and oxidation of the resulting C2 hydroxyl group. Addition of isopropenyl lithium to the C2 ketone of 549, from the top face, afforded 550. Removal of the TMS groups, cleavage of the acetonide and MOM group followed by hydrogenolysis of the benzyl ether in 550 furnished 3-epiryanodol (555). On the other hand, removal of the OTMS group at C3 of 549 with SmI2/MeOH provided 551. Treatment of 551 with a reagent mixture of cyclopropyllithium and LaCl3·2LiCl led to alcohol 552, which was converted into cinnzeylanol (556) via a five-step procedure. Moreover, addition of MeCHCHCH2MgBr to the C2 ketone of 551 followed by ozonolysis and reductive workup with NaBH4 delivered alcohol 553. Removal of the TMS, MOM group in 553, and subsequent hydrogenolysis of the benzyl ether gave cinncassiol B (557) together with a small amount of cinncassiol A (558). Meanwhile, cinncassiol A (558) could be selectively obtained from 553 by deprotection and treatment with HCl or more directly from 557 by treatment with HCl. In 2015, Overman’s group reported a new strategy for synthesizing trans-clerodane diterpenoids, in which transhydronaphthalene and oxacyclic fragments are coupled by stereoselective 1,6-addition of a tertiary cuprate or a tertiary carbon radical to β-vinylbutenolide. They utilized this approach to achieve the total synthesis of (−)-solidagolactone (566), (−)-16-hydroxycleroda-3,13-dien-15,16-olide (567, PL3), and (−)-annonene (568) (Scheme 51).93 Nickel-catalyzed regioseAA


Chemical Reviews

Review

Scheme 50. Inoue’s Divergent Total Syntheses of Five Members of Ryanodane Diterpenoids

yielded leucosceptroids L (600) and M (601). Removal of the C11 hydroxyl group in 598 followed by oxidation and epimerization resulted in norleucosceptroid C (602), while direct oxidation of 598 led to norleucosceptroid B (596). The union of 596 with phosphonate 599 gave rise to leucosceptroid K (603). A sequential selective 1,6-hydride addition and asymmetric olefin isomerization via proton transfer catalysis (604) delivered leucosceptroid G (605). α-Deoxygenation of 605 yield leucosceptroid I (606) and its H-11 epimer leucosceptroid J (607), while DIBAL-H reduction of 605 followed by acidic workup furnished leucosceptroid A (608). αDeoxygenation of 608 and the following epimerization with NEt3 gave leucosceptroid B (609). Exposure of 608 to singlet oxygen produced the endoperoxide 610. The sequence of reduction of 610 with DMS, acylation of the resulting hydroxyl group, chromatography, and base-induced intramolecular aldol reaction gave leucosceptroid C (613). Additionally, treatment of 610 with PPh3 and DIPEA provided leucosceptroid P (612) through Kornblum−DeLaMare-type rearrangement. Finally, competing spirocyclization and elimination of 610 followed by subsequent cleavage of peroxide bonds led to leucosceptroid O (611) and leucosceptroid K (603), respectively. 2.2.4. Meroterpenoids. (+)-Machaeriol B (622), (+)-machaeriol D (620), and (+)-Δ8-THC (621) belong to the cannabinoid family and feature a tricyclic dibenzopyran motif with trans connectivity between the cyclohexane subunit and the pyran skeleton. In 2015, the Studer group reported a short and divergent total synthesis of 620−622 from a common precursor (Scheme 54).97 Methylation of the dienolate generated from commercially available (S)-perillic acid (614) upon treatment with LDA and DMPU delivered an isomeric mixture of carboxylic acid 615 (anti/syn = 1.7:1). Pd-catalyzed stereospecific decarboxylative coupling of 615 with aryl iodides

Scheme 51. Overman’s Divergent Total Syntheses of (−)-Solidagolactone (566), PL3 (567), and (−)-Annonene (568)

hydroxylation, and the following IBX oxidation furnished norleucosceptroid A (595) and norleucosceptroid B (596). αHydroxylation of 594 prior to cleavage of the p-methoxyphenyl ether produced norleucosceptroid F (597) and compound 598. Oxidation of the hydroxyl group in 597 and subsequent Horner−Wadsworth−Emmons reaction with phosphonate 599 AB


Chemical Reviews

Review

Scheme 52. Yang’s Divergent Total Syntheses of Nine Members of the Cladiellin Family

bromide 629 via a number of conventional transformations. Condensation of 629 with carbanion generated from geranyl phenyl sulfide (630), and subsequent desulfurization followed by removal of the TBS group and oxidation with PCC, led to the common synthetic precursor 631. Regioselective installation of the double bond followed by deprotection of MOM ether provided (+)-antroquinonol (632), while removal of the MOM group followed by elimination of β-methoxy group furnished (+)-antroquinonol D (633). In 2014, Kobayashi and co-workers achieved the divergent total synthesis of eight natural products, including hericenones A (642), B (640), and I (644), hericenols B−D (637−639), and erinacerins A (641) and B (643) from the common intermediate 636 (Scheme 56).99 These natural products differ mainly in the side chain and redox state, and this is crucial for their divergent syntheses. Coupling aryl bromide 634 and stannane 635 afforded common intermediate 636. Hericenol B (637) was prepared from 636 through deprotection of the MOM group, reduction with LiAlH4, and removal of TBS group. Treatment of 637 with silica gel in MeOH followed by PPTS gave hericenol D (639). Similar process in the presence of H2O yielded hericenol C (638). After transformation of 636 into hericenone B (640) in eight steps, erinacerin A (641) was generated by a proton mediated cyclization. Moreover, 636 was converted into hericenone A (642) in four steps. Luche reduction of the ketone in hericenone A (642) furnished erinacerin B (643). Finally, a similar cyclization of hericenone A (642) delivered hericenone I (644). In 2015, Trotta described the total synthesis of oridamycin A (650) and oridamycin B (651) from a common intermediate 648 (Scheme 57).100 Structurally, the two indolosesquiterpenes share a carbazole core fused to a trans-decalin ring system with

616a and 616b was conducted to afford 617a and 617b, respectively. The construction of the trans-configured pyran core (618a and 618b) from 617a or 617b was subsequently achieved through selective deprotection of one methyl ether by treatment with TMSCl and NaI. Deprotection of another methyl ether in 618a furnished (+)-Δ8-THC (621). Hydroboration of 618b with disiamylborane (Sia 2 BH) gave intermediate 619. Subsequent radical reduction of 619 followed by a deprotection step led to (+)-machaeriol B (622), while the sequence of oxidation of 619 with H2 O2/NaOH and deprotection of the methyl ether provided (+)-machaeriol D (620). It is worthy of mentioning that the divergent approach is convincingly demonstrated by the five-step syntheses of (+)-machaeriol B (622) and (+)-machaeriol D (620) (thus far the shortest route toward 620) and the four-step syntheses of (+)-Δ8-THC (621) and an analogue. In 2015, Chen and co-workers reported the first total synthesis of (+)-antroquinonol (632) and (+)-antroquinonol D (633) from a common precursor 631 (Scheme 55).98 Structurally, the two molecules share a unique quinonol core with a sesquiterpene side chain. Considering quinonol compounds are prone to be aromatized under several conditions, the α,β-unsaturated ketone was installed at the final stage from the intermediate 631 via two different protocols to provide the two targets, respectively. The enantioselective addition of diethylzinc to 623 in the presence of catalytic (+)-morpholinoisoborneol (MIB) followed by allylation of the resulting secondary alcohol gave 624 with 93% ee. Ir-catalyzed isomerization of allyl ether 624 to vinyl ether and subsequent Claisen rearrangement led to an aldehyde, which was converted to the hexenol 625 through sequential allylation of the aldehyde and RCM reaction. Alcohol 625 was then converted to allylic AC


Chemical Reviews

Review

Scheme 53. Magauer’s Divergent Total Syntheses of 16 Leucosceptroid Natural Products

system. Because 658 and 659 are unstable and highly polar, their structures are confirmed by conversion into dimethyl esters 660 and 661. In 2016, Kuramochi and co-workers reported the first total syntheses of juglorescein (657) and juglocombins A (658) and B (659) from the common intermediate 655, which was constructed through a bioinspired dimerization of 1,4-naphthoquinone 654 (Scheme 58).101 The anaphthoquinone monomer 654 was prepared by addition of Grignard reagent generated from aryl bromide 652 to optically active epoxide 653, protection of the resulting alcohol, and subsequent PIDA oxidation. Treatment of 654 with DBU in an oxygen atmosphere resulted in a sequential intermolecular and intramolecular Michael addition followed by oxidation of the resulting hydroquinone to provide the desired dimer 655, in which five new stereogenic centers were generated in a single step. Epoxide 655 was successfully converted into 656 through a four-step sequence. Compound 656 was converted to juglocombins A (658) and B (659) as an unstable tautomeric equilibrium mixture through a sequence of Dess−Martin oxidation, Pinnick oxidation, oxidation of the 1,4-dihydroxynaphthalene moiety, and removal of the four MOM groups. Because of the instability of 658 and 659, they were converted into dimethyl esters 660 and 661 through methylation with

four contiguous stereocenters. The only difference between oridamycin A (650) and B (651) manifests at the C16 quaternary center; oridamycin A (650) bears an equatorial methyl, while oridamycin B (651) possesses an equatorial hydroxymethyl. The trans-decalin ring system (646) was generated from the known compound 645 through an oxidative radical cyclization. Oxidation of alcohol 646 to the corresponding aldehyde followed by the addition of Grignard reagent generated from 647 afforded the common intermediate 648 as a mixture of diastereomers. Elimination of alcohol 648 with TFA followed by a thermal 6π-electrocyclization/aromatization procedure under aerobic conditions, and removal of the Boc group with TFA yielded the free carbazole, which was further converted to oridamycin A (650) via sequential stereoselective reduction of the ketone moiety and dealkylation of the methyl ester. Alternatively, after converting 648 to the carbazole intermediate by using the same protocol described above, condensation of the ketone with MeONH2·HCl followed by Pd(OAc)2-catalyzed selective C−H oxidation yielded acetate 649. Finally, global deprotection and subsequent dealkylation of the methyl ester furnished oridamycin B (651). 2.3. Polyketides

Juglorescein (657) and juglocombins A (658) and B (659) share a highly oxygenated, 6/6/5/6/6-fused pentacyclic ring AD


Chemical Reviews

Review

diastereomer 669, which was transformed to 670 through selective 4′-acetylation. Final global deprotection of the pyranonaphthoquinone core in 668, 669, and 670 furnished griseusin C (671), 4′-deacetyl-griseusin A (672), and griseusin A (673), respectively. The present synthesis is also the first to use hydroxy-directed C−H olefination in a total synthesis. Indoxamycins share a 5−5−6 tricyclic cage-like carbon framework possessing six contiguous stereogenic centers. In 2013, Ding and co-workers reported the first and divergent total syntheses of indoxamycins A (684), C (685), and F (686) from a common precursor 680, which is equipped with the core ring system and three quaternary carbon centers (Scheme 60).103 Esterification of 674 and 675 followed by Ireland− Claisen rearrangement and subsequent methyl esterification afforded compound 676, which was converted to dienyne 677 in three steps. Pd-catalyzed reductive cyclization of 677 generated (±)-678 or (+)-678 under two different conditions. Installation of the quaternary center at the C5 position via a two-step procedure, followed by regioselective reduction of the ester and subsequent Dess−Martin oxidation, yielded aldehyde 679. The subsequent tandem 1,2-addition/oxa-Michael/methylenation reaction of 679 furnished the common intermediate 680. Sequential reduction of 680 generated the allylic alcohol 681, the precursor toward indoxamycins C (685) and F (686). Nucleophilic chlorination of 681, subsequent olefination with 682 followed by hydrolysis of the allylic chloride led to indoxamycin C (685). Additionally, treatment of 681 with benzenesulfenyl chloride followed by HWE olefination and Mislow−Evans rearrangement resulted in an allylic alcohol, which was converted to indoxamycin F (686) through the finalstage saponification. On the other hand, conversion of 680 to corresponding enol triflate followed by reductive detriflation delivered alkene 683, which was further transformed to indoxamycin A (684) through reduction of the ester and the following HWE olefination with phosphonate 682. In 2013, Lee’s group reported the convergent and enantioselective total synthesis of amphidinolides O (697) and P (698), which share a novel 15-membered macrolide with one six-membered-ring bridged hemiacetal moiety, an epoxide at C8−C9, and seven chiral centers (Scheme 61).104 Their structures only differ in the functional group at C11 position, so

Scheme 54. Studer’s Divergent Total Syntheses of (+)-Machaeriol B (622), (+)-Machaeriol D (620), and (+)-Δ8-THC (621)

trimethylsilyldiazomethane (TMSCHN2). Meanwhile, epoxide 655 was transformed into juglorescein (657) over five steps. In 2015, Thorson’s group achieved the first and enantioselective total syntheses of griseusin A (673), 4′-deacetylgriseusin A (672) and griseusin C (671) from the common precursor 668, which is equipped with the fused pentacyclic ring system (Scheme 59).102 The intermediate 663 was prepared from 662 in eight steps. Palladium-catalyzed hydroxy-directed C−H olefination of 663 with 664 delivered methylene isochroman 666 accompanied by byproduct 665, which was converted to 666 through sequential silylation and Saegusa−Ito oxidation. Removal of the TBS group in 666 followed by stereoselective epoxidation and subsequent regioselective cyclization afforded the common precursor 668. Reduction of the ketone in 668 led to the natural 4′-axial

Scheme 55. Chen’s Divergent Total Syntheses of (+)-Antroquinonol (632) and (+)-Antroquinonol D (633)

AE


Chemical Reviews

Review

Scheme 56. Kobayashi’s Divergent Total Syntheses of Eight Natural Products

reported the unified synthesis of three pterocarpans (−)-medicarpin (705), (−)-sophoracarpan A (706), and (±)-kushecarpin A (707) from a common precursor 703 (Scheme 62).105 The chromane ketal 703 was obtained through an orthoquinone methide Diels−Alder reaction of nonracemic enol ether 700 with compound 701, which were prepared from the identical compound 699 via two different three-step sequences. Reduction of the ketal in 703 followed by oxidative cyclization and further debenzylation delivered (−)-medicarpin (705). Exposure of 703 to BF3·Et2O and PhSH led to the thioether 704, which was transformed to the corresponding methyl acetal, followed by oxidative cyclization and debenzylation, affording (−)-sophoracarpan A (706). Starting from racemic sophoracarpan A (706), (±)-kushecarpin A (707) was obtained through the sequence of oxidative dearomatization reaction, selective reduction of the enone within the dienone, and cleavage of the resulting peroxy bond.

Scheme 57. Trotta’s Divergent Total Syntheses of Oridamycins A (650) and B (651)

2.4. The Other Natural Products

Microcladallenes A−C (715−717) share a unique cis-fused 2,9dioxabicyclo[6.4.0]dodecene skeleton possessing a secondary bromide functional group and a (R)-bromoallene appendage. In 2015, Kim and co-workers reported the substrate-controlled asymmetric total syntheses of microcladallenes A−C (715− 717) from a common precursor 710 (Scheme 63).106 The key intermediate 710 was constructed from diene 709, prepared from the known aldehyde 708, through the sequence of RCM reaction, deprotection of the aldehyde, and SmI2-mediated reductive cyclization. Compound 710 was then converted to 711, the common precursor for microcladallenes A (715) and C (717), through a seven-step sequence, including the key bromination reaction via nucleophile-assisting leaving group. Exposure of 711 to TIPS-acetylene under Yamaguchi’s conditions followed by stereoselective L-selectride reduction and removal of the TIPS group afforded propargylic alcohol 712. Trisylation of the hydroxyl group in 712 and subsequent copper-catalyzed anti-SN2′ reaction by exposure to LiCuBr2 delivered microcladallene A (715). Epoxidation of 711 followed by the installation of the β-oriented vicinal cisdichloride functionality gave the desired amide 713, which was

the two targets were derived from the same intermediate 696. The synthesis commenced with constructing the two fragments 689 and 694. (Z)-2-Butene-1,4-diol (687) could be converted to fragment 689 in 10 steps. Another fragment 694 was prepared from L-aspartic acid (690). Coupling of fragments 689 and 694 promoted by EDCI and DMAP followed by RCM reaction generated the 15-membered product 695, which was further converted to the common synthetic precursor 696 through a five-step sequence. Addition of methyl lithium to the ketone in 696, dehydration with Martin sulfurane, and removal of the acetal group yielded amphidinolide P (698), while direct deprotection of the acetal group in 696 furnished amphidinolide O (697). Pterocarpans constitute the second largest family of plantderived isoflavonoids. They share a tetracyclic core comprised of a dihydrobenzofuran or chromane conjoined in cis-fashion with a dihydrobenzopyran. In 2015, Pettus and co-workers AF


Chemical Reviews

Review

Scheme 58. Kuramochi’s Divergent Total Syntheses of Juglorescein (657) and Juglocombins A (658) and B (659)

Scheme 59. Thorson’s Divergent Total Syntheses of Griseusin A (673), 4′-Deacetyl-griseusin A (673), and Griseusin C (671)

further converted to microcladallene C (717) via a five-step sequence identical to that described for 715. Meanwhile, 710 could be readily converted to amide 714 over five steps. Finally, microcladallene B (716) was obtained from 714 following the pathway that is described for 715 and 717. (+)-Trewianin aglycone (726) and (+)-19-hydroxy-sarmentogenin (727) are two cardiotonic steroids carrying oxygenation at the C11- and C19-positions. Nagorny and co-workers have developed a methodology for accessing oxygenated steroids by a tandem copper catalyzed asymmetric Michael addition/aldol cyclization sequence.107 Employing this methodology, they disclosed a divergent total synthesis of these two natural cardenolides (Scheme 64).108 The diketone 718 was converted to enone 719 in three steps. Copper catalyzed

Michael addition of chlorinated ketoester 720 with enone 719 afforded 721. Aldol cyclization of 721 with p-TSA followed by epimerization with NaHMDS provided steroid 722. Reduction of 722 with DIBAL-H followed by quenching with water and formic acid gave the common intermediate 723 in one pot. Selective protection of the primary alcohol in 723 with TIPSCl, oxidation of the secondary alcohol, and hydrogenation delivered 724, an epimer of 725 with opposite configuration at C5. Similarly, 724 could be transformed to (+)-trewianin aglycone (726) in nine steps. Hydrogenation of 723 followed by selective protection of the primary alcohol with TIPSCl and oxidation gave 725, which could be converted to (+)-19hydroxy-sarmentogenin (727) in nine steps. AG


Chemical Reviews

Review

Scheme 60. Ding’s Divergent Total Syntheses of Indoxamycins A (684), C (685), and F (686)

Scheme 61. Lee’s Divergent Total Syntheses of Amphidinolides O (697) and P (698)

Scheme 62. Pettus’s Divergent Total Syntheses of (−)-Medicarpin (705), (−)-Sophoracarpan A (706), and (±)-Kushecarpin A (707)

3. DIVERSITY FROM FRAMEWORK REORGANIZATION OF COMMON INTERMEDIATE 3.1. Alkaloids

3.1.1. Indole Alkaloids. 3.1.1.1. Leuconolam−Leuconoxine−Mersicarpine Indole Alkaloids. The leuconoxine alkaloids, biosynthetically originated from the Aspidosperma subfamily of monoterpene indole alkaloids, has drawn significant attention from the synthetic community during the past few years AH


Chemical Reviews

Review

the leuconoxine alkaloids by using different strategies for constructing the key structural motif. In 2013, Zhu and co-workers reported the first and divergent synthesis of leuconoxine group of alkaloids from a common intermediate 731 by unprecedented oxidation/reduction/ cyclization processes, which allowed the enantioselective total syntheses of eight natural products including (−)-mersicarpine (742), (−)-scholarisine G (105) (or (−)-leuconodine B), (+)-melodinine E (107), (−)-leuconoxine (108), (−)-leuconolam (745), (−)-leuconodine A (743), (+)-leuconodine F (744), and (−)-leuconodine C (747) (Scheme 65).109,110 The common intermediate 731 could be accessible via a series of transformations from the chiral 729, which was readily prepared from β-ketoester 728 followed by the protocol developed by Stoltz and co-workers. Diketone ester 731 was readily converted to mersicarpine (742) through a one-flask protocol involving a reduction/cyclization/oxidation sequence. Hydrogenation of 731 with Pd/C in the presence of Ac2O followed by oxidation with oxygen afforded unstable compound 734, which further gave lactam 735 as a mixture of diastereomers upon the addition of potassium hydroxide. Lactam 735 was smoothly converted to (−)-scholarisine G (105) through hemiaminal formation and subsequent intramolecular aldolization reactions. (−)-Scholarisine G (105) could be readily converted to (+)-melodinine E (107) through mesylation and subsequent DBU-promoted elimination. (+)-Melodinine E (107) could be straightforwardly converted to (−)-leuconoxine (108), (−)-leuconolam (475), (−)-leuconodine A (743), (+)-leuconodine F (744), and (−)-leuconodine C (747). A highly diastereoselective hydrogenation of (+)-melodinine E (107) furnished (−)-leuconoxine (108). In a reverse biomimetic fashion, treatment of (+)-melodinine E (107) with acid resulted in an equilibrium process through the formation of N-acyliminium ion intermediate 737, which subsequently underwent intermolecular addition of water to generate (−)-leuconolam (745). In addition, reaction of (+)-melodinine E (107) with copper(II) 2-ethyl hexanoate in the presence of TFA provided 739 as a mixture of two diastereomers, which could be directly converted to (−)-leuconodine A (743) upon the addition of NaHCO3. Further oxidation of the secondary alcohol provided (−)-leuconodine F (744). Moreover, treatment of (+)-melodinine E (107) with PIFA and AgOTf led to 740, which subsequently underwent dearomatization and rearomatization to afford the desired 746. Finally, removal of trifluoroacetyl group of 746 as well as hydrogenation of the double bonds delivered (−)-leuconodine C (747). This simple synthetic strategy is truly impressive for the protecting-group-free synthesis of structurally complex and diverse alkaloids under such operationally simple conditions. In 2014, Dai and co-workers developed the racemic divergent total syntheses of six leuconolam−leuconoxine−mersicarpine indole alkaloids including rhazinilam (98), leuconodines B (105) and D (752), leuconoxine (108), mersicarpine (742), and leuconolam (745) inspired by their potential biosynthesis pathways (Scheme 66).111 Azide 749 was readily prepared from commercially available 748 over seven steps. Witkop−Winterfeldt oxidation of indole 749 followed by transannular cyclization afforded the pivotal intermediate 751, which was then diversified into the different natural products by modifying the functional groups of 751. Treatment of crude 751 with PPh3 proceeded smoothly to produce mersicarpine (742) through a Staudinger−aza-Wittig process. Moreover, catalytic

Scheme 63. Kim’s Divergent Total Syntheses of Microcladallenes A−C (715−717)

Scheme 64. Nagorny’s Divergent Total Syntheses of (+)-Trewianin Aglycone (726) and (+)-19-Hydroxysarmentogenin (727)

because of their intriguing structures and interesting biological properties. The groups of Zhu, Dai, and Stoltz and Liang have reported the divergent total syntheses of several members of AI


Chemical Reviews

Review

Scheme 65. Zhu’s Divergent Total Syntheses of Eight Leuconoxine Indole Alkaloids

Scheme 66. Dai’s Divergent Total Syntheses of Six Leuconolam−Leuconoxine−Mersicarpine Indole Alkaloids

hydrogenation of 751 followed by acid-catalyzed cyclization provided Zhu’s intermediate (736), which could be converted to leuconodine B (105), leuconolam (745), rhazinilam (98), and leuconoxine (108) successively. In addition, the first total synthesis of leuconodine D (752) was achieved from leuconoxine (108) by chemoselective reduction of the fivemembered lactam in the presence of the six-membered lactam via methylation with Meerwein’s salt and reduction with NaBH3CN. In 2015, Stoltz and Liang reported the racemic divergent total syntheses of mersicarpine (742), scholarisine G (105), leuconolam (745), melodinine E (107), and leuconoxine (108) from the common diketone 756, which is structurally similar to Zhu’s intermediate 731 (Scheme 67).112 The new approach to three different classes of alkaloids relies on careful control of

the cyclization conditions of the common acyclic 756 in Staudinger reaction. The synthesis commenced with known lactone 753, which could be prepared by palladium-catalyzed asymmetric decarboxylative allylic alkylation in 80% yield and 98% ee. Lactone 753 was converted to azide 754 over four steps. Jones oxidation with concomitant esterification, which was followed by a Sonogashira coupling, gave 755. Rutheniumcatalyzed oxidation of the alkyne triple bond and Boc deprotection using TMSOTf produced the common intermediate 756. Treatment of 756 with PPh3 in a solvent mixture of THF and water provided mersicarpine (742). Interestingly, Staudinger reaction of 756 in the absence of water gave 757 as diastereomeric mixtures, in which the more favorable sixmembered imine was formed by an aza-Wittig reaction followed by aminal formation. Treatment of 757 with NaH AJ


Chemical Reviews

Review

Scheme 67. Stoltz and Liang’s Divergent Total Syntheses of Five Indole Alkaloids

763. Heteroannulation of 763 with bromoacetaldehyde delivered enamine aldehyde 764, which further underwent cyclization followed by dehydration and tautomerization to give tetrahydroindolizine 765. Compound 765 was then converted to (−)-rhazinilam (98) through a reduction/hydrolysis/macrolactamization sequence. Alternatively, heteroannulation of 763 with oxalyl chloride provided dioxopyrrole 766, which served as the common precursor for the syntheses of (−)-leucomidine B (768) and (−)-leucomidine F (744). Compound 766 was transformed to (−)-leucomidine B (768) through a substratedirected highly diastereoselective hydrogenation, while 1,4conjugate addition of methanol to β,γ-unsaturated α-keto amide in 766 followed by trapping of the resulting enol with an excess amount of trimethylsilyldiazomethane afforded 767. Finally, 767 was converted to (−)-leucomidine F (744) through a sequence of saponification of the methyl ester/ hydrogenation of the nitro group/lactamization/transannular cyclization. 3.1.1.2. Kopsifoline alkaloids. Since 2010, the Boger group have reported a divergent total syntheses of four classes of natural products kopsinine (774) (−)-kopsifoline D (777), (−)-deoxoapodine (779), and (+)-fendleridine (70) from a common pentacyclic intermediate 772 by late-stage formation of four different key strategic bonds uniquely embedded in each natural product core structure (Scheme 69).114−116 The common intermediate 772 was efficiently constructed by using the powerful intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazole 769, which formed three rings, four C−C bonds, and five stereogenic centers including three contiguous quaternary centers in a single step. Notably, the methyl ester not only served as a necessary part of the target molecules but play a crucial role in the mentioned cascade cyclization. The asymmetric syntheses of these molecules were based on the optically pure intermediate 772, which was separated by semipreparative chiral column. To achieve the total synthesis of kopsinine (774), (+)-772 was converted to the methyldithiocarbonate 773 over five steps. Subsequent SmI2-mediated radical cyclization followed by kinetic protonation completed the entire skeleton of the target molecule, which was treated by the Lawesson’s reagent and Raney Ni to produce the kopsinine (774). On another hand, intermediate (+)-772 could be converted to compound 775 over seven steps, which served as an advanced common intermediate for (−)-kopsifoline D (777) and (−)-deoxoapodine (779). For the synthesis of (−)-kopsifoline D (777), compound 775 was transformed to iodide 776 in three steps.

generated 758. Acylation of amine 758 followed by intramolecular aldol reaction afforded scholarisine G (105), which was further transformed to leuconoxine (108) through melodinine E (107). Interestingly, the authors observed the unstable intermediate 760, which was treated with acidic conditions to furnish leuconolam (745). In 2016, the Zhu group achieved the enantioselective total synthesis of (−)-rhazinilam (98), (−)-leucomidine B (768), and (+)-leuconodine F (744) from a common intermediate imine 763 (Scheme 68).113 The keto ester 762 was synthesized from the known β-ketoester 761 over eight steps. The one-pot Staudinger reduction/cyclization of 762 provided the key imine Scheme 68. Zhu’s Divergent Total Syntheses of (−)-Rhazinilam (108), (+)-Leuconodine F (744), and (−)-Leucomidine B (768)

AK


Chemical Reviews

Review

Scheme 69. Boger’s Divergent Total Syntheses of Four Kopsifoline Alkaloids

Scheme 70. Qin and Song’s Divergent Total Syntheses of Four Subfamilies of Kopsia Indole Alkaloids

of these alkaloids, namely (−)-isokopsine (789), (−)-kopsine (791), (−)-kopsanone (792), (−)-fruticosine (793), and (+)-methyl chanofruticosinate (794) from an advanced common intermediate 785, which contains the isokopsinetype skeleton (Scheme 70).117 Intermediate 785 was accessed from 782, which was generated from 748 in 12 steps via the following combined protocol. A Cu(II)-catalyzed intramolecular cyclopropanation of 782 gave 783. Removal of the Troc group under Zn/AcOH/EtOH accompanied by opening of cyclopropane ring and subsequent capture of resulting iminium cation by ethoxy group followed by Mannich reaction provided 784. Deprotection of 784 with TFA followed by cyanation and subsequent SmI2-mediated acyloin condensation furnished 785. With the common intermediate 785 in hand, a sequence of hydrolysis, condensation, and radical decarboxylation was performed to afford 787 with the isokopsine skeleton as well as 788 with the kopsine skeleton. Installation of the

Cbz deprotection and subsequent intramolecular ring closure of 776 afforded (−)-kopsifoline D (777). Treatment of 775 with TBAF resulted in removal of the silyl ether, and the subsequent spontaneous oxa-Michael addition yielded tetrahydrofuran 778, which was eventually converted to (−)-deoxoapodine (779). In addition, (+)-fendleridine (70) was also obtained from (−)-772. Treatment of ester (−)-772 with NH3 followed by dehydration provided nitrile 780, which was treated with HFpyridine to form the tetrahydrofuran ring to provide 781 that contains the entire skeleton of (+)-fendleridine (70). Subsequent six steps of transformations of 767 successfully yielded (+)-fendleridine (70). The Kopsia indole alkaloids feature a rigid and cage-like polycyclic skeleton with multiple stereocenters including three quaternary carbon centers, thus their syntheses represent a highly challenging task. In 2017, Qin, Song, and co-workers reported the asymmetric total syntheses of all four subfamilies AL


Chemical Reviews

Review

intermediate ene-yne that is activated by the electronwithdrawing substituent in hand, they conceived a coppercatalyzed 6-endo cyclization to form the common intermediate 803. After Pd-catalyzed hydrogenation without isolation, the intermediate subsequently underwent the vital Diels−Alder reaction with the vinylindole serving as the diene to afford 807 containing the main structure of the aspidosperma, which was readily converted to vincadifformine (10) in four steps. Removal of the protecting group, followed by silyl enolate formation to generate the precursor, Diels−Alder reaction, occurred spontaneously to furnish the andranginine-type scaffold 808. Compound 808 was converted to andranginine (810) in two steps. Treatment of 802 with the copper catalyst under simple heating, a cascade transformation generated the desired catharanthine derivative 809, which was transformed to the catharanthine (795) by a straightforward four-step sequence. 3.1.1.4. Akuammiline Alkaloids. (−)-Aspidophylline A (817), (−)-2(S)-cathafoline (818), and (+)-strictamine (819) belong to the family of akuammiline alkaloids, which is a subset of the monoterpene indole alkaloids. Structurally, they share a common indoline/indolenine fused azabicyclo[3.3.1]nonane system. In 2016, Garg and co-workers have accomplished the total syntheses of these three natural products from the common intermediate 813 (Scheme 73).120 The ketone 812 was readily available from the starting material 811 by virtue of 15 steps. Fischer indolization of ketolactone 812 and phenylhydrazine with TFA provided the key adduct 813. To complete the synthesis of (−)-aspidophylline A (817), saponification of ester 813 delivered the furoindoline 816. Cleavage of the nosyl of 816 and followed by N-formylation provided (−)-aspidophylline A (817). Additionally, treatment of 813 with Et3SiH and TFA afforded 814, which was then transformed to aminochloride 815 through a straightforward seven-step sequence. Chloride 815 was readily converted to (+)-strictamine (819) through PCC oxidation and subsequent deprotection. Alternatively, (−)-2(S)-cathafoline (818) was accessed from 815 by an N-methylation/deprotection sequence. In the same year, the Li group achieved the total syntheses of aspidodasycarpine (827), lonicerine (828), and the proposed structure of lanciferine (830) from the advanced common intermediate 824 (Scheme 74).121 Notably, the pentacyclic lactol 824 contains the entire indoline/indolenine fused azabicyclo[3.3.1]nonane system of target molecules, including the exocyclic olefin and four stereocenters. Compound 822 could be prepared from 820 and 821 over six steps. Aucatalyzed Toste cyclization of 822 in the 6-exo-dig way proceeded smoothly to provide tetracycle 823. Ketone 823 was converted to the pivotal lactol 824 over nine steps. Oxidation of 824 followed by saponification afforded oxofuroindoline 825. AZADO oxidation of 825 delivered the corresponding carboxylic acid, which underwent iodolactonization, transesterification, and the formation of epoxide to give 829. Desulfonation of 829 followed by reductive amination and coupling with cinamic anhydride provided the proposed lanciferine (830). In addition, reductive opening of the lactol 824 and aminal formation in situ provided furoindoline 826, which could be converted to aspidodasycarpine (827) and lonicerine (828) via a sequence of oxidation, methylation, and deprotection. In 2017, the Gao group reported the first asymmetric total syntheses of scholarisine K (841) and alstolactine A (842) from

methoxycarbonate group onto the secondary amine of 787 and 788 delivered (−)-isokopsine (789) and (−)-kopsine (791), respectively. Meanwhile, 788 could be converted to (−)-kopsanone (792) via radical hydroxylation. In addition, cleavage of the C16−C22 bond with Pb(OAc)4 afforded (+)-methyl chanofruticosinate (794). Reduction of isokopsine (789) with NaBH4 followed by cleavage of the C16−C22 bond with Pb(OAc)4 afforded 790, which underwent an intramolecular aldol condensation to provide (−)- fruticosine (793). 3.1.1.3. Iboga-Type Alkaloids. Natural product modification for the preparation of a number of structurally related, biologically active, and less abundant natural products holds significant potential for material access but is also very challenging due to lack of tunable and selective methods. In 2014, Stephenson reported a novel visible-light catalyzed photoredox synthesis of (−)-pseudotabersonine (799), (−)-pseudovincadifformine (800), and (+)-coronaridine (801) from natural product (+)-catharanthine (795), which is abundant and lacks notable bioactivity (Scheme 71).118 Scheme 71. Stephenson’s Divergent Total Syntheses of Three Indole Alkaloids

(+)-Catharanthine (795) could be converted to the common intermediate 796 under visible light irradiation in the presence of an Ir catalyst and trimethylsilylcyanide through an unusual fragmentation of the C16−C21 bond. The efficiency of this transformation was further improved in a flow photochemical reactor with the intention to decrease reaction time, improve scalability, and allow for the safe, controlled generation of HCN. Compound 796 was transformed to (−)-pseudotabersonine (799) and (−)-pseudovincadifformine (800) via a Pictet−Spengler-type reaction under their corresponding conditions, respectively. In addition, hydrogenation of 796 and subsequent treatment with TFA delivered skeleton rearranged (+)-coronaridine (801). In 2014, Oguri and co-workers achieved the efficient and divergent syntheses of three skeletally distinct monoterpenoid indole alkaloids, (±)-vincadifformine (10), (±)-andranginine (810), and (−)-catharanthine (795), by utilizing three distinct types of Diels−Alder reaction to furnish corresponding skeleton structures (Scheme 72).119 With the stabilized AM


Chemical Reviews

Review

Scheme 72. Oguri’s Divergent Total Syntheses of Three Monoterpenoid Indole Alkaloids

Scheme 73. Garg’s Divergent Total Syntheses of Three Akuammiline Alkaloids

Scheme 74. Li’s Divergent Total Syntheses of Aspidodasycarpine (827), Lonicerine (828), and Lanciferine (830)

the advanced common intermediate 839 (Scheme 75).122 The synthesis commenced with the known chiral aldehyde 831, which could be converted to the [3.3.1] bicyclic ring system 832 in a six-step sequence. Subsequent installation of the sixmember lactone onto 832 through a series of transformations

involving an intramolecular alkylation gave ketone 835, which was elaborated to hydro-indole 837 via the interrupted Fischer indolization and base-assisted lactone opening. Sequential oxidation of the primary alcohol 837 to carboxylic acid followed by iodolactonization delivered the iodide 838, which AN


Chemical Reviews

Review

underwent transesterification and epoxide formation under basic conditions to afford the desired common intermediate 839. Removal of the Cbz group and reductive amination provided scholarisine K (841). On the other hand, treatment of 839 with H2SO4 afforded lactone 840, which was readily transformed to alstolactine A (842) via Cbz-deprotection and N-methylation. 3.1.1.5. The Other Indole Alkaloids. In 2017, the Jia group achieved the divergent total syntheses of naucleamides A−C (853−855), E (856), geissoschizine (849), geissoschizol (850), (E)-isositsirikine (851), and 16-epi-(E)-isositsirikine (852) from the common intermediate 847, in which the syntheses of naucleamides A−C (853−855) and E (856) were achieved for the first time (Scheme 76).123 The dienal 844 was generated from crotonic aldehyde 843 in four steps. Asymmetric Michael addition of 844 and 845 catalyzed by 846 followed by acid-promoted Pictet−Spengler cyclization in one pot afforded the desired product 847 as well as other isomers. Deprotection of 847 and in situ intramolecular lactonization gave naucleamide C (853). Reduction of naucleamide C (853) with NaBH4 provided naucleamide A (854) and B (855) as diastereoisomers. A key biomimetic C− H oxidation of 854 with DDQ was developed and used to furnish naucleamide E (856). On the other hand, a ring opening/regeneration strategy provided the known deformyl geissoschizine (848). Reduction of 848 with LiAlH4 yielded geissoschizol (850). Formylation of 848 delivered geissoschizine (849), which was reduced with NaBH4 to give (E)isositsirikine (851) and 16-epi-(E)-isositsirikine (852). Indeed, 847 could serve as the common intermediate for many monoterpenoid indole alkaloids. In 2015, Sarpong described a unified approach to the two subfamilies of prenylated indole alkaloids, which has yielded the first synthesis of (−)-17-hydroxy-citrinalin B (863) as well as syntheses of (+)-stephacidin A (864) and (+)-notoamide I (865) (Scheme 77). 124 (+)-Stephacidin A (864) and (+)-notoamide I (865) possess the bicyclo[2.2.2] diazaoctane moiety, but (−)-17-hydroxycitrinalin B (863) lacks this

Scheme 75. Gao’s Divergent Total Syntheses of Scholarisine K (841) and Alstolactine A (842)

Scheme 76. Jia’s Divergent Total Syntheses of Eight Monoterpenoid Indole Alkaloids

AO


Chemical Reviews

Review

B (863). In addition, chemoselective carbamoylation of the primary amine of 859 followed by DMP oxidation of the hydroxyl group and treatment of the resulting ketone with K2CO3 resulted in Dieckmann-type condensation to afford the desired bicyclo [2.2.2]diazaoctane 862. Finally, removal of the ketone group in the pyrrolidine ring using a Wolff−Kishner protocol followed by reduction of the chromanone carbonyl group and elimination of the resulting hydroxyl group yielded (+)-stephacidin A (864). Oxidation of (+)-stephacidin A with MnO2 delivered (+)-notoamide I (865). In 2016, the Li group reported the total syntheses of four prenylated indole alkaloids (+)-notoamides F (877), I (865), R (876), and (−)-sclerotiamide (879), in which the total syntheses of 876, 877, and 879 were achieved for the first time (Scheme 78).125 The synthesis features an oxidative azaPrins cyclization to construct the bicyclo-[2.2.2]diazaoctane in a highly stereoselective manner, and a cobalt-catalyzed radical cycloisomerization to generate the cyclohexenyl ring. The known 866 was converted to dipeptide 867 in a four-step sequence. Subsequent Fe(III)-mediated stereoselective oxidative aza-Prins cyclization of 867 gave 869, which reacted with Grignard reagent derived from 870 with iPrMgCl to produce ketone 871. Cobalt-catalyzed radical cycloisomerization of 871 followed by oxidation with DMP provided 873. Removal of the benzyl group of 873, followed by Cu-catalyzed propargylation, afforded ether 875, which underwent allenyl Claisen rearrangement, as well as simultaneous deprotection delivered (+)-notoamide I (865). Further reduction of 865 provided (+)-notoamide R (876), which was readily converted to (+)-notoamide F (877) and (−)-sclerotiamide (879) via methylation and oxidative rearrangement, respectively. 3.1.2. Lycopodium Alkaloids. In 2013, the Lei group reported the collective total synthesis of Lycopodium alkaloids (−)-8-deoxyserratinine (888), (+)-fawcettimine (20), (+)-fawcettidine (889), (+)-alopecuridine (891), and (−)-lycojapodine A (892) from a common precursor 883, which has been used for the total synthesis of 888, 20, and 889,126 inspired by the proposed biosynthesis of the fawcettimine- and serratinine-type alkaloids (Scheme 79).127 The known enone 317 was

Scheme 77. Sarpong’s Divergent Total Syntheses of Three Prenylated Indole Alkaloids

structure moiety. Key to the success of this approach was the identification of a late-stage common intermediate 859, which bears a functionalized fused hexecyclic framework. To complete the synthesis of (−)-17-hydroxy-citrinalin B (863), oxidation of 859 using oxone resulted in the remarkably diastereoselective spiro-oxindole formation as well as the chemoselective oxidation of an amino group to a nitro group to provide 861. Chemoselective reductive removal of the tertiary amide carbonyl group of 861 smoothly delivered 17-hydroxycitrinalin

Scheme 78. Li’s Divergent Total Syntheses of (+)-Notoamides F (877), I (865), R (876), and (−)-Sclerotiamide (879)

AP


Chemical Reviews

Review

Scheme 79. Lei’s Divergent Total Syntheses of Five Lycopodium Alkaloids

Scheme 80. Tu and Wang’s Divergent Total Syntheses of Four Lycopodium Alkaloids

converted to dione 882 in a five-step procedure. Intramolecular C-alkylation of dione 882 provided spirocycle 883, which could be converted to these target molecules in two similar paths. Reduction, dihydroxylation, and sodium periodate cleavage of 883 afforded aldehyde 884, which was converted to diol 885 by using SmI2-mediated pinacol coupling that has been employed by Tu.128 Ley-oxidation of diol 885 afforded diketone 886, which could be transformed to teracycle 887 via removal of Boc group and displacement of the tertiary alcohol. Diketone 887 could be converted to 8-deoxyserratinine (888) through selective reduction. Alternatively, SmI2-mediated reductive cleavage of the C4−N bond in 887 followed by cyclization gave fawcettimine (20). Harsher reductive conditions cleaved the C4−N bond and eliminated water in one pot to yield fawcettidine (889). Similarly, 883 could be converted to 890. Removal of the Boc group of 890 with TFA successfully afforded (+)-alopecuridine (891). Finally, an unprecedented DMP/TFA-mediated tandem oxidation of 891 led to (−)-lycojapodine A (892) through a novel tautomer locking strategy. Tu and Wang have reported the total synthesis of fawcettimine-type Lycopodium alkaloids utilizing the Heathcock disconnection strategy. In 2013, they accomplished the total syntheses of four fawcettimine-type Lycopodium alkaloids,

(−)-lycojaponicumin C (901), (−)-8-deoxyserratinine (888), (+)-fawcettimine (20), and (+)-fawcettidine (889) by virtue of a versatile common intermediate 898 (Scheme 80).129 It is noteworthy that 898 is characterized with a 6/5/5 tricyclic system, which is different from the 6/5/9 tricycle of the Heathcock-inspired strategies. This key tricycle 898 was assembled from the carbene addition/cyclization, decarboxylation, and functionalization of 897, which could be prepared through Mukaiyama−Michael addition from known enone 893 and vinyl diazoacetate 894. Removal of the ketal of 898 delivered 899. Intramolecular Schmidt reaction of 899 followed by chemoselective reduction of the amide with Lawesson’s reagent and Raney nickel give tetracycle 887. Given that there are six possible sites for nitrogen insertion in this challenging intramolecular Schmidt reaction, it is particularly impressive that it yielded the desired product along with only one minor byproduct. Tetracycle 887 served as another common intermediate. Regioselective reduction of 887 with NaBH4 afforded (−)-8-deoxyserratinine (888). Treatment of 887 with Zn/AcOH delivered (+)-fawcettidine (889). Alternatively, a SmI2-mediated selective C−N cleavage of 887 followed by aza-ketalization afforded (+)-fawcettimine (20). Finally, azaWittig reaction of 898 followed by selective reduction with NaBH3CN, removal of the glycol, and protection of the AQ


Chemical Reviews

Review

Scheme 81. Taniguchi’s Divergent Total Syntheses of Three Lycopodium Alkaloids

Scheme 82. Zhao’s Divergent Total Syntheses of Three Lycopodium Alkaloids

resulting amine provided tetracycle 900. Installation of the enone, removal of the Cbz protecting group, and methylation of the resulting amine produced (−)-lycojaponicumin C (901). This synthesis demonstrates the remarkable impact of creative retrosynthetic strategy on natural product synthesis. In 2013, the Taniguchi group achieved the total syntheses of lycopoclavamine B (910), lycoposerramine T (911). and serratine (912) in racemic form from an advanced common Heathcock-like tricycle 905, which bears the 6/5/9 tricyclic ring (Scheme 81).130 The key tricycle 905 was constructed by an efficient Diels−Alder reaction of diene 902 with alphaalkynylcyclopentenone 903 and the stereoselective introduction of a tertiary hydroxyl group. Treatment of 905 with m-CPBA afforded two epoxide diastereomers 906 and 907, which can be separated and used in a divergent synthesis of the aforementioned natural products. Removal of the Ns group of the major diastereomer 907 accompanied by in situ intramolecular nucleophilic attack of the epoxide provided alcohol 909, which was subsequently oxidized with IBX and hydrolyzed with KOH to afford serratine (912). Additionally, acid-mediated ring opening of epoxide 906 accompanied by elimination and protection of the resulting amine afforded 908, which could be converted to lycoposerramine T (911) via oxidation followed by deprotection. 908 was also converted to lycopoclavamine B (910) by a sequence of saponification, oxidation, and removal of the Boc group accompanied by aminoketalization.

In 2013, Zhao accomplished the total syntheses of (−)-lycopladine D (921), (+)-fawcettidine (889), and (+)-lycoposerramine Q (920) in a divergent approach from a common intermediate 914 (Scheme 82).131 The stereochemistry at C-4 and C-5 was modulated by changing the sequence of the formation of azonane and the hydroboration oxidation of the double bond at C-4 and C-5. It is noteworthy that the stereochemistry at C-4, C-5, and C-15 of (−)-lycopladine D (921) is different from that of other (+)-fawcettimine (20) class members. The key intermediate 914 was assembled from a Hajos−Parrish-like diketone 913 by a five-step sequence. To achieve the total syntheses of (+)-lycoposerramine Q (920) and (+)-fawcettidine (889), successive hydroboration of 914 with 9-BBN and a BH3-THF complex and subsequent oxidation by NaBO4 followed by the formation of azonane afforded 915, which could be converted to 916 in three steps. Reduction of 916 followed by treatment with oxalic acid in AcOH gave (+)-lycoposerramine Q (920). Further oxidation of (+)-lycoposerramine Q (920) afforded (+)-fawcettidine (889). To achieve the total synthesis of (−)-lycopladine D (921), selective hydroboration of terminal olefin of 914 with 9-BBN followed by oxidation with NaBO4 afforded primary alcohol, which was transformed into azonane ring 917 by a modified intramolecular Mitsunobu reaction. Olefin 917 could be converted to 918 through the second hydroboration oxidation, removal of the ketal, and silylation. The stereochemistry of 918 at C-4 and C-5 was opposite to AR


Chemical Reviews

Review

that of 915 due to the steric hindrance of the azonane ring of 915. Ketone 918 was subjected to Tf2O and subsequent Pdcatalyzed carbonylation to provide ester 919, which was converted to (−)-lycopladine D (921) via an allylic oxidation with in situ oxidation, hydrogenation, detosylation, and biomimetic aminoketalization. In 2013, the Mukai group reported the total syntheses of four fawcettimine-related Lycopodium alkaloids, fawcettimine (20), fawcettidine (889), lycoposerramine Q (920), and lycoflexine (21) from a similar common Heathcock-like tricycle 18 (Scheme 83).132 However, this synthesis was achieved in a

Scheme 84. Dai’s Divergent Total Syntheses of Lyconadins A (934) and C (935)

Scheme 83. Mukai’s Divergent Total Syntheses of Four Lycopodium Alkaloids

similar protocol employed in lyconadin A (934) synthesis, ketone 932 was readily converted to lyconadin C (935). The lycodine-type alkaloids are a subset of the Lycopodium alkaloids containing a common bicycle[3.3.1]none core structure attached with two piperidine rings at different oxidation states. (−)-Lycodine (942) and (+)-flabellidine (943) belong to lycodine-type alkaloids and have different oxidation states at the right-hand piperidine ring. In 2014, Takayama achieved the asymmetric total synthesis of 942 and 943 from an advanced common intermediate 941 (Scheme 85).134 Inspired by the biogenesis of Lycopodium alkaloids, a distinct strategy for the construction of the tetracyclic lycodine racemic fashion. The common intermediate 21 was prepared by the Pauson−Khand reaction of dienyne 924 followed by chemical manipulations of the bicyclic compound. Removal of the Ns group of 18 followed by a Mannich reaction led to lycoflexine (21). The fawcettimine (20) was obtained by removal of the Ns group. Elimination of the hydroxyl group of fawcettimine (20) provided fawcettidine (889). Reduction of ketone 889 and inversion of the stereochemistry of the resulting hydroxyl group afforded lycoposerramine Q (920). In 2014, Dai and co-workers also achieved the total synthesis of lyconadins A (934) and C (935) from the common intermediate 928 (Scheme 84).133 Ketone 928 was prepared from the commercially available enone 317 in four steps. Reductive amination of 928 and subsequent addition of HCl and HCHO successfully delivered the desired cage-like ketone 929, which was formed supposedly through a concerted aza-[4 + 2] cyclization or a stepwise Mannich/aza-Michael process instead of an aza-Michael/Mannich process. Ketone 929 was further converted to the known unsaturated ketone 931 in a three-step sequence involving Lebel-modified Witting procedure, allylic oxidation, and Dess−Martin oxidation. Finally, ketone 931 was transformed to lyconadin A (934) following the Fukuyama−Yokoshima pyridone synthesis protocol. Likewise, ketone 928 could be converted to 930 in three steps. Amine 930 would undergo a tandem ketal removal/Mannich reaction to furnish tricyclic ketone 932. Finally, following the

Scheme 85. Takayama’s Divergent Total Syntheses of (+)-Flabellidine (942) and (−)-Lycodine (943)

AS


Chemical Reviews

Review

could be applied to the synthesis of all such 7-membered-ring containing Lycopodium alkaloids. The common intermediate 950 was prepared from cyclohexenone 317 in five steps. For the total synthesis of (+)-fastigiatine (965), intermediate 950 was converted to β-ketoester 951 through five transformations. Staudinger reduction of 951 with PPh3 followed by treatment with HCl resulted in a formal [3 + 3]-cycloaddition to give tetracycle 953 as a single diastereomer. Alkylation of 953 with MeI followed by the addition of PhSH afforded corresponding N-methylamine. Heating the resultant compound in trifluoroethanol (TFE) provided 954, presumably via a sequence of retro-aldol reaction, formation of iminium ion, and biomimetic transannular Mannich reaction. Finally, removal of the tertbutyloxycarbonyl group in 954 followed by acylation furnished (+)-fastigiatine (965). Likewise, 950 was readily converted to 955−957, which served as common intermediates for the construction of another five natural products. For the total synthesis of (−)-himeradine A (966), treatment of 955 with Barton’s base induced 7-endo-trig intramolecular cyclization followed by deprotection with PhSH and in situ condensation provided imine 958. Staudinger reduction of 958 and subsequent acylation gave pentacyclic core 961, which was then converted to 962 over six steps through modification of the side chain. Finally, treatment of 962 with TFA smoothly furnished (−)-himeradine A (966). Similarly, 956 and 957 was transformed to 959 and 960, respectively. Treatment of 959 with TFA to remove the tert-butyloxycarbonyl group with concomitant decarboxylation and subsequent exposure to HCl generated the tetracycle core 964. Removal of benzyl group, substitution of the hydroxyl group with bromide, and alkylation resulted in (−)-dehydrolycopecurine (967). Additional diastereoselective reduction yielded the (−)-lycopecurine (968). Chemselective reduction of imine 960, removal of tertbutyloxycarbonyl group, followed by construction of the C− N bond afforded amine 963. Finally, heating 963 in NH3/ MeOH solution afforded (+)-lyconadin B (969). During the conversion of 963 to (+)-lyconadin B (969), a trace amount of (+)-lyconadin A (934) was observed, which was presumably formed via autoxidation. Thus, heating neat lyconadin B (969) at 160 °C under an atmosphere of air delivered (+)-lyconadin A (934). In 2017, the Fan group achieved the divergent total syntheses of eight Lycopodium alkaloids and four unnatural C12 epimers in racemic form, using natural product lycodoline (974) as the common intermediate (Scheme 88).137 The readily available 970 was converted to [3.3.1] bridge ring 971 in six steps. A novel Pd-catalyzed oxidative dehydrogenation/hetero-Michael cascade reaction was subsequently developed, which enabled the synthesis of the bridgehead acetate-functionalized [3.3.1] bicyclic ring system 972 from 971. Afterward, reductive amination of hemiacetal 972 afforded tricyclic product 973, which was subsequently converted to lycodoline (974) according the Heathcock’s protocol including Oppenauer oxidation, aldol condensation, and hydrogenation. N-Oxidation of 974 using m-CPBA produced obscurumine A (975). The kinetically favored α-hydroxylation of 974 delivered serratezomine (976). Swern oxidation of 976 led to huperzine O (977). The thermodynamically controlled α-hydroxylation of 974 yielded lycoposerramine G (981), which could be converted to miyoshianine A (982) by treatment with H2O2. A bioinspired fragmentation/Mannich cyclization cascade reaction of 982 delivered lycojaponicumin D (986), transforming the 6/6/6/6 fused ring system of lycodoline (974) to the 5/7/6/6

skeleton from a linear precursor has been developed via a highly efficient cascade cyclization including a 1,4-conjugate addition, isomerization of double bond, and a Mannich-like reaction. The linear precursor 938 was prepared from 937 by a straightforward five-step sequence, which was synthesized from 936 through a diastereoselective Hosomi−Sakurai allylation. Upon treatment of 938 with (+)-CSA, the tetracyclic core structure was obtained. Debenzylation and simultaneous Boc protection followed by removal of Boc group gave the advanced common intermediate 941, which was chemoselectively acetylated to provide (+)-flabellidine (942). Meanwhile, selective oxidation of 941 with IBX delivered (−)-lycodine (943). In 2014, Zhai and co-workers developed a unified strategy for the total syntheses of fawcettimine (20), lycoflexine (21), and lycoflexine N-oxide (948) from an advanced common intermediate 18 (Scheme 86).135 This key Heathcock-type Scheme 86. Zhai’s Divergent Total Syntheses of Fawcettimine (20), Lycoflexine (21), and Lycoflexine NOxide (948)

tricycle 18 was available from enone 317, which was converted to 944 over three steps. Diels−Alder reaction of 944 with 1,3butadiene under microwave conditions gave diketone 945, which was transformed to dimesylate 946 over six steps. Double N-alkylation followed by removal of both MOM groups and oxidation furnished 18. Upon exposure to PhSH, 18 was smoothly converted to fawcettimine (20) through desulfonation/aminal formation and after spontaneous epimerization of the C4 stereocenter to the thermodynamically favored diastereomer. Alternatively, tricycle 18 could be transformed to lycoflexine (21) by a one-pot desulfonation/Mannich reaction. Subsequent oxidation of lycoflexine (21) smoothly afforded lycoflexine N-oxide (948). A unique subset of the Lycopodium alkaloids bearing a 7membered ring is structurally distinct from other members of the Lycopodium alkaloid family. Biosynthetically, they are derived from a common biosynthetic precursor. Inspired by their biosynthetic pathway, in 2014, Shair reported a unified strategy for the synthesis of this subclass of natural products and accomplished the first total syntheses of (+)-fastigiatine (965), (−)-lycopecurine (968), (−)-himeradine A (966), and (−)-dehydrolycopecurine (967) as well as the total syntheses of (+)-lyconadins A (934) and B (969) from the common intermediate 950 (Scheme 87).136 Theoretically, this strategy AT


Chemical Reviews

Review

Scheme 87. Shair’s Divergent Total Syntheses of Six Lycopodium Alkaloids

Scheme 88. Fan’s Divergent Total Syntheses of Eight Lycopodium Alkaloids

12-epi-lycodolone N-oxide (988). Similarly, anhydrolycodoline (978) was transformed to 4-hydroxy-12-epi-lycodolone N-oxide (989). Finally, 12-epi-flabelliformine (979) as well as 12-epiflabelliformine N-oxide (980) was obtained successively

tetracyclic framework of lycojaponicumin D (986). Dehydroxylation of 974 provided anhydrolycodoline (978), which was elaborated to 12-epi-lycodoline (987) via a co-mediated Mukaiyama hydration. Subsequent N-oxidation of 987 afforded AU


Chemical Reviews

Review

Scheme 89. Fan’s Divergent Total Syntheses of Palhinines A (1000) and D (999)

through the Mn-mediated Mukaiyama hydration and Noxidation. In 2017, the Fan group reported the first total synthesis of palhinines A (1000) and D (999) based on a common intermediate 995 containing an oxa-azabicyclo[5.2.1]decane with an isoxazolidine moiety (Scheme 89).138 The synthetic work commenced with the known tricyclic compound 991, which could be readily prepared from 990 in eight steps. Compound 991 was then readily converted to aldehyde 992 via a conventional approach. Reductive amination of aldehyde 992 followed by condensation with formaldehyde afforded the unusual nitrone-alkene 994, which was converted to the common intermediate 995 via a microwave-prompted regioand stereoselective intramolecular [3 + 2] cycloaddition. From the common intermediate 995, two target natural products were prepared in a similar protocol. N-Allylation of 995 followed by reductive cleavage of the activated N−O bond provided the desired azonane 997. Inversion of the hydroxyl configuration of 997 by oxidation followed by subsequent chemo- and stereoselective reduction, removal of the ketal, and N-deallylation accompanied by a spontaneous aza-ketalization delivered palhinine D (999). Likewise, compound 996 bearing the N-methyl could be established from 995 according to a similar protocol as described for the synthesis of palhinine D (999). Treatment of 996 with HCl smoothly afforded palhinine A (1000). 3.1.3. The Other Alkaloids. The diterpenoid alkaloids constitute the largest and most complicated group of terpenoid alkaloids featuring polycyclic and cagelike structures. Biogenetically, the atisine-type skeleton serves as the key precursor of a range of more complex diterpenoid alkaloids. The denudatinestype skeleton could be constructed through the formation of the C7−C20 bond from atisine-type skeleton. Subsequent 1,2alkyl shift of denudatines-type skeleton generated the aconitinetype skeleton. Furthermore, formation of C14−C20 bond from the atisine-type skeleton afforded hetidine-type skeleton, which was transformed to the hetisine-type skeleton by the formation of C6−N bond (Scheme 90). Inspired by this biosynthetic pathway, in 2016, Liu, Qin, and co-workers reported a unified approach to construct four different types of skeletons of diterpenoid alkaloids and achieved the total syntheses of two natural products dihydroajaconine (1001) (atisine type) and gymnandine (1002) (denudatine type) from the common intermediate

Scheme 90. Biosynthetic Approach of Several Types of Diterpenoid Alkaloids

1011 (atisine type) (Scheme 91).139 The ketone 1011 was prepared by Corey−Seebach coupling of fragments 1007 and 1008 and an oxidative dearomatization/intramolecular Diels− Alder cycloaddition (IMDA) cascade. The ketone 1011 was then converted to 1013 over six steps. Exposure of oaminobenzamide 1013 to NaNO2 resulted in C−H oxidation to provide aminal 1016 (ajaconine skeleton) and hemiaminal 1017. Treatment of 1016 with [Cp2Zr(H)Cl] gave imine 1018, which was transformed to 1019 (denudatin-type skeleton) through SmI2-mediated azapinacol coupling followed by acetylation. Furthermore, a six-step functional group transformation of 1019 was conducted to provide natural product gymnandine (1002). Likewise, dihydroajaconine (1001) could be obtained from 1017 via a sequence of oxidation and reduction. In addition, similar to analogue 1013, 1012 was also converted to 1014 (ajaconine-subtype skeleton) via the C−H oxidation, which subsequently formed the desired 1015 (hetidine-type skeleton) through the aza-Prins cyclization. In 2013, the Gademann group accomplished the first total syntheses of bubbialine (1028) and virosaine A (1029) utilizing a common intermediate 1024 containing the basic skeleton of 1028 (Scheme 92).140 The commercially available 1,4-cyclohexadiene 1020 was readily converted to the silyl protected aquilegiolide 1021 over 10 steps. Vinylogous Mannich reaction of 1021 and aminol 1022 using triisopropylsilyl triflate as the Lewis acid gave the desired adduct 1023. Removal of Boc followed by treatment of the resulting product with KH2PO4 AV


Chemical Reviews

Review

Scheme 91. Liu and Qin’s Divergent Total Syntheses of Dihydroajaconine (1001) and Gymnandine (1002)

facilitated an intramolecular aza-Michael addition to furnish tetracycle 1024. Treatment of 1024 with HF·pyridine afforded bubbialine (1028). The common intermediate 1024 could also be converted to the N-hydroxypyrrolidine 1026 via a selective N-oxidation followed by Cope elimination. Finally, the formation of nitrone 1027 followed by in situ intramolecular [1,3]-dipolar cycloaddition and subsequent removal of the silyl group afforded virosaine A (1029). Rutaecarpine (1037) and luotonin A (1038) belong to the same family of quinazolinone alkaloids. The distinct structural difference lies in that rutaecarpine (1037) possesses a 5,6membered fused B,C-ring structure, while luotonin A (1038) has a 6,5-membered fused B,C-ring system. In 2016, Cheon accomplished the total syntheses of luotonin A (1038) and rutaecarpine (1037) through controlled cyclization of a common intermediate 1032 (Scheme 93).141 Aldimine 1032 was readily available through the condensation of aniline 1030 and aldehyde 1031. The cyanide-mediated imino-Stetter reaction of aldimine 1032 successfully provided indole 1035, which was converted to rutaecarpine (1037) through reduction of the ester to the corresponding alcohol followed by the formation of a 6-membered C-ring via an intramolecular Mitsunobu reaction. In addition, microwave-promoted thermal

Scheme 92. Gademann’s Divergent Total Syntheses of Bubbialine (1028) and Virosaine A (1029)

Scheme 93. Cheon’s Divergent Total Syntheses of Rutaecarpine (1037) and Luotonin A (1038)

AW


Chemical Reviews

Review

Scheme 94. Li’s Divergent Total Syntheses of Seven Humulanolides

Scheme 95. Baran’s Divergent Total Syntheses of (−)-Methyl Atisenoate (1062) and (−)-Isoatisine (1064)

catalyst afforded the regio- and stereoselective hydrogenated product 6,7,9,10-tetrahydroasteriscunolide (1047), which subsequently underwent DBU-mediated intramolecular Michael addition to provide asteriscanolide (1048). 6,7,9,10-Tetradehydroasteriscanolide (1050) could be prepared from asteriscunolide D (1043) via the MeONa-promoted transannular Morita− Baylis−Hillman reaction followed by BF3·Et2O-mediated elimination. Moreover, irradiation of asteriscunolide D (1043) with a UV lamp generated asteriscunolides A, B, and C (1044−1046) in yields of 46%, 18%, and 18%, respectively. This synthesis represents the first example of the use of an intramolecular ROM−RCM cascade reaction for the construction of a bicyclic skeleton containing an 11-membered ring. 3.2.2. Diterpenoids. In 2014, the Baran group reported the syntheses of (−)-methyl atisenoate (1062), (−)-isoatisine (1064), and the hetidine skeleton (1063) via a unified approach from naturally abundant (−)-steviol (1051) (Scheme 95).143 To pursue 1062, methylation of 1051 followed by Mukaiyama peroxygenation with concomitant cleavage of the C13−16 bond gave diketone 1052. Aldol cyclization of 1052 and subsequent elimination of alcohol furnished 1053. Wolff− Kishner reduction followed by re-esterification afforded (−)-methyl atisenoate (1062). (−)-Steviol could be converted

6π-electrocyclization of 1032 to construct the quinolone scaffold provided 1036. Finally, the formation of a 5-membered C-ring delivered luotonin A (1038). 3.2. Terpenes

3.2.1. Sesquiterpene Lactone. Asteriscunolides A−D (1043−1046), 6,7,9,10-tetradehydroasteriscanolide (1047), asteriscanolide (1048), and 6,7,9,10-tetrahydroasteriscunolide (1050) are members of humulanolides, which structurally belong to the sesquiterpene lactone family. In 2014, Li and coworkers described the collective synthesis of these natural products in only 5−7 steps without the need for protecting groups (Scheme 94).142 Asteriscunolide D (1043) served as the precursor of other target molecules, and it was prepared by using an intramolecular ring-opening/ring-closing metathesis (ROM/RCM) cascade reaction for the construction of the synthetically challenging 11-membered ring. Tetraene 1040, the key ROM/RCM precursor, was synthesized from the readily available 1039 over five steps. Compound 1040 readily underwent the ROM/RCM cascade reaction in the presence of the Hoveyda−Grubbs II catalyst to provide asteriscunolide D (1043). Asteriscunolide D (1043) was then converted to other target molecules via photoinduced isomerization reaction or transannular reaction. Treatment of 1043 with Wilkinson AX


Chemical Reviews

Review

Scheme 96. Liu’s Divergent Total Syntheses of Four Atisane-Type Diterpenoids

Scheme 97. Xu’s Divergent Total Syntheses of Five Atisane-Type Diterpenes and Diterpenoid Alkaloids

to 1054 in a six-step sequence, which served as the common intermediate to access the hetidine skeleton (1063) and (−)-isoatisine (1064). Suárez modification of the Hofmann− Löffer−Freytag (HLF) reaction of 1054 followed by hydrolysis provided iodo-aldehyde 1056 exclusively. Reaction of 1056 with allylamine provided the hetidine skeleton (1063) through a tandem condensation/azomethine ylide isomerization/intramolecular Mannich cyclization. In addition, reduction of the ketone in 1054 provided 1058, which could be readily converted to (−)-isoatisine (1064). In 2015, Liu accomplished the divergent total syntheses of four atisane-type diterpenoids, namely crotobarin (1078), crotogoudin (1079), 16S,17-dihydroxy-atisan-3-one (1080), and atisane-3β,16α-diol (1081) (Scheme 96).144 Inspired by the atisane-type diterpenoids being biogenetically derived from a tricyclic carbocation intermediate, a structure similar to podocarpane-type diterpenoid, they explored the transforma-

tion of the podocarpane-type skeleton to tetracyclic diterpenoids and identified compound 1070 as the common intermediate. For the formation of podocarpane-type skeleton, coupling of 1065 and 1066 provided compound 1067, which underwent an Fe(III)-catalyzed cascade polycyclization and subsequent Ce(II)-mediated oxidative dearomatization provided unmasked ortho-benzoquinone 1068. Diels−Alder reaction of 1068 with trimethylsilylacetylene in the presence of activated MnO2 smoothly delivered tetracyclic diketone 1069. Selective protection of the less hindered carbonyl group in 1069 followed by desilylation afforded the common intermediate 1070. To complete the synthesis of crotobarin (1078), compound 1070 was converted to 1071 over three steps. Selective acetylation of 1071 followed by Baeyer−Villiger oxidation furnished lactone 1072, which was converted to 1073 via an unusual removal-of-ketal/lactone-opening/isopreneformation/second-lactonization cascade reaction. Finally, AY


Chemical Reviews

Review

DMP oxidation of 1073 and subsequent Wittig olefination afforded crotobarin (1078). Additionally, sequential reduction of intermediate 1070 gave diol 1074, which subsequently underwent co-catalyzed hydroxylation accompanied by selective oxidation provided 1075. Following the same sequence for the construction of crotobarin (1078), compound 1075 was readily converted to crotogoudin (1079). In addition, deprotection of the ketal moiety of 1074 and SmI2-mediated dehydroxylation provided ketone 1076, which could be easily transformed to 16S,17-dihydroxy-atisan-3-one (1080) and atisane-3β,16α-diol (1081). In 2016, Xu and co-workers have accomplished the collective total syntheses of several members of the atisane-type diterpenes and biogenetically related atisine-type diterpenoid alkaloids including dihydroajaconine (1090), spiramilactone B (1091), spiraminol (1092), and spiramine C (1093) and D (1094) from a common intermediate 1088 (Scheme 97).145 The synthesis of the pivotal hexacyclic intermediate 1088 was achieved through a unique retro Diels−Alder/intramolecular Diels−Alder cascade sequence, which allowed rapid access to the tricyclo[6.2.2.0] ring system and a diastereoselective Rucatalyzed 1,7-enyne cycloisomerization to construct the highly functionalized tetracyclic atisane skeleton 1085. Dihydroajaconine (1090) could be obtained by reduction and condensation of 1088 followed by NaBH4 reduction of 1089. Meanwhile, inversion of the hydroxyl group configuration in 1088 provided spiramilactone B (1091). DIBAL-H reduction of spiramilactone B (1091) afforded spiraminol (1092), which upon condensation with ethanolamine furnished spiramine C (1093) and D (1094). In 2013, the Reisman group described the first total syntheses of two ent-kauranoid natural products, namely (−)-trichorabdal A (1106) and (−)-longikaurin E (1107) in a divergent approach from a common intermediate 1103 (Scheme 98).146 The synthesis of 1103 commenced with the known lactone 1100, which was an intermediate in the total synthesis of maoecrystal Z by the same group and was prepared from γ-cyclogeraniol (1095) in five steps including a diastereoselective Ti(III)-mediated reductive epoxide coupling reaction and a diastereoselective Sm(II)-mediated reductive cyclization.147 Lactone 1100 was converted to the tricyclic 1101 through desilylation and DMP oxidation of the resulting alcohol, followed by SmI2-mediated reductive cyclization. Protection of alcohol 1101 as the MOM ether followed by deprotonation with KHMDS and trapping with TBSCl delivered silyl ketene acetal 1102, which underwent an intramolecular Pd-catalyzed oxidative cyclization to build the bicyclo[3.2.1]octane framework and generate an all-carbon quaternary center, furnishing the key common intermediate 1103. Ozonolytic cleavage of exo-olefin 1103 followed by αmethylenation provided ketone 1104, which was further converted to (−)-trichorabdal A (1106) via global deprotection and selective oxidation of the primary alcohol. Likewise, global deprotection of 1103, selective oxidation of the primary alcohol, and acetylation of the secondary alcohol provided aldehyde-lactone 1105. SmI2-mediated reductive cyclization of 1105 gave the corresponding lactol, which underwent ozonolysis of the alkene and α-methylenation to deliver (−)-longikaurin E (1107). These syntheses, together with their previous synthesis of (−)-maoecrystal Z, demonstrate that three architecturally distinct ent-kauranoids can be prepared from the common, nonbiomimetic intermediate.

Scheme 98. Reisman’s Divergent Total Syntheses of (−)-Trichorabdal A (1106) and (−)-Longikaurin E (1107)

In 2013, the Nakada group developed a divergent synthetic approach for scabronines, which enabled the enantioselective total syntheses of (−)-episcabronine A (1122), (−)-scabronine A (1121), and G (1120) from a common intermediate 1112 containing a 5/6/7 tricyclic ring framework (Scheme 99).148 The preparation of 1112 started with the known aldehyde 1108, which was converted to allene 1109 in eight steps. Oxidative dearomatization of 1109 followed by an inverse electron demand Diels−Alder reaction gave tricycle 1110, which was then transformed to diol 1111 in five steps. Oxidative cleavage of 1,2-diol 1111 with PIDA followed by ring closing metathesis with Grubbs II catalyst produced 1112. (−)-Scabronine G (1120) was obtained from 1112 through removal of the TBDPS group and sequential oxidation. Compound 1112 was transformed to enone 1113, which served as another common intermediate for (−)-scabronine A (1121) and (−)-episcabronine A (1122). Stereoselective CBS reduction of 1113 followed by desilylation and selective oxidation of the primary hydroxyl group afforded aldehyde 1114. Reaction of 1114 with MeONa resulted in an oxaMichael addition/acetalization cascade reaction to deliver 1115, which was subsequently methylated and hydrolyzed to give (−)-scabronine A (1121). In addition, compound 1113 was converted to aldehyde 1116. Similarly, treatment of 1116 with MeONa followed by acidic methanol provided 1119, which was hydrolyzed to afford (−)-episcabronine A (1122). In 2016, Magauer described the total syntheses of marine diterpenoids (+)-dolabellane V (1128) and (+)-dictyoxetane (1129) by using a [5.6.7] tricyclic ring system framework 1125 as the common intermediate (Scheme 100).149 The synthesis commenced with installation of two side chains on 1123 through a six-step sequence. The metathesis reaction of diene AZ


Chemical Reviews

Review

Scheme 99. Nakada’s Divergent Total Syntheses of Three Diterpenoids

has the characteristic 5/7/6/3 tetracyclic skeleton (Scheme 101).150−152 Enone 1132 was synthesized via the Rh-catalyzed Pauson−Khand cyclization of 1131, which could be readily prepared from the commercially available (+)-3-carene (1130) in five steps. Stereoselective addition, dihydroxylation, and subsequent protection with N,N-carbonyldiimidazole (CDI) delivered 1133. Treatment of 1133 with BF3·OEt2 triggered the pivotal vinylogous pinacol rearrangement to afford ingenane 1134 bearing the entire skeleton of (+)-ingenol (1145), which was converted to (+)-ingenol (1145) via late-stage oxidation. In addition, Mukaiyama hydration and a selective oxidation afforded 1136, which underwent dehydrative ring opening to form diene 1137. Second Mukaiyama hydration of 1137 followed by chemoselective oxidation provided diketone 1138, which underwent ring closure of the cyclopropane to give 1142. Finally, installation of two additional oxygen atoms, one methyl group, and the proper C12 and C10 stereochemistry gave the desired (+)-phorbol (1146). It is worth noting that the newest method used in this synthesis is a Stille coupling, invented in the 1980s. Thus, this synthesis emphasizes the equal importance of strategy design with the development of new synthetic methodologies for the total synthesis of complex natural products.

Scheme 100. Magauer’s Divergent Total Syntheses of (+)-Dolabellane V (1128) and (+)-Dictyoxetane (1129)

1124 with the Stewart−Grubbs catalyst smoothly provided 1125. With 1125 in hand, formation of silyl ether, followed by photomediated oxidation, delivered the allylic alcohol 1126. Mesylation of alcohol 1126 followed by treatment with NaH afforded the oxetane 1127 via the 4-exotet cyclization. Finally, treatment of 1127 with NIS resulted in concomitant trimethylsilyl ether deprotection and the 5-exo-trig cyclization to form the trans-tetrahydrofuran, which upon hydrogenolysis led to simultaneous dehalogenation of the primary iodide and cleavage of the benzyl ether, providing (+)-dictyoxetane (1129). Moreover, treatment of 1125 with Tf2O and 2,6lutidine initiated Grob fragmentation to furnish the 11membered macrocycle, which underwent deprotection of benzyl group with DDQ to afford (+)-dolabellane V (1128). The Baran group achieved the total syntheses of two highly challenging diterpenoids, namely (+)-ingenol (1145) and (+)-phorbol (1146), from a common intermediate 1132 that

3.3. Polyketides

Periconiasins A−E (1155−1159) belong to the family of polyketide-amino acid hybrid metabolites, and they are biogenetically originated from a common intermediate. Inspired by their biosynthetic pathway, in 2016, Tang, Liu, and co-workers developed a unified synthetic strategy to achieve the first total syntheses of periconiasins A−E (1155− 1159) from the common intermediate 1154 (Scheme 102).153 The linear polyketide−amino acid hybrid precursor 1152 was assembled from 1148 and 1149 through a tandem aldol condensation/Grob fragmentation and sequential selenylation and oxidative elimination. Diels−Alder reaction of 1152 provided 1153, which could be converted to 1154 over four steps. Removal of the PMB group from 1154 with DDQ gave periconiasin A (1155), which was then transformed to BA


Chemical Reviews

Review

Scheme 101. Baran’s Divergent Total Syntheses of (+)-Ingenol (1145) and (+)-Phorbol (1146)

Scheme 102. Tang and Liu’s Divergent Total Syntheses of Periconiasins A−E (1155−1159)

periconiasin E (1156) by the proposed biomimetic transannular carbonyl-ene reaction. Additionally, Dess−Martin oxidation of periconiasin A (1155) afforded periconiasin C (1157), which could be converted to periconiasin B (1158) by regio- and diastereoselective reduction of the C17 ketone. Meanwhile, periconiasin B (1158) was subjected to the

reaction conditions employed for the synthesis of periconiasin E (1156), and it resulted in the direct formation of periconiasin D (1159) by tandem transannular carbonyl-ene reaction/ etherification. In 2013, the Tong group reported the divergent total syntheses of five natural products cephalosporolides C and E− BB


Chemical Reviews

Review

G (1164, 1166−1168) and (4-OMe-)G (1165) from cephalosporolide B (1163), a parent natural product within the family (Scheme 103).154 To achieve the synthesis of

Scheme 104. Zhang and Yang’s Divergent Total Syntheses of Three Natural Products

Scheme 103. Tong’s Divergent Total Syntheses of Six Cephalosporolides

formation followed by hydrolysis of benzoylate afforded (+)-brazilide A (1177). In 2015, Tang and co-workers have achieved the first total syntheses of rubialatins A (1185) and B (1186) from a common intermediate 1183 based on a biomimetic approach (Scheme 105).156 The key quinone 1184 was rapidly accessed from 1179 and 1,4-naphthoquinone 1180 through a NaHinduced ring contraction/Michael addition/aldol cascade reaction followed by CAN oxidation. Direct epoxidation of 1184 delivered the desired rubialatin A (1185). Moreover,

cephalosporolide B (1163), rhododendrol (1160) was used as the starting material and was converted to epoxide 1161 in eight steps. Treatment of 1161 with PCC triggered the oxidative ring expansion to furnish ten-membered lactone 1162. Rh-catalyzed deoxygenation of epoxide 1162 followed by desilylation afforded cephalosporolide B (1163). With the common intermediate in hand, a bioinspired intermolecular oxa-Michael addition of 1163 proceeded smoothly to provide 4-OMe-cephalosporolide G (1165) as a single diastereomer. Analogously, cephalosporolide G (1164) was obtained through oxa-Michael addition with BnOH followed by debenzylation. In addition, epoxidation of 1163 followed by SmI2-mediated reductive ring opening of the resulting epoxide gave cephalosporolide C (1166). Treatment of cephalosporolide C (1166) or cephalosporolide G (1164) with TFA realized the biomimetic ring-contraction rearrangement to deliver a 3:1 mixture of cephalosporolide E (1167) and cephalosporolide F (1168). In 2013, Zhang, Yang and co-workers reported the total syntheses of (+)-brazilin (1175), (−)-brazilein (1176), and (+)-brazilide A (1177) from a common intermediate 1172, which has the characteristic 6/5/6/6 tetracyclic framework (Scheme 104).155 Mitsunobu reaction of indene 1169 and 3hydroxyphenol benzoate (1170) and subsequent Sharpless asymmetric dihydroxylation furnished diol 1171, which underwent the intramolecular Friedel−Crafts reaction followed by hydrolysis of benzoylate to afford the common intermediate 1172. Treatment of 1172 with BBr3 furnished (+)-brazilin (1175), which was further oxidized with PhI(OAc)2 to provide (−)-brazilein (1176). Likewise, selective Birch reduction of the aromatic ring bearing two methoxyl groups in 1172, following the formation of benzoate and oxidative cleavage of the electron rich double bond, provided diester 1173. Treatment of 1173 with TBSOTf followed by epoxidation provided epoxide 1174. Finally, BF3·OEt2-mediated oxirane ring opening/lactone

Scheme 105. Tang’s Divergent Total Syntheses of Rubialatins A (1185) and B (1186)

BC


Chemical Reviews

Review

photoirradiation of 1184 afforded rubialatin B (1186) through skeletal rearrangement.

Scheme 108. Jiang’s Divergent Total Syntheses of 14 Aspidosperma Alkaloids

4. DIVERSITY FROM ASSEMBLING DIFFERENT APPENDAGES AND COMMON INTERMEDIATE 4.1. Alkaloids

4.1.1. Indole Alkaloids. 4.1.1.1. Monoterpenoid Indole Alkaloids. Sarpagine alkaloids, a subfamily of monoterpenoid Scheme 106. Gaich’s Divergent Total Syntheses of Three Sarpagine Alkaloids

Scheme 107. Takayama’s Divergent Total Syntheses of Five Sarpagine Related Alkaloids

BD


Chemical Reviews

Review

Scheme 109. Zhu’s Divergent Total Syntheses of (−)-Rhazinilam (98) and (−)-Leucomidine B (768)

Scheme 111. Tang and Wang’s Divergent Total Syntheses of Akuammicine (7) and Strychnine (8)

Scheme 110. Fan’s Divergent Total Syntheses of (+)-Deethylibophyllidine (1236) and (+)-Limaspermidine (69)

1190, followed by deprotection and a ring enlargement reaction, provided the desired tricyclic product 1191. Fischer indole cyclization of 1191 with different phenylhydrazines followed by hydrolysis furnished 1192−1194 eventually. It is worth noting that the present synthesis is concise (eight steps) from known 1187 requires no protecting groups and can be carried out on multigram scale. In 2016, Takayama and co-workers also reported a divergent total synthesis of five sarpagine-related indole alkaloids from common intermediate 1198 (Scheme 107).158 The strategy they used was similar to that of Gaich.157 Azabicyclononane 1195 was transformed into alkynyl silyl enol ether 1196 in six steps. Gold-catalyzed 6-exo-dig cyclization of 1196 furnished tricyclic compound 1197, which was converted to 1198 in four steps. Protection of alcohol 1198 with an acetyl group, Fischer indole annulation of the corresponding ketone with phenylhydrazine 1199, followed by introduction of a hydroxyl group afforded 1200. Birch reduction of 1200 at −78 °C delivered hydroxygardnerine (1202) by removal of benzyl group, while the same reaction at −30 °C gave gardnerine (1201) via further deoxygenation. Direct C−H oxidation of hydroxygardnerine (1202) with DDQ provided hydroxygardnutine (1203). Moreover, Fischer indole annulation of 1198 with 1-benzyl-1phenylhydrazine followed by hydroboration/oxidation furnished 1204. Birch reduction of 1204 at −30 °C gave (E)16-epi-normacusine B (1205). In addition, 1204 could be converted to 1206 in four steps, which gave koumine (1207) by Pd-catalyzed Tsuji−Trost cyclization. The common intermediate and strategy of Gaich and Takayama’s syntheses are similar, and they proved to be convenient and efficient for the collective total synthesis of sarpagines and sarpagine-related indole alkaloids. Using a similar divergent strategy, Jiang and co-workers reported the total syntheses of 14 natural products of Aspidosperma alkaloids in 2017 (Scheme 108).159 Aspidosperma

indole alkaloids, consist of more than 90 congeners. To divergently access a large number of sarpagines from an advanced common intermediate, Gaich identified ketone 1191 as a shared late-stage synthetic intermediate by careful analysis of the common structure pattern of sarpagines. Thus, (+)-vellosimine (1192), (+)-10-methoxyvellosimine (1193), and (+)-N-methylvellosimine (1194) were prepared from ketone 1191 in one step by Fischer indolization of the corresponding phenylhydrazines with different substitution patterns (Scheme 106).157 The synthesis of 1191 commenced with [5 + 2] cyclization of chiral ketene 1187 and oxidopyridinium 1188, which afforded bicyclic enone 1189. Enone 1189 was transformed into tricycle 1190 through an intramolecular Pd-catalyzed enolate coupling. Wittig reaction of BE


Chemical Reviews

Review

Scheme 112. Qin’s Collective Total Syntheses of Four Families of Monoterpenoid Indole Alkaloids

alkaloids such as (+)-dehydrodeacetyl-pyrifolidine (1217), (+)-dehydrodeacetyl-aspidospermine (1218), and (+)-dehydroaspidospermidine (1219) possess a similar skeleton and different substitutions at the phenyl ring. They achieved the diversity by using Fischer indolization of the common tricyclic ketone 1213 with different phenylhydrazines at late stage. [4 + 2] cycloaddition of 1208 and 1209 generated lactone 1210, which was converted to ketone 1213 over eight steps on gram scales. Fischer indolization of 1213 with phenylhydrazines 1214, 1215, and 1216 afforded (+)-dehydrodeacetylpyrifolidine (1217), (+)-dehydrodeacetylaspidospermine (1218), and

(+)-dehydroaspidospermidine (1219), respectively. These three alkaloids were readily converted into the other 11 Aspidosperma alkaloids. Monoacid 1222, a ten-carbon synthon with an all-carbon stereogenic center, could be regarded as an equivalent of the monoterpene unit and used as a key starting material for the synthesis of monoterpene indole alkaloids. In 2014, the Zhu group reported a phosphoric acid-catalyzed desymmetrization of bicyclic bislactone to synthesize 1222 and applied it to the divergent total syntheses of (−)-rhazinilam (98) and (−)-leucomidine B (768) (Scheme 109).160 After many BF


Chemical Reviews

Review

Scheme 113. Li’s Divergent Total Syntheses of Drimentines A (1295), G (1294), F (1297), and Indotertine A (1298)

attempts, they chose 1220 as starting material and 1221 as organocatalyst for desymmetrization to give monoacid 1222, which was converted into cyclic imine 1223 in seven steps. It is worth noting that both 1223 and ent-1223 could be achieved by chemoselective reduction of acid or ester group. Employing cyclic imine 1223 as the common intermediate, (−)-rhazinilam (98) and (−)-leucomidine B (768) were obtained. Coupling 1223 with partner 1224 followed by oxidation with Ag2CO3 afforded 1226, which underwent a three-step sequence to furnish (−)-rhazinilam (98). Mannich condensation of 1223 and partner 1227 followed by transamidation provided 1228. Hydrogenation of 1228 followed by indole cyclization delivered (−)-leucomidine B (768). (+)-Deethylibophyllidine (1236) and (+)-limaspermidine (69) possess a common densely functionalized hydrocarbazole scaffold with an all-carbon quaternary stereocenter at C4a, which could be one of the key challenges in their asymmetric synthesis. In 2015, Fan’s group reported a divergent synthesis of 1236 and 69 from the common intermediate 1233 (Scheme 110).161 Enone 1232 was synthesized by a Takemoto-type

Scheme 114. Jia’s Divergent Total Syntheses of Decursivine (1304) and Serotobenine (1307)

Scheme 115. Garg’s Divergent Total Syntheses of C7-Substituted Indolactam Alkaloids

BG


Chemical Reviews

Review

followed by intramolecular aldol condensation with PTSA provided enone 1234, which could be hydrogenated and deprotected to furnish 1235. Reduction of ketone to methene and lactam to amine followed by introducing the methyl ester finally yielded (+)-deethylibophyllidine (1236). Divergently, Pd-catalyzed anti-Markovnikov oxidation of the allylic group in 1233 followed by an aldol condensation to form the 6membered ring afforded 1237, which could be converted to (+)-limaspermidine (69) over 10 steps. There is another example that a novel methodology could provide new strategy for the total synthesis of natural products. In 2017, Tang, Wang, and co-workers reported a ligandpromoted catalytic [4 + 2] annulation of indole derivatives and cyclobutanes for the synthesis of versatile cyclohexa-fused indolines with excellent diastereoselectivity.162 This novel synthetic method is applied for the total syntheses of akuammicine (7) and strychnine (8) from the common intermediate 1244 (Scheme 111). Thus, annulation of 1238 and cyclobutane 1239 in the presence of Cu(PF6)2 and 1240 provided tricyclic compound 1241, which was then converted into tetracyclic compound 1244 over seven steps. Deprotection of 1244 followed by N-alkylation with 1245 afforded 1247, which underwent an intramolecular Heck reaction to give akuammicine (7). Similarly, removal of Boc group followed by coupling with 1246 yielded 1248, an intermediated for the synthesis of strychnine (8) according to reference.163 In 2017, the Qin group reported the collective syntheses of 33 monoterpenoid indole alkaloids belonging to four families by employing their newly developed Ts-protected aniline nitrogen radical cascade process. The major diastereoisomers achieved by their synthesis are shown in Scheme 112.164 Starting from aldehyde 1249, deprotonation followed by photocatalyzed oxidation in the presence of Ir(dtbbpy)(ppy)2PF6 yielded N-radical intermediate 1250, which underwent a cascade radical addition through intermediate 1251 to provide 1252 as a common intermediate for six members of the eburnamine−vincamine family along with a minor isomer (Scheme 112A). 1252 was transformed into 1253 by protection of aldehyde, removal of Ts group, and oxidation aromatization. Lactam 1253 was reduced and deprotected to afford (+)-eburnamenine (1254). Hydrolysis of 1254 gave (−)-eburnamine (1255) and (+)-isoeburnamine (1256) as isomers. Further oxidation of 1255 and 1256 furnished (+)-eburnamonine (1257). Moreover, (−)-vincamine (1258) and (−)-vallesamidine (1259) were generated from the common intermediate 1252 in several steps. Subsequently, an intramolecular radical addition of substrate 1260 with MVK followed by Aldol cyclization sequence furnished 1261 as the major diastereoisomer along with other minor isomers, which bore the core skeleton of the family of yohimbine alkaloids (Scheme 112B). Finally, 11 alkaloids were generated from 1261 and its isomers. Similarly, nine members of the corynanthe family and 11 members of the heteroyohimbine family of alkaloids were achieved by radical coupling of benzyl acrylate with 1271 and 1276, respectively (Scheme 112C,D). 4.1.1.2. The Other Indole Alkaloids. The drimentines belong to the subclass of pyrroloindoline alkaloids that possess the pyrroloindoline core and aliphatic groups at the C3 position. The difference among drimentines A (1295), G (1294), and F (1297) lies in the diketopiperazine motif, consisting of a valine or leucine unit. In 2013, Li and co-workers disclosed the collective synthesis of drimentines A (1295), G (1294), F (1297), and indotertine A (1298), a biosynthetically relevant

Scheme 116. Movassaghi’s Divergent Total Syntheses of Three Dimeric Cyclotryptamine Alkaloids

Scheme 117. Li’s Divergent Total Syntheses of Aflavazole (1344) and 14-Hydroxyaflavinine (1340)

thiourea-amine catalyzed desymmetrization of spirocyclic paradienoneimide 1229 followed by tandem aminolysis/azaMichael addition. Treatment of 1232 with NaOH resulted in aza-Michael addition to afford 1233. Ozonolysis of 1233 BH


Chemical Reviews

Review

Scheme 118. Knölker’s Divergent Total Syntheses of Murrafolines A (1355), B (1358), C (1353), and D (1361)

alkaloid (Scheme 113).165 Starting from (+)-scareolide (1283), 1284 was generated by reduction with DIBAL-H, Suárez cleavage and hydrolysis. Treatment of 1284 with SOCl2 followed by ozonolysis gave 1285. Coupling of 1285 and cyclotryptophan 1287 by a photocatalyzed conjugate addition followed by deprotection afforded 1288 as the common intermediate. Coupling of 1288 with Boc-N-Me-L-valine 1291 provided 1296, which could be converted to drimentine F (1297) through formation of diketopiperazine ring and the transformation of ketone group into methene. Similarly, drimentines A (1295) and G (1294) were obtained from 1288 and corresponding Boc-L-leucine 1290 and Boc-L-valine 1289, respectively. Finally, exposure of 1297 to Bi(OTf)3 yielded indotertine A (1298). In 2014, the Jia group reported the second-generation synthesis of decursivine (1304) and serotobenine (1307) as well as its analogues in a divergent manner (Scheme 114).166 Compared with the previous parallel strategy, a late-stage arylation via an unprecedented Pd-catalyzed C−H activation/ oxidation sequence to form the furan ring was developed and applied to achieve the diversity and efficiency. The common tricyclic intermediate 1301 was generated by coupling of commercially available 5-hydroxy-tryptamine 1300 with 2,2dichloropropionic acid 1299 followed by Wiktop photocyclization/elimination sequence. Reaction of 1301 with aryl

iodide 1302 in the presence of Pd(OAc)2 gave tetracycle 1303, which was reduced with Sm and I2 to furnish decursivine (1304). Similarly, the concise total synthesis of serotobenine (1307) was accomplished from 1301 in three steps. Thus, the total synthesis of decursivine (1304) and serotobenine (1307) was achieved in only four and five steps from commercially available starting material, respectively, which represents the shortest route to these alkaloids. Indolactam V (1312) and C7-substituted indolactam alkaloids, such as (−)-pendolmycin (1316), (−)-lyngbyatoxin A (1320), and (−)-teleocidin A-2 (1321), have been widely studied because of their bioactivities. Structurally, they possess a common indole and 9-membered ring core and have different substitutes at the C7 position. Therefore, it is possible to achieve the total synthesis of these natural products by latestage introduction of the challenging C7 substitutions. In 2014, the Garg group achieved the divergent synthesis of targeted alkaloids through the common intermediate 1313 (Scheme 115).167 Indolyne precursor 1309 was generated from 1308 in seven steps. Exposure of 1309 to CsF and trapping of the resulting indolyne by amine 1310 afforded 1311, which was transformed to indolactam V (1312) in six steps. Protection of alcohol 1312 and bromination at C7 position afforded 1313. Cross-coupling of bromide 1313 with zinc enolate partner 1314 catalyzed by [Pd(tBu3P)Br]2 delivered 1315, which was BI


Chemical Reviews

Review

diterpenoids following a biomimetic and collective strategy (Scheme 117).169 Starting from the commercially available 1332, common intermediate 1333 was generated in 17 steps. Nozaki−Hiyama reaction of 1333 with acetaldehyde and isovaleraldehyde followed by three more steps afforded alkyl 1334 and 1335, which underwent a Prins cyclization in the presence of AlI3 to give 1336 and 1337, respectively. Stille coupling of 1336 with 1341 followed by Julia−Kocienski olefination afforded 1343. 6π-Electrocyclization/oxidative aromatization of 1343 followed by reductive cleavage of the benzyl ether and desulfonation furnished aflavazole (1344). After coupling of 1337 with 1338, 14-hydroxyaflavinine (1340) was generated in two steps. 4.1.2. Carbazole Alkaloids. Murrafolines are a family of biscarbazole alkaloids bearing a common carbazole girinimbine (1347) moiety and other different carbazoles are linked to the C4′ position of pyran ring in 1347. After having prepared some monomeric carbazoles including 1347,170 Knölker and coworkers achieved the collective total synthesis of several murrafolines (Scheme 118).171 Alkyne 1346 was chosen as the common intermediate, which was synthesized from aniline 1345 in four steps. Sonogashira coupling of alkyne 1346 and 1348 afforded 1349, which was heated in situ to undergo a tandem Claisen rearrangement/isomerization and 6π-electrocyclization to afford 1351. Hydrogenation of the double bond in the pyran ring occurred with concomitant removal of the benzyl group to give compound 1352. Treatment of 1352 and prenal with Ti(OiPr)4 provided murrafoline C (1353) through the formation of a dimethylpyran ring. Alternatively, annulation of 1352 with citral followed by a proton mediated cyclization delivered murrafoline A (1355). Similarly, murrafolines B (1358) and D (1361) were synthesized from 1346. Bismurrayafoline A (1369), bismurrayafolinol (1365), and chrestifolines B−D (1366−1368) are biscarbazole alkaloids possessing a common carbazole moiety and a different carbazole linked by a methylene group. Knölker and coworkers reported the total synthesis of five biscarbazole alkaloids by connecting different carbazoles with the common intermediate 1363 to achieve efficiency and step economy (Scheme 119).172 Carbazole 1363 was prepared from aniline 1362 in five steps. Following the modified Ullman protocol, coupling of 1363 with 1370 provided 1364. Reduction of 1364 delivered bismurrayafolinol (1365), which could be oxidized to chrestifoline D (1368). Similarly, coupling of 1363 with 1371, 1372, and 1373 furnished bismurrayafoline A (1369) and chrestifoline B (1366) and C (1367), respectively. Dictyodendrins are marine natural products possessing a common pyrrolo[2,3-c]carbazole core. In 2017, Ohno and coworkers reported the divergent syntheses of dictyodendrins B (208), C (1387), E (209), and F (2220) employing a gold catalyzed annulation of a diyne and a pyrrole to construct the pyrrolo[2,3-c]carbazole core as the key step (Scheme 120).173 The diyne 1378 was obtained from 1374 in nine steps mainly by metal-catalyzed cross coupling reaction. Treatment of 1378 with [BrettPhosAu(MeCN)SbF6] in the presence of Boc-Npyrrole (1379) afforded 1382, in which three bonds and two aromatic rings were formed. Carbazole 1382 was transformed into the common intermediate 1384 by deprotection, bromination, alkylation with 203, and Suzuki−Miyama coupling with 1383. Dibromination of 1384 followed by regioselective debromination and Ullmann coupling with NaOMe provided the known 1386, which could be converted to dictyodendrin C (1387) over three steps. Deprotection of

Scheme 119. Knölker’s Divergent Total Syntheses of Bismurrayafoline A (1369), Bismurrayafolinol (1365), and Chrestifolines B−D (1366−1368)

converted to (−)-pendolmycin (1316) in three steps. Similarly, coupling of 1313 with zinc enolate 1317 gave diastereomeric products 1318 and 1319 as epimers, and they could be converted to (−)-lyngbyatoxin A (1320) and (−)-teleocidin A2 (1321) in three steps, respectively. The dimeric cyclotryptamine alkaloids exhibit many biological activities including analgesic, antiviral, antifungal activities, and cytotoxicity against human cancer cell lines. meso-Chimonanthine (1330) and desmethyl-meso-chimonanthine (1329) (DMMC), two dimeric cyclotryptamine alkaloids, were synthesized in a divergent manner by Movassaghi and coworkers in 2014 (Scheme 116).168 Treatment of cyclotryptamine 1323 with Rh2(esp)3, DIB, and H2NSO3Ar (Ar = 2,6difluorobenzene) afforded arylsulfamate ester 1324. Coupling of 1324 with 1325 afforded sulfamide 1326. Oxidation of sulfamide 1326 with 1,3-dichloro-5,5-dimethylhydantoin provided diazene 1327. Photolysis of diazene 1327 as a thin film in the absence of solvent gave chiral dimer 1328, which served as a common intermediate for the synthesis of 1329 and 1330. Deprotection of the trichloroethyl carbamate and sulfonyl group in 1328 with Na(Hg) followed by reduction of methyl carbamate delivered (−)-DMMC (1329). Conversion of trichloroethyl carbamate in 1328 to ethyl carbamate followed by deprotection of sulfonyl group and reduction of carbamate to methyl group resulted in meso-chimonanthine (1330), which could be transformed to meso-calycanthine (1331) by treatment with acid. Aflavazole (1344) and 14-hydroxyaflavinine (1340) are two indole diterpenoids, which share a common fused cisdecahydronaphthalene motif. In 2016, Li and co-workers accomplished the first total synthesis of these two indole BJ


Chemical Reviews

Review

Scheme 120. Ohno’s Divergent Total Syntheses of Dictyodendrins B (208), C (1387), E (209), and F (220)

In 2017, the Cheon group reported the divergent total syntheses of arcyriaflavin A (1391) and calothrixin B (1393) from the common intermediate bisindole 1389, which was prepared via a cyanide-catalyzed imino-Stetter reaction of 1388 (Scheme 121).176 Protection of 1389 with Bn followed by Friedel−Crafts reaction and oxidation gave 1390, which was transformed to arcyriaflavin A (1391) by intramolecular condensation, dehydration, amination, and deprotection. In addition, hydrolysis of 1389 followed by benzannulation and Vilsmeier−Haack reaction provided indolocarbazole 1392. Calothrixin B (1393) was generated from 1392 by an oxidation/hydrolysis/quinoline formation sequence. 4.1.3. Terpenoid Alkaloids. The architecturally complex diterpenoid alkaloids are classed into C20, C19, and C18 subfamilies based on the contiguous carbon atoms of the framework. Cochlearenine (1400), N-ethyl-1α-hydroxy-17veratroyldictyzine (1402), and paniculamine (1401) belong to the C20 family, while weisaconitine D (1398) and liljestrandinine (1399) belong to the C18 and C19 families, respectively. After network analysis, the Sarpong group developed a unified synthetic strategy to access the C20, C19, and C18 diterpenoid alkaloids and accomplished the collective total syntheses of five diterpenoid alkaloids using 1397 as a common intermediate (Scheme 122).177,178 Diels−Alder reaction followed by hydrogenation afforded racemic 1396, which could be transformed to the common intermediate 1397 in nine steps. They first synthesized liljestrandinine (1399) and

Scheme 121. Cheon’s Divergent Total Syntheses of Arcyriaflavin A (1391) and Calothrixin B (1393)

1386 followed by aerobic oxidation gave dictyodendrin F (220). On the other hand, introducing the side chain to 1384 at C2 position followed by FGTs gave the known 1385, which was converted to dictyodendrin B (208) by sulfonation and deprotection. In addition, according to Tokuyama’ work,174,175 dictyodendrin E (209) was obtained from 1385. BK


Chemical Reviews

Review

Scheme 122. Sarpong’s Divergent Total Syntheses of Five Diterpenoid Alkaloids

Scheme 123. Liu’s Divergent Total Syntheses of Six 5-Aryl-4-hydroxy-2-pyridone Alkaloids

weisaconitine D (1398) from the common intermediate 1397 and later prepared cochlearenine (1400) in 15 steps. Oxidation of 1400 with H2O2 gave paniculamine (1401). N-Ethyl-1αhydroxy-17-veratroyldictyzine (1402) was also furnished in two steps. Thus, the web-based deterministic graphing program they developed to analyze these topologically complex molecules should be valuable in the analysis and synthesis of other architecturally challenging molecules. 4.1.4. The Other Alkaloids. 4-Hydroxy-2-pyridone alkaloids like pretenellin B (1407), prebassianin B (1409), farinosone A (1410), militarinone D (1408), pyridovericin (1411), and torrubiellone C (1412) contain a common 5-aryl4-hydroxy-2-pyridone core and different polyene side chains at C3 position. In 2014, Liu and co-workers synthesized these natural products in a divergent approach by connecting the side chains and the common intermediate 1405 at late stage (Scheme 123).179 The bromide 1404 was generated from 1403 in five steps. Suzuki−Miyama coupling of 1404 with aryl boronic acid afforded the common intermediate 1405. Aldol reaction of ketone 1405 with aldehyde 1406 in the presence of NaH followed by removal of the benzyl and methyl group delivered pretenellin B (1407). Natural products 1408−1412 were prepared with the corresponding aldehydes following the

Scheme 124. She’s Divergent Total Syntheses of Myrifabrals A (1418) and B (1420)

BL


Chemical Reviews

Review

Scheme 125. Sato’s Divergent Total Syntheses of Madangamines A, C, and E (1433−1435)

similar procedure. Furthermore, their bioactivity was also investigated. Myrifabrals A (1418) and B (1420) belong to the Myrioneuron alkaloids. She and co-worker reported a concise divergent total synthesis of these two natural products in 2016 (Scheme 124).180 Tandem Mannich/amidation of 1414 with tetrahydropyridine 1415 to construct the skeleton of the molecule afforded 1416. Reduction of 1416 with LiAlH4 gave common intermediate 1417, which was transformed to myrifabral A (1418) by treatment with HCl. Exposure of 1417 to aza-acetal 1419 in the presence of HCl furnished myrifabral B (1420). Madangamines A, C, and E (1433−1435) share a common ABCE tetracyclic moiety and possess a variety of D-rings. In 2017, Sato and co-workers disclosed the divergent total syntheses of 1433−1435 from a common ABCE-tetracyclic intermediate via late-stage modification of the D-ring (Scheme 125).181 They formed the tetrahydropyridine ring by a Nicatalyzed β-carbon elimination reaction and reduced the ketone with CBS reagent to introduce the chirality, thus affording 1423. Alcohol 1423 was then transformed to 1424 in six steps. Cycloisomerization of 1424 afforded the cis-fused bicyclic system 1425, which was then converted to 1426 over five steps. Acyliminium cyclization of 1426 with TFA gave tricyclic compound 1427. Z-Selective hydroboration/oxidation of 1427 followed by Stille coupling with 1436 provided the skipped diene 1428. Removal of the Boc group in 1428 followed by macrolactamization with Mukaiyama reagent and removal of the TIPS group delivered 1429. Oxidation of alcohol 1429 followed by Wittg olefination and cleavage of the TIPS group

Scheme 126. Evans’ Divergent Total Syntheses of Nortrilobolide (1447) and Thapsigargin (1449)

BM


Chemical Reviews

Review

Scheme 127. Gao’s Divergent Total Syntheses of Hamigerans D (1462), G (1457), L (1470), N (1459), O (1466), P (1464), and Q (1468)

common intermediate 1429 with 1437 and 1438 over several steps, respectively.

Scheme 128. Li’s Divergent Total Syntheses of Ileabethoxazole (1477), Pseudopteroxazole (1481), and secoPseudopteroxazole (1479)

4.2. Terpenoids

afforded 1430, which was converted to madangamine A (1433) in four steps. Similarly, the syntheses of madangamines C (1435) and E (1434) were accomplished by connecting the

4.2.1. Sesquiterpenes. In 2017, inspired by the carbon− carbon bond formation sequence of terpenoids in nature, Evans and co-workers disclosed the concise, efficient, and scalable total synthesis of nortrilobolide (1447) and thapsigargin (1449) by employing tricyclic compound 1445 as an advanced common intermediate (Scheme 126).182 The commercially available (R)-(−)-carvone (1440) was readily converted to 1442 in three steps. Selective ozonolysis of the more electronrich olefin in 1442 followed by an in situ intramolecular aldol condensation gave cyclopentene derivative 1443, which underwent the sequential pinacol coupling/lactonization cascade reaction to provide lactone 1444. Lactone 1444 could be transformed to the common intermediate 1445 in three steps on gram scales. Selective acylation of 1445 followed by deprotection and Yamaguchi acylation of the newly formed alcohol provided nortrilobolide (1447). Moreover, selective acylation followed by oxidation of 1445 furnished a ketone, which was modified with an octanoyloxy side chain at the α position of ketone by the oxidation of Mn(OAc)3 to give 1448. Reduction of 1448 followed by Yamaguchi acylation delivered thapsigargin (1449). Notably, the total syntheses of 1447 and 1449 were achieved in only 10 and 12 linear steps, respectively, from carvone (1440). Thus, the present syntheses represent the shortest routes and are significantly more efficient than those reported by others. 4.2.2. Diterpenoid. Hamigerans are a class of natural products, and most of them possess a 5−6−6 or 5−7−6 tricyclic system. Particularly, hamigerans D (1462), N (1459), O (1466), P (1464), and Q (1468) also have a benzoxazine D ring bearing different substitutions at C18, which are biosynthetically regarded as hybrids of hamigeran G (1457) and amino acids.183 Moreover, hamigeran G (1457) is the BN


Chemical Reviews

Review

Scheme 129. Luo’s Divergent Total Syntheses of Six Amphilectane and Serrulatane Diterpenoids

Scheme 130. Overman’s Divergent Total Syntheses of Cheloviolenes A (1506), B (1508), and Dendrillolide C (1509)

Scheme 131. Yamano’s Divergent Total Syntheses of Amarouciaxanthins A (1513) and B (1515)

biosynthetic precursor of hamigeran L (1470) through oxidative cleavage. On the basis of the biosynthetic hypothesis, Gao and co-workers achieved the collective total syntheses of hamigerans D (1462), G (1457), L (1470), N (1459), O (1466), P (1464), and Q (1468) (Scheme 127).184 The known epoxide 1450, generated from (R)-piperitone, was converted into cyclopentane 1451 through protection of the alcohol, acid promoted semipinacol rearrangement, and subsequent protection of the resulting aldehyde. 1451 was transformed to triflate 1452 in three steps. Suzuki−Miyaura coupling of 1452 and 1453 followed by deprotection and McMurry reaction of the two aldehyde groups afforded tricyclic compound 1454, which was then converted to 1456 in 13 steps. Bromination of the C ring followed by oxidation to introduce a diketone group gave hamigeran G (1457). Condensation of hamigeran G (1457) with L-phenylalanine followed by decarboxylation led to intermediate 1458, which underwent a 6π electrocyclization to furnish hamigeran N (1459) and 18-epi-hamigeran N (1460). Similarly, hamigerans D (1462), N (1459), O (1466), P (1464), and Q (1468) along with their 18-epi-epimers were

synthesized by coupling of hamigeran G (1457) with corresponding amino acids. Finally, protection of phenol group with MOM followed by oxidative cleavage of diketone to form a diacid group and removal of a MOM group successfully delivered hamigeran L (1470). This type of divergent total synthesis demonstrated the power, efficiency, and economy of divergent strategy and validated the BO


Chemical Reviews

Review

Scheme 132. Tang and Hsung’s Divergent Total Syntheses of Five Meroterpenoids

Scheme 134. George’s Divergent Total Syntheses of Five Members of Hyperjapones and Hyperjaponols

Scheme 133. Cramer’s Divergent Total Syntheses of Six Meroterpenoids

Ileabethoxazole (1477), pseudopteroxazole (1481), and secopseudopteroxazole (1479) are three benzoxazole alkaloids that possess multisubstituted aromatic cores, which enhances the difficulty of their chemical synthesis. In 2016, the Li group accomplished the total syntheses of these three natural products from a common intermediate 1474 in a collective fashion (Scheme 128).185 They started from (+)-isopulegol (1471) and furnished compound 1472 in six steps. A cascade alkyne carbopalladation/Stille reaction between alkynyl triflate 1472 and oxazolyl stannane under optimized conditions successfully afforded triene 1473 with the desired E-geometry of a double bond. Heating triene 1473 at 140 °C under air in one pot provided the common intermediate 1474 via 6π electrocyclization/aromatization. Compound 1474 was transformed to iodo compound 1475 in six steps. Radical cyclization of 1475 using AIBN and Bu3SnH led to 5-exo-dig cyclization and afforded compound 1476 as an inconsequential geometric mixture. Treatment of 1476 with DBU followed by an excess of MeLi produced natural product ileabethoxazole (1477). Compound 1474 was converted to aldehyde 1478 in five steps, which served as an advanced intermediate for pseudopteroxazole (1481) and seco-pseudopteroxazole (1479). Wittig olefination of 1478 with PPh3CMe2 gave seco-pseudopteroxazole (1479). When 1478 was subjected to the MacMillan conditions, a radical cyclization occurred to provide tetracyclic compound 1480 as a single isomer, which underwent Wittig olefination to afford pseudopteroxazole (1481). Amphilectane and serrulatane diterpenoids like (+)-erogorgiaene (1486), (+)-pseudopteroxazole (1481), and (−)-pseudopterosin A (1491) possess similar complex structures. The main difference among them is at the benzene ring. After careful retrosynthetic analysis, Luo and co-workers adopted a collective synthetic strategy for the synthesis of these natural

biosynthetic approach for the synthesis of hamigerans. It is conceivable that this strategy can be applied to the total synthesis of other hamigerans and benefit their bioactivity study. BP


Chemical Reviews

Review

Scheme 135. Wright’s Divergent Total Syntheses of (+)-Frondosins A (1561) and B (1557)

Scheme 136. Shair’s Divergent Total Syntheses of (−)-Nemorosone (1570) and (+)-Secohyperforin (1571)

Scheme 137. Kato’s Divergent Total Syntheses of (+)-Gregatins B (1580) and E (1577)

products by formation of the benzene rings at a late stage (Scheme 129).186 The commercially available 2-cyclohexen-1one (1482) was converted to 1483 over four steps. A sequence of Sonogashira coupling of 1483 with propyne, transformation of the ethyl ester to acid, and gold catalyzed cyclization furnished lactone 1484. The advanced common intermediate 1485 was generated by a key gold-promoted Cope rearrangement of 1484. Hydroboration of 1485 followed by Suzuki coupling with 1488 installed the side chain. Diels−Alder reaction of the resulting product followed by elimination of CO2 and cyclopentadiene delivered (+)-erogorgiaene (1486). (+)-Seco-pesudopterosin A aglycone (1487) was prepared through a hydroboration, Suzuki coupling, annulation sequence. Heck reaction of 1485 with 1488 followed by acidcatalyzed cyclization provided 1489 and 1490 as diastereoisomers, which were transformed to (−)-pseudopterosin A (1491) and (+)-pseudopteroxazole (1481) in several steps, respectively. Furthermore, furan ring formation and Cope rearrangement of 1483 furnished 1497 as another advanced common intermediate, which was converted to (+)-amphilectolide (1498) and (+)-caribenol A (1499) in four steps. As shown above, 1483 could serve as the common intermediate for all these six natural products. The use of common intermediate 1483 allows for structural diversity, while the use of advanced common intermediate 1485 and 1497 favors step economy. Therefore, many factors are considered when choosing a common intermediate for the collective or divergent total synthesis.

Cheloviolenes A (1506), B (1508), and dendrillolide C (1509) are three rearranged spongian diterpenoids with different cis-2,8-dioxabicclo[3.3.0]octan-3-one ring systems as side chains. Overman and co-workers reported a divergent total synthesis of these three natural products by coupling of a tertiary radical generated directly from a tertiary alcohol with a 3-chloro-5-alkoxybutenolide (Scheme 130).187 The known compound 1500 was readily converted to 1501 in three steps. Deprotonation of 1501 with LiTMP induced Stork epoxy/nitrile cyclization to afford 1502, which was transformed to the common intermediate 1503 through a hydrogenation/ methylation and oxidation/elimination sequence. Treatment of 1503 with oxalyl chloride followed by K2HPO4 gave potassium BQ


Chemical Reviews

Review

divergent total syntheses of five cyclobutane containing chromane natural products, namely clusiacyclols A (1519) and B (1520), eriobrucinol (1521), as well as iso-eriobrucinols A (1522) and B (1523) (Scheme 132).189 The common intermediate 1518 was prepared by an unexpected cationic [2 + 2] cycloaddition of 1517, which was synthesized from phloroglucinol 1516 and citral through oxa-[3 + 3] annulation. Notably, the tandem oxa-[3 + 3] annulation/cationic [2 + 2] cycloaddition were also investigated; however, it failed to give 1518 but yielded 1524 instead as the major product. Benzoylation of 1518 with AlCl3 and ZnBr2 provided clusiacyclols A (1519) and B (1520), respectively. A [3 + 3] annulation of 1518 with ethyl propiolate mediated by InCl3 afforded iso-eriobrucinols A (1522) and B (1523) as mixtures. When InCl3 was replaced with ZnCl2, eriobrucinol (1521) was generated together with iso-eriobrucinols A (1522) and B (1523). Bicyclogermacrene (1528) is a rather frequently occurring constituent of essential oils from various plants. Bicyclogermacrene is regarded as the biosynthetic origin of a wide range of terpenoids and meroterpenoids including newly isolated psiguadials A (1533), C (1535), and D (1534). Inspired by its biosynthetic pathway, in 2014, Cramer and co-workers reported a biomimetic synthesis of these natural products employing bicyclogermacrene (1528) as the common intermediate (Scheme 133).190 They first synthesized 1528 in seven steps from (+)-2-carene (1525). Treatment of 1528 with mild acid gave cyclization product (+)-ledene (1530). Hydroboration of ledene followed by oxidative workup provided (+)-viridiflorol (1532), while hydroxylation of ledene with cobalt and PhSiH3/O2 furnished (−)-palustrol (1531). Selective epoxidation of 1528 with m-CPBA followed by autointramolecular cyclization delivered (+)-spathulenol (1529). Coupling of 1528 with 1536 under the optimized conditions provided psiguadial A (1533) in 1% yield and psiguadial D (1534) in 7% yield. Alternatively, coupling of 1528 with 1538 smoothly afforded psiguadial D (1534). Psiguadial C (1535) was subsequently generated by epoxidation of psiguadial D (1534).

Scheme 138. Brückner’s Divergent Total Syntheses of (+)-Gregatins B (1580) and E (1577)

hemioxalate salt, which underwent the photocatalyzed radical coupling with 1504 in the presence of Ir[dF(CF 3 )ppy]2(dtbbpy)PF6 to give 1505. The total synthesis of cheloviolene A (1506) was accomplished from 1505 in four steps. Similarly, the total synthesis of cheloviolene B (1508) was also achieved from 1503. Finally, elimination of the hydroxyl group in cheloviolene B (1508) successfully provided dendrillolide C (1509). 4.2.3. Tetraterpenoids. In 2013, Yamano and co-workers accomplished the total synthesis of amarouciaxanthins A (1513) and B (1515) using 1511 as a common intermediate (Scheme 131).188 Starting from (−)-actinol (1510), the common intermediate 1511 and the two partners were generated in several steps. Condensation of aldehyde 1511 with phosphonium salt 1512, oxidation of the resulting diol, and subsequent epoxy ring opening, followed by desilylation provided amarouciaxanthin A (1513). Following the same protocol, amarouciaxanthin B (1515) was obtained from 1511 and partner 1514. 4.2.4. Meroterpenoids. Meroterpenoids belong to a large subgroup of natural products with a mixed polyketide terpenoid origin. In 2013, Tang, Hsung, and co-workers reported the

Scheme 139. Saikawa and Nakata’s Divergent Total Syntheses of (+)-Lanctonamycin (1595) and Lactonamycin Z (1597)

BR


Chemical Reviews

Review

Scheme 140. Nicolaou’s Divergent Total Syntheses of Trioxacarcins A, C, and D and DC-45-A1 (1599−1602)

terpene. Furthermore, it is regarded as a nonenzymatic biosynthesis because of its complexity but racemic nature. In 2016, George and co-workers accomplished the collective total syntheses of hyperjapones A (1541), B (1546), and D (1547) and hyperjaponols A and C (1543−1544) in a biomimetic manner (Scheme 134).191 Acylation of phloroglucinol (1516) followed by trimethylation gave norflavesone (1539), which served as the common intermediate. Oxidation of 1539 into α,β-unsaturated ketone followed by hetero-Diels−Alder reaction with humulene (1540) afforded hyperjapone A (1541). Epoxidation of hyperjapone A (1541) with m-CPBA followed by acid-catalyzed rearrangement delivered hyperjaponol C (1544). Treatment of epoxide 1542 with tetracyanoethylene and LiBr furnished hyperjaponol A (1543). Similarly, oxidative hetero-Diels−Alder reaction of 1539 with caryophyllene (1545) provided hyperjapones B (1546) and D (1547) as two isomers, which mainly because of the βα and ββ conformation mixtures of 1545 in solution. (+)-Frondosins A (1561) and B (1557), two marine-derived meroterpenoid natural products, share a common bicyclo[5.4.0] undecene core with different hydroquinone moiety. In 2014, Wright and co-workers reported the synthesis of these two natural products by coupling a common intermediate dibromoenone 1550 with two different hydroquinone moieties (Scheme 135).192 Hydrogenation of ketone 1548 with (S,S)Noyori catalyst followed by protection of the alcohol afforded 1549. Diels−Alder reaction of 1549 with tetrabromocyclopropene followed by treatment with AgNO3 and protection of alcohol gave enone 1550. Suzuki coupling of 1550 with aryl trifluoroborate salt 1551 followed by exposure of the resultant

Scheme 141. Tong’s Divergent Total Syntheses of Musellarins A−C (1615−1617)

Hyperjapones and hyperjaponols are a family of structurally related meroterpenoids, which are biosynthetically produced by a hetero-Diels−Alder reaction of aromatic polyketide and BS


Chemical Reviews

Review

Scheme 142. Tong’s Asymmetric Divergent Total Syntheses of Musellarins A−C (1615−1617)

a continuous study on hyperforin and its bioactivity,193 Shair and co-workers achieved the divergent total synthesis of these natural products from an advanced common intermediate 1568 (Scheme 136).194 Enantioselective Sharpless epoxidation of 1562 and protection in situ with MsCl followed by bromide displacement gave 1563. Alkylation of 1564 with bromide 1563 afforded 1565, which underwent a Lewis acid catalyzed epoxide-opening cascade cyclization to provide the bicyclic product 1566. Allylic oxidation of 1566 with Pearlman’s catalyst followed by treatment of the resultant peroxide with DBU yielded enone 1567, which was transformed into the common intermediate 1568 in five steps. Bridgehead acylation of 1568 with benzoyl chloride followed by desilylation furnished 1569. Prenylation of 1569 followed by demethylation delivered (−)-nemorosone (1570). Similarly, (+)-secohyperforin (1571) was also readily synthesized from 1568 in four steps.

Scheme 143. Carreira’s Divergent Total Syntheses of Hippolachnin A (1633) and Gracilioethers E (1634) and F (1630)

4.3. Polyketides

(+)-Gregatins B (1580) and E (1577) possess a common 4oxo-3-furancarboxylate core with different side chains. In 2013, Kato and co-workers reported a divergent synthesis of 1577 and 1580 by coupling the common intermediate stannane 1575 with a vinyl iodide or borate (Scheme 137).195 Weinreb amide 1572 was converted to propargylic acetate 1573 in seven steps. Pd-catalyzed oxidative cyclization/carbonylation of 1573 gave 1574, which was transformed to vinyl stannane 1575 over six steps. Coupling of 1575 with vinyl iodide 1576 furnished (+)-gregatin E (1577) directly. After changing the stannane group to iodide group, Suzuki−Miyaura coupling of the resulting 1578 with borate 1579 yielded (+)-gregatin B (1580). In 2014, Brückner and co-workers also disclosed the divergent total synthesis of (+)-gregatins B (1580) and E (1577) by Heck coupling of the common intermediate 1584 with various iodoolefins in the last step (Scheme 138).196 Dihydroxylation of 1581 afforded the diol 1582, which was transformed to 1583 in six steps. Although attempts to eliminate the OMs group in mesylate 1583 using base failed,

product to CuI delivered benzuofuran 1552, which was readily converted to conjugated ketone 1553. A conjugated addition of Bu3P and 1553 followed by two steps of elimination via intermediate 1554 and 1555 to remove the oxo-bridge yielded 1556. (+)-Frondosin B (1557) was generated from 1556 by a reduction, dimethylation, and demethylation process. (+)-Frondosin A (1561) could also be prepared from the Suzuki coupling product of 1550 with trifluoroborate salt 1558 in 15 steps. The polycyclic polyprenylated acylphloroglucinols (PPAPs) contain a densely substituted, highly oxygenated bicyclo[3.3.1]nonane core and have over 160 members, including (−)-nemorosone (1570) and (+)-secohyperforin (1571). As BT


Chemical Reviews

Review

Scheme 144. Studer’s Divergent Total Syntheses of Pallidol (1640), Quadrangularin A (1641), and Ampelopsin D (1642)

final-stage glycosylation of the common alcohol 1593 (Scheme 139).197 The synthesis commenced with the known phenol 1586, which was transformed to anhydride 1587 in seven steps. Cycloaddition of the diene generated from 1587 with quinone 1588 afforded 1589. Dihydroxylation of 1589 followed by desilylation and removal of MOM group gave 1590, which was treated with PdCl2 and CO followed by acid catalyzed lactonization to deliver pentacyclic compound 1591. Protection of 1591, Friedel−Crafts acetylation with P2O5 followed by two steps of deprotection afforded (±)-lactonamycinone (1592). Protection of the phenol group with TBS yielded common intermediate 1593. Glycosylation of 1593 with 1594 catalyzed by Yb(OTf)3 followed by deprotection furnished α-glucoside lanctonamycin (1595). In addition, glycosylation of 1593 with 1596 followed by dihydroxylation and removal of TBS group gave lanctonamycin Z (1597). In addition to the desired αglucosides, β-glucosides were also generated as an epimer during the glycosylation process. The trioxacarcins A, C, and D and DC-45-A1 (1599−1602) share the common parent structure of trioxacarcin DC-45-A2 (1603) but contain varying numbers of carbohydrate units. Having finished the total synthesis of trioxacarcin DC-45-A2 (1602),198 Nicolaou and co-workers further achieved the collective total syntheses of trioxacarcins A, C, and D and DC45-A1 (1599−1602) from the common precursor namely protected DC-45-A2 (1598) by the gold-catalyzed glycosylation (Scheme 140).199 Protection of the tertiary alcohol in 1598 followed by removal of the PMB group, coupling of the resulting alcohol with 1605 and final desilylation gave trioxacarcin DC-45-A1 (1602). Coupling of 1598 with 1606 in the presence of Ph3PAuOTf followed by removal of the PMB group afforded 1604, which was further coupled with 1605 to deliver trioxacarcin A (1599) after deprotection. Other trioxacarcins could be generated by similar coupling reactions with different carbohydrate partners. Notably, various derivatives of trioxacarcin with different carbohydrate motifs could be furnished easily by employing this strategy, which would benefit their bioactivity investigation. Musellarins A−C (1615−1617) belong to diarylhepnoid natural products containing linkages of seven carbons between the two aromatic rings. They differ only in the aryl group substitutions. In 2014, Tong and co-workers achieved the first

Scheme 145. Sun’s Divergent Total Syntheses of (+)-Pallidol (1640), (+)-Quadrangularin A (1641), and (+)-Isopaucifloral F (1650)

they managed to prepare the vinyl compound 1584 as the common intermediate by replacing the OMs group with phenyl selenide followed by oxidation/elimination in the absence of base. Heck reaction of 1584 with the corresponding iodide 1576 and 1585 delivered (+)-gregatins E (1577) and B (1580), respectively. Obviously, this synthesis is more efficient than the synthesis reported by Kato and co-workers. Lanctonamycin (1595) and lactonamycin Z (1597) possess a common aglycon with different carbohydrate moieties. In 2013, Saikawa, Nakata, and co-workers disclosed the total syntheses of lanctonamycin (1595) and lactonamycin Z (1597) through a BU


Chemical Reviews

Review

Scheme 146. Kawabata’s Divergent Total Syntheses of Strictinin (1660) and Tellimagrandin II (1662)

globally deprotected in two steps to furnish musellarins A−C (1615−1617). Hippolachnin A (1633) and gracilioethers E (1634) and F (1630) belong to the Plakortin polyketides family, which share the common cyclopentafuran core motif. Carreira and coworkers have developed a unified route to these natural products and achieved the total syntheses of these three natural products from the common intermediate cyclobutene 1628 (Scheme 143).202,203 Cyclobutene 1628 could be readily accessed from (±)-4-acetoxy-cyclopentenone 1627 in four steps. Prins cyclization of 1628 in the presence of Sc(OTf)3 and paraformaldehyde afforded ethylidenecyclobutane 1629. Ozonolysis of 1629 followed by Baeyer−Villiger oxidation and a direct C−H oxidation gave gracilioether F (1630). Etherification of 1628 followed by an ene-type cyclization provided 1631, which was an intermediate of hippolachnin A (1633) and gracilioether E (1634).203 Stereoselective hydrogenation of the exocyclic double bond in 1631 and installation of the vinylogous carbonate afforded hippolachnin A (1633). In addition, ozonolysis of 1631 followed by Baeyer−Villiger oxidation and installation of the vinylogous carbonate furnished gracilioether E (1634).

and collective total synthesis of musellarins A−C (1615−1617) by introducing the aryl group with different substituents via Heck coupling of enol ether 1614 and aryl diazonium salts at the late stage (Scheme 141).200 Isovanillin (1609) was transformed to furan compound 1610 in six steps. Achmatowica rearrangement of 1610 afforded 1611. Reduction of hemiacetal 1611 with TFA and triethylsilane followed by a Friedel−Crafts conjugated cycloaddition promoted by acid gave 1612. Treatment of ketone 1612 with PhNTf2 and base gave vinyl triflate, which underwent deoxygenation with pallidium and formic acid to give the undesired tetrahydropyran 1613. Isomerization of 1613 with Wilkinson catalyst provided enol ether 1614 as a common intermediate. Finally, a late-stage Heck coupling of 1614 with corresponding aryl diazonium salts 1618−1620 followed by one or two deprotection steps furnished musellarins A−C (1615−1617). In 2015, Tong and co-workers further accomplished the asymmetric total synthesis of musellarins A−C (1615−1617) (Scheme 142).201 Isovanillin (1609) was transformed to ketone 1621 in five steps. Noyori asymmetric hydrogenation of ketone 1621 afforded enantiomerically pure furfuryl alcohol 1622. Achmatowica rearrangement of 1622 followed by acetylation and deoxygenation of acetal group using Zn gave 1623 as a common intermediate containing a double bond. Heck coupling of 1623 with 1618−1620 provided 1624−1626, respectively. Protection of the resulting hydroxyl groups and subsequent Friedel−Crafts cyclization promoted by triflic anhydride afforded the tricyclic compounds, which were

4.4. The Other Natural Products

Pallidol (1640), quadrangularin A (1641), and ampelopsin D (1642) are three resveratrol-based oligomers which belong to the class of natural polyphenols. Structurally, they share a common 2,3-trans-diaryl-indane scaffold but contain different aryl groups. To gain maximum flexibility for the comprehensive BV


Chemical Reviews

Review

Scheme 147. Lawrence and Sherburn’s Divergent Total Syntheses of Endiandric Acid A (1675), Kingianins A, D, and F (1677− 1679) and Kingianic Acid E (1676)

(1650) (Scheme 145).205 The chiral para-tolyl sulfoxide 1648 was generated from 1646 in two steps, including condensation with benzoate 1647 and elimination. Nazarov cyclization of 1648 promoted by AlCl3 followed by reductive removal of the para-tolyl sulfoxide auxiliary group provided ketone 1649. Triflation of 1649 followed by coupling with (4methoxybenzyl)magnesium chloride catalyzed by iron delivered the known alkene 1637. Following the protocol reported by Studer,204 1637 was readily converted to (+)-quadrangularin A (1641) and (+)-pallidol (1640). In addition, oxidative cleavage of olefin 1638 followed by deprotection with BBr3 gave (+)-isopaucifloral F (1650). The ellagitannins are a diverse class of hydrolyzable tannins, a type of polyphenols. Strictinin (1660) and tellimagrandin II (1662) are two ellagitannin natural products, which possess a common D-glucose core with different numbers of hexanhyroxydiphenoyl units and galloyl units. In 2015, Kawabata and coworkers disclosed the elegant total synthesis of 1660 and 1662 from the common intermediate 1658, which was efficiently constructed through the sequential and regioselective introduction of galloyl(oxy) groups to unprotected glucose (Scheme 146).206 Stereoselective glycosylation of unprotected glucose (1651) with 1652 under Mitsunobu conditions afforded 1653. Regioselective acylation of 1653 at C4-OH catalyzed by

synthesis of more natural and non-natural derivatives, it is desirable to introduce the aryl groups at the late stage of synthesis. In 2014, the Studer group disclosed the collective total syntheses of racemic 1640−1642 from a common intermediate 1636 by assembling different aryl groups at late stage (Scheme 144).204 A large scale of indene carboxylic 1636 was readily prepared from the commercial available 3,5dimethoxybenzyl acid 1635 over eight steps. A novel palladium-catalyzed decarboxylative coupling of 1636 with 4iodoanisole smoothly afforded indene 1637. The oxidative Heck reaction of 1637 and 3,5-dimethoxyphenylboronic acid with TEMPO as an external oxidant provided the protectedquadrangularin A (1638) with well controlled E configuration of the double bond and trans-substituted 2,3-diaryl group. Global deprotection of 1638 with BBr3 provided quadrangularin A (1641). Ampelopsin D (1642) was synthesized from 1636 in a similar approach. Meanwhile, hydroboration/oxidation of 1638 with BH3/H2O2 followed by cyclization/deprotection afforded pallidol (1640). It is worth noting that this strategy can be used to prepare other natural and non-natural derivatives for their biological studies. In 2016, Sun and co-workers reported the divergent enantioselective total syntheses of (+)-pallidol (1640), (+)-quadrangularin A (1641), and (+)-isopaucifloral F BW


Chemical Reviews

Review

ASSOCIATED CONTENT

organocatalyst 1654 followed by introduction of another galloyl group at C6-OH in one pot gave 1658. Removal of benzyl group in 1658 furnished phenol 1659, which underwent oxidative phenol coupling followed by removal of the MOM groups to give strictinin (1660). In addition, the introduction of two additional galloyl groups at C2-OH and C3-OH of diol 1658 followed by deprotection afforded 1661, which was transformed to tellimagrandin II (1662) following the same procedure for 1660. The present synthesis represents a novel retrosynthetic approach to natural glycosides. It demonstrates the usefulness of catalyst-controlled regioselective functionalization in the synthesis of complex natural products with minimal use of protective groups. The endiandric acids, kingianins, and kingianic acids possess complex and synthetically challenging polycyclic frameworks. Biosynthetically, they share a common bicyclo[4.2.0]octadiene−CH2CO2H motif, which could be regarded as the product of a thermal 8π−6π electrocyclization of tetraene. In 2015, Lawrence, Sherburn, and co-workers reported the collective total syntheses of endiandric acid A (1675), kingianins A, D, and F (1677−1679), and kingianic acid E (1676) from a common conjugated tetrayne 1666 (Scheme 147).207 Tetrayne 1665 was synthesized from 1663 through formylation, followed by alkylation/bromination sequence and Negishi cross coupling with 1664. Removal of the TMS group in 1665 gave 1666. Metalation of 1666 resulted in tetrayne Grignard reagent, which was alkylated with 1667 to afford 1670. Reduction of 1670 generated the corresponding (Z,Z,Z,Z)-tetraene 1673, which was directly heated to induce the domino 8π−6π electrocyclization−intramolecular Diels− Alder sequence. Subsequent deprotection and oxidation of the alcohol to acid delivered endiandric acid A (1675). Similarly, kingianic acid E (1676) was formed following the same protocol. Metalation of 1666 followed by Negishi coupling with benzyl bromide 1669 afforded 1672, which was converted to kingianins A (1677), D (1678), and F (1679) in six steps by following their previously reported procedures.208

Special Issue Paper

This paper is an additional review for Chem. Rev. 2017, volume 117, issue 18, “Natural Product Synthesis”.

AUTHOR INFORMATION Corresponding Author

*Phone: 86-10-82805166. Fax: 86-10-82802724. E-mail: yxjia@ bjmu.edu.cn. ORCID

Yanxing Jia: 0000-0002-9508-6622 Notes

The authors declare no competing financial interest. Biographies Lei Li was born in Inner Mongolia, China. He received his B.Sc. degree in Pharmacy from Peking university in 2013. His undergraduate research focused on the study of cyclic peptides. Li began his graduate study under the direction of professor Yanxing Jia at Peking university since 2013. He focuses on the total synthesis of amaryllidaceae and indole alkaloids. Zhuang Chen was born in Sichuan, China. He received his B.Sc. in Pharmacy from the Peking University in 2014. Currently, Zhuang Chen is a graduate for Ph.D. degree in the group of Professor Yanxing Jia at Peking University and focuses on the total synthesis of complexed indole alkaloids and terpenes. Xiwu Zhang was born and raised in Shandong, China. He received his B.Sc. in Pharmacy with Highest Honors from Jilin University in 2015. Then he continued his Ph.D. study in the Jia group at Peking University. His research interests focus on total synthesis of diterpenoid natural products. Yanxing Jia received his B.Sc. (1997) and Ph.D. (2002) degree in organic chemistry from Lanzhou University under the direction of Professor Yongqiang Tu. After five years of a postdoctoral stay with Professor Jieping Zhu at Institut de Chimie des Substances Naturelles, CNRS, France, he joined the School of Pharmaceutical Sciences of Peking University as an associate professor in 2007 and was promoted to a full Professor in 2011. His research interests focus on total synthesis of natural products and medicinal chemistry. He has authored of 80 scientific publications including Angew. Chem. Int. Ed., J. Med. Chem., Org. Lett., and Chem. Commun. He was awarded for Distinguished Faculty Award by Chinese−American Chemistry & Chemical Biology Professors Association and the Young Investigator in Medicinal Chemistry in China from the Chinese Pharmaceutical Association.

5. SUMMARY AND OUTLOOK As this review illustrates, during the past few years, the divergent total syntheses of complex natural products from a common intermediate have attracted enormous attention in the chemical community. A number of powerful and unified strategies have been developed by emulating the natural biosynthesis or through innovative transformations. In the process, we have gained a much better understanding of the chemical logic of biochemical transformations. Furthermore, there are several elegant examples that not only achieved the first and divergent total syntheses of targets but also are highly efficient and concise and can be prepared on a gram-scale. Thus, the reliable access and supply of synthetic analogues are ensured for these families of natural products. It is also astonishing that the divergent total syntheses of some of the most complex natural products, such as ryanodane diterpenoids, diterpenoid alkaloids, and akuammiline alkaloids have been recently achieved. However, many families of complex natural products have not yet been divergently accessed. Further refinement of the existing methods and development of novel unified strategies are needed to meet this challenge. We hope this review will encourage synthetic chemists continue to explore the remarkable divergent syntheses and design ever efficient routes in their pursuit of new synthetic targets.

ACKNOWLEDGMENTS This research was supported by the National Natural Science Foundation of China (nos. 21372017 and 21572008). REFERENCES (1) Wöhler, F. Ueber Künstliche Bildung Des Harnstoffs. Ann. Phys. 1828, 88, 253−256. (2) Nicolaou, K. C.; Vourloumis, D.; Winssinger, N.; Baran, P. S. The Art and Science of Total Synthesis at the Dawn of the Twenty-First Century. Angew. Chem., Int. Ed. 2000, 39, 44−122. (3) Nicolaou, K. C. Inspirations, Discoveries, and Future Perspectives in Total Synthesis. J. Org. Chem. 2009, 74, 951−972. (4) Nicolaou, K. C.; Chen, J. S. Classics in Total Synthesis III; WileyVCH: Weinheim, Germany, 2011. BX


Chemical Reviews

Review

(5) Hoffmann, R. W. Natural Product Synthesis: Changes over Time. Angew. Chem., Int. Ed. 2013, 52, 123−130. (6) Keasling, J. D.; Mendoza, A.; Baran, P. S. Synthesis: A Constructive Debate. Nature 2012, 492, 188−189. (7) Wang, P.; Dong, S. W.; Shieh, J. H.; Peguero, E.; Hendrickson, R.; Moore, M. A. S.; Danishefsky, S. J. Erythropoietin Derived by Chemical Synthesis. Science 2013, 342, 1357−1360. (8) Wilson, R. M.; Dong, S. W.; Wang, P.; Danishefsky, S. J. The Winding Pathway to Erythropoietin Along the Chemistry-Biology Frontier: A Success at Last. Angew. Chem., Int. Ed. 2013, 52, 7646− 7665. (9) Paterson, I.; Anderson, E. A. The Renaissance of Natural Products as Drug Candidates. Science 2005, 310, 451−453. (10) Li, J. W. H.; Vederas, J. C. Drug Discovery and Natural Products: End of an Era or an Endless Frontier? Science 2009, 325, 161−165. (11) David, B.; Wolfender, J. L.; Dias, D. A. The Pharmaceutical Industry and Natural Products: Historical Status and New Trends. Phytochem. Rev. 2015, 14, 299−315. (12) Newman, D. J.; Cragg, G. M. Natural Products as Sources of New Drugs from 1981 to 2014. J. Nat. Prod. 2016, 79, 629−661. (13) Rodrigues, T.; Reker, D.; Schneider, P.; Schneider, G. Counting on Natural Products for Drug Design. Nat. Chem. 2016, 8, 531−541. (14) Crane, E. A.; Gademann, K. Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis. Angew. Chem., Int. Ed. 2016, 55, 3882−3902. (15) Hendrickson, J. B. Systematic Synthesis Design.IV. Numerical Codification of Construction Reactions. J. Am. Chem. Soc. 1975, 97, 5784−5800. (16) Gaich, T.; Baran, P. S. Aiming for the Ideal Synthesis. J. Org. Chem. 2010, 75, 4657−4673. (17) Kuttruff, C. A.; Eastgate, M. D.; Baran, P. S. Natural Product Synthesis in the Age of Scalability. Nat. Prod. Rep. 2014, 31, 419−432. (18) Mulzer, J. Trying to Rationalize Total Synthesis. Nat. Prod. Rep. 2014, 31, 595−603. (19) Wender, P. A. Toward the Ideal Synthesis and Molecular Function through Synthesis-Informed Design. Nat. Prod. Rep. 2014, 31, 433−440. (20) Fischbach, M. A.; Clardy, J. One Pathway, Many Products. Nat. Chem. Biol. 2007, 3, 353−355. (21) Gravel, E.; Poupon, E. Biogenesis and Biomimetic Chemistry: Can Complex Natural Products Be Assembled Spontaneously? Eur. J. Org. Chem. 2008, 2008, 27−42. (22) Boger, D. L.; Brotherton, C. E. Total Syntheses of Azafluoranthene Alkaloids - Rufescine and Imeluteine. J. Org. Chem. 1984, 49, 4050−4055. (23) Jones, S. B.; Simmons, B.; Mastracchio, A.; MacMillan, D. W. C. Collective Synthesis of Natural Products by Means of Organocascade Catalysis. Nature 2011, 475, 183−188. (24) Anagnostaki, E. E.; Zografos, A. L. ″Common Synthetic Scaffolds″ in the Synthesis of Structurally Diverse Natural Products. Chem. Soc. Rev. 2012, 41, 5613−5625. (25) Serba, C.; Winssinger, N. Following the Lead from Nature: Divergent Pathways in Natural Product Synthesis and DiversityOriented Synthesis. Eur. J. Org. Chem. 2013, 2013, 4195−4214. (26) Shimokawa, J. Divergent Strategy in Natural Product Total Synthesis. Tetrahedron Lett. 2014, 55, 6156−6162. (27) Han, J. C.; Li, C. C. Collective Synthesis of Natural Products by Using Metathesis Cascade Reactions. Synlett 2015, 26, 1289−1304. (28) Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Function-Oriented Synthesis, Step Economy, and Drug Design. Acc. Chem. Res. 2008, 41, 40−49. (29) Burns, N. Z.; Baran, P. S.; Hoffmann, R. W. Redox Economy in Organic Synthesis. Angew. Chem., Int. Ed. 2009, 48, 2854−2867. (30) Newhouse, T.; Baran, P. S.; Hoffmann, R. W. The Economies of Synthesis. Chem. Soc. Rev. 2009, 38, 3010−3021. (31) Li, C. J.; Trost, B. M. Green Chemistry for Chemical Synthesis. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 13197−13202.

(32) Trost, B. M. The Atom Economy - a Search for Synthetic Efficiency. Science 1991, 254, 1471−1477. (33) Wender, P. A.; Miller, B. L. In Organic Synthesis: Theory and Applications; JAI Press: Greenwich, CT, 1993. (34) Schreiber, S. L. Target-Oriented and Diversity-Oriented Organic Synthesis in Drug Discovery. Science 2000, 287, 1964−1969. (35) Burke, M. D.; Schreiber, S. L. A Planning Strategy for DiversityOriented Synthesis. Angew. Chem., Int. Ed. 2004, 43, 46−58. (36) Wilson, R. M.; Danishefsky, S. J. Small Molecule Natural Products in the Discovery of Therapeutic Agents: The Synthesis Connection. J. Org. Chem. 2006, 71, 8329−8351. (37) Danishefsky, S. On the Potential of Natural Products in the Discovery of Pharma Leads: A Case for Reassessment. Nat. Prod. Rep. 2010, 27, 1114−1116. (38) Chen, K.; Baran, P. S. Total Synthesis of Eudesmane Terpenes by Site-Selective C−H Oxidations. Nature 2009, 459, 824−828. (39) Pan, G.; Williams, R. M. Unified Total Syntheses of Fawcettimine Class Alkaloids: Fawcettimine, Fawcettidine, Lycoflexine, and Lycoposerramine B. J. Org. Chem. 2012, 77, 4801−4811. (40) Lebold, T. P.; Kerr, M. A. Total Synthesis of Eustifolines A−D and Glycomaurrol Via a Divergent Diels−Alder Strategy. Org. Lett. 2007, 9, 1883−1886. (41) Zhao, S.; Andrade, R. B. Domino Michael/Mannich/NAlkylation Route to the Tetrahydrocarbazole Framework of Aspidosperma Alkaloids: Concise Total Syntheses of (−)-Aspidospermidine, (−)-Tabersonine, and (−)-Vincadifformine. J. Am. Chem. Soc. 2013, 135, 13334−13337. (42) Li, Z.; Zhang, S.; Wu, S.; Shen, X.; Zou, L.; Wang, F.; Li, X.; Peng, F.; Zhang, H.; Shao, Z. Enantioselective Palladium-Catalyzed Decarboxylative Allylation of Carbazolones: Total Synthesis of (−)-Aspidospermidine and (+)-Kopsihainanine A. Angew. Chem., Int. Ed. 2013, 52, 4117−4121. (43) Shen, X.-L.; Zhao, R.-R.; Mo, M.-J.; Peng, F.-Z.; Zhang, H.-B.; Shao, Z.-H. Catalytic Enantioselective and Divergent Total Synthesis of (+)-10-Oxocylindrocarpidine, (+)-Cylindrocarpidine, (−)-N-Acetylcylindrocarpinol, and (+)-Aspidospermine. J. Org. Chem. 2014, 79, 2473−2480. (44) Mewald, M.; Medley, J. W.; Movassaghi, M. Concise and Enantioselective Total Synthesis of (−)-Mehranine, (−)-Methylenebismehranine, and Related Aspidosperma Alkaloids. Angew. Chem., Int. Ed. 2014, 53, 11634−11639. (45) White, K. L.; Movassaghi, M. Concise Total Syntheses of (+)-Haplocidine and (+)-Haplocine Via Late-Stage Oxidation of (+)-Fendleridine Derivatives. J. Am. Chem. Soc. 2016, 138, 11383− 11389. (46) Tan, P. W.; Seayad, J.; Dixon, D. J. Expeditious and Divergent Total Syntheses of Aspidosperma Alkaloids Exploiting Iridium(I)Catalyzed Generation of Reactive Enamine Intermediates. Angew. Chem., Int. Ed. 2016, 55, 13436−13440. (47) Sugimoto, K.; Toyoshima, K.; Nonaka, S.; Kotaki, K.; Ueda, H.; Tokuyama, H. Protecting-Group-Free Total Synthesis of (−)-Rhazinilam and (−)-Rhazinicine Using a Gold-Catalyzed Cascade Cyclization. Angew. Chem., Int. Ed. 2013, 52, 7168−7171. (48) Umehara, A.; Ueda, H.; Tokuyama, H. Total Syntheses of Leuconoxine, Leuconodine B, and Melodinine E by Oxidative Cyclic Aminal Formation and Diastereoselective Ring-Closing Metathesis. Org. Lett. 2014, 16, 2526−2529. (49) Arai, S.; Nakajima, M.; Nishida, A. A Concise and Versatile Synthesis of Alkaloids from Kopsia Tenuis: Total Synthesis of (±)-Lundurine A and B. Angew. Chem., Int. Ed. 2014, 53, 5569−5572. (50) Kirillova, M. S.; Muratore, M. E.; Dorel, R.; Echavarren, A. M. Concise Total Synthesis of Lundurines A−C Enabled by Gold Catalysis and a Homodienyl Retro-Ene/Ene Isomerization. J. Am. Chem. Soc. 2016, 138, 3671−3674. (51) Adams, T. C.; Payette, J. N.; Cheah, J. H.; Movassaghi, M. Concise Total Synthesis of (+)-Luteoalbusins A and B. Org. Lett. 2015, 17, 4268−4271. (52) Hodges, T. R.; Benjamin, N. M.; Martin, S. F. Syntheses of Gliocladin C and Related Alkaloids. Org. Lett. 2017, 19, 2254−2257. BY


Chemical Reviews

Review

(53) Zhao, G.; Xie, X.; Sun, H.; Yuan, Z.; Zhong, Z.; Tang, S.; She, X. Bioinspired Collective Syntheses of Iboga-Type Indole Alkaloids. Org. Lett. 2016, 18, 2447−2450. (54) Harada, T.; Shimokawa, J.; Fukuyama, T. Unified Total Synthesis of Five Gelsedine-Type Alkaloids: (−)-Gelsenicine, (−)-Gelsedine, (−)-Gelsedilam, (−)-14-Hydroxygelsenicine, and (−)-14,15-Dihydroxygelsenicine. Org. Lett. 2016, 18, 4622−4625. (55) Shimokawa, J.; Harada, T.; Yokoshima, S.; Fukuyama, T. Total Synthesis of Gelsemoxonine. J. Am. Chem. Soc. 2011, 133, 17634− 17637. (56) Younai, A.; Zeng, B.-S.; Meltzer, H. Y.; Scheidt, K. A. Enantioselective Syntheses of Heteroyohimbine Natural Products: A Unified Approach through Cooperative Catalysis. Angew. Chem., Int. Ed. 2015, 54, 6900−6904. (57) Liu, H.; Zhang, X.; Shan, D.; Pitchakuntla, M.; Ma, Y.; Jia, Y. Total Syntheses of Festuclavine, Pyroclavine, Costaclavine, EpiCostaclavine, Pibocin A, 9-Deacetoxyfumigaclavine C, Fumigaclavine G, and Dihydrosetoclavine. Org. Lett. 2017, 19, 3323−3326. (58) Liang, J.; Hu, W.; Tao, P.; Jia, Y. Total Synthesis of Dictyodendrins B and E. J. Org. Chem. 2013, 78, 5810−5815. (59) Yamaguchi, A. D.; Chepiga, K. M.; Yamaguchi, J.; Itami, K.; Davies, H. M. L. Concise Syntheses of Dictyodendrins A and F by a Sequential C−H Functionalization Strategy. J. Am. Chem. Soc. 2015, 137, 644−647. (60) Sun, Z.; Zhou, M.; Li, X.; Meng, X.; Peng, F.; Zhang, H.; Shao, Z. Catalytic Asymmetric Assembly of Octahydroindolones: Divergent Synthesis of Lycorine-Type Amaryllidaceae Alkaloids (+)-A-Lycorane and (+)-Lycorine. Chem. - Eur. J. 2014, 20, 6112−6119. (61) Cai, S.-L.; Yuan, B.-H.; Jiang, Y.-X.; Lin, G.-Q.; Sun, X.-W. Asymmetric Cinnamylation of N-Tert-Butanesulfinyl Imines with Cinnamyl Acetates: Total Syntheses of (+)-Lycoricidine and (+)-7Deoxypancratistatin. Chem. Commun. 2017, 53, 3520−3523. (62) Paladino, M.; Zaifman, J.; Ciufolini, M. A. Total Synthesis of (+)-3-Demethoxyerythratidinone and (+)-Erysotramidine Via the Oxidative Amidation of a Phenol. Org. Lett. 2015, 17, 3422−3425. (63) Umihara, H.; Yoshino, T.; Shimokawa, J.; Kitamura, M.; Fukuyama, T. Development of a Divergent Synthetic Route to the Erythrina Alkaloids: Asymmetric Syntheses of 8-Oxo-Erythrinine, Crystamidine, 8-Oxo-Erythraline, and Erythraline. Angew. Chem., Int. Ed. 2016, 55, 6915−6918. (64) In, J.; Lee, S.; Kwon, Y.; Kim, S. Divergent Total Synthesis of the Tricyclic Marine Alkaloids Lepadiformine, Fasicularin, and Isomers of Polycitorols by Reagent-Controlled Diastereoselective Reductive Amination. Chem. - Eur. J. 2014, 20, 17433−17442. (65) Amat, M.; Pinto, A.; Griera, R.; Bosch, J. Enantioselective Synthesis of Lepadins A−D from a Phenylglycinol-Derived Hydroquinolone Lactam. Chem. - Eur. J. 2015, 21, 12804−12808. (66) Pandey, G.; Janakiram, V. Aza-Quaternary Scaffolds from Selective Bond Cleavage of Bridgehead-Substituted 7Azabicyclo[2.2.1]Heptane: Total Synthesis of (+)-Cylindricines C−E and (−)-Lepadiformine A. Chem. - Eur. J. 2015, 21, 13120−13126. (67) Jiang, S. Z.; Lei, T.; Wei, K.; Yang, Y. R. Collective Total Synthesis of Tetracyclic Diquinane Lycopodium Alkaloids (+)-Paniculatine, (−)-Magellanine, (+)-Magellaninone and Analogues Thereof. Org. Lett. 2014, 16, 5612−5615. (68) Kozaka, T.; Miyakoshi, N.; Mukai, C. Stereoselective Total Syntheses of Three Lycopodium Alkaloids, (−)-Magellanine, (+)-Magellaninone, and (+)-Paniculatine, Based on Two PausonKhand Reactions. J. Org. Chem. 2007, 72, 10147−10154. (69) Lin, K. W.; Ananthan, B.; Tseng, S. F.; Yan, T. H. Exceedingly Concise and Elegant Synthesis of (+)-Paniculatine, (−)-Magellanine, and (+)-Magellaninone. Org. Lett. 2015, 17, 3938−3940. (70) Zhao, L.; Tsukano, C.; Kwon, E.; Takemoto, Y.; Hirama, M. Total Syntheses of Complanadines A and B. Angew. Chem., Int. Ed. 2013, 52, 1722−1725. (71) Li, L.; Yang, Q.; Wang, Y.; Jia, Y. Catalytic Asymmetric Total Synthesis of (−)-Galanthamine and (−)-Lycoramine. Angew. Chem., Int. Ed. 2015, 54, 6255−6259.

(72) Ma, X.-Y.; An, X.-T.; Zhao, X.-H.; Du, J.-Y.; Deng, Y.-H.; Zhang, X.-Z.; Fan, C.-A. Au-Catalyzed [2 + 3] Annulation of Enamides with Propargyl Esters: Total Synthesis of Cephalotaxine and Cephalezomine H. Org. Lett. 2017, 19, 2965−2968. (73) King, S. M.; Calandra, N. A.; Herzon, S. B. Total Syntheses of (−)-Acutumine and (−)-Dechloroacutumine. Angew. Chem., Int. Ed. 2013, 52, 3642−3645. (74) Sherwood, T. C.; Trotta, A. H.; Snyder, S. A. A Strategy for Complex Dimer Formation When Biomimicry Fails: Total Synthesis of Ten Coccinellid Alkaloids. J. Am. Chem. Soc. 2014, 136, 9743−9753. (75) Maehara, T.; Motoyama, K.; Toma, T.; Yokoshima, S.; Fukuyama, T. Total Synthesis of (−)-Tetrodotoxin and 11-Norttx6(R)-Ol. Angew. Chem., Int. Ed. 2017, 56, 1549−1552. (76) Cai, S.-L.; Song, R.; Dong, H.-Q.; Lin, G.-Q.; Sun, X.-W. Practical Asymmetric Synthesis of Amathaspiramides B, D, and F. Org. Lett. 2016, 18, 1996−1999. (77) Chiyoda, K.; Shimokawa, J.; Fukuyama, T. Total Syntheses of All the Amathaspiramides. Angew. Chem., Int. Ed. 2012, 51, 2505− 2508. (78) Mfuh, A. M.; Zhang, Y.; Stephens, D. E.; Vo, A. X. T.; Arman, H. D.; Larionov, O. V. Concise Total Synthesis of Trichodermamides A, B, and C Enabled by an Efficient Construction of the 1,2Oxazadecaline Core. J. Am. Chem. Soc. 2015, 137, 8050−8053. (79) Wang, J.; Chen, S.-G.; Sun, B.-F.; Lin, G.-Q.; Shang, Y.-J. Collective Total Synthesis of Englerin A and B, Orientalol E and F, and Oxyphyllol: Application of the Organocatalytic [4 + 3] Cycloaddition Reaction. Chem. - Eur. J. 2013, 19, 2539−2547. (80) Sun, W.-B.; Wang, X.; Sun, B.-F.; Zou, J.-P.; Lin, G.-Q. Catalytic Asymmetric Total Synthesis of Hedyosumins A, B, and C. Org. Lett. 2016, 18, 1219−1221. (81) Bennett, N. B.; Stoltz, B. M. A Unified Approach to the Daucane and Sphenolobane Bicyclo[5.3.0]Decane Core: Enantioselective Total Syntheses of Daucene, Daucenal, Epoxydaucenal B, and 14-Para-Anisoyloxydauc-4,8-Diene. Chem. - Eur. J. 2013, 19, 17745− 17750. (82) Carreras, J.; Livendahl, M.; McGonigal, P. R.; Echavarren, A. M. Gold(I) as an Artificial Cyclase: Short Stereodivergent Syntheses of (−)-Epiglobulol and (−)-4β,7α- and (−)-4α,7α-Aromadendranediols. Angew. Chem., Int. Ed. 2014, 53, 4896−4899. (83) Bürki, C.; Bonjoch, J.; Bradshaw, B.; Villa, G.; Renaud, P. Total Synthesis of Aignopsanes, a Class of Sesquiterpenes: (+)-Aignopsanoic Acid A, (−)-Methyl Aignopsanoate A, and (−)-Isoaignopsanoic A. Chem. - Eur. J. 2015, 21, 395−401. (84) Cheng, X.; Micalizio, G. C. Synthesis of Neurotrophic SecoPrezizaane Sesquiterpenes (1r,10s)-2-Oxo-3,4-Dehydroneomajucin, (2s)-Hydroxy-3,4-Dehydroneomajucin, and (−)-Jiadifenin. J. Am. Chem. Soc. 2016, 138, 1150−1153. (85) Liu, W.; Li, H.; Cai, P.-J.; Wang, Z.; Yu, Z.-X.; Lei, X. Scalable Total Synthesis of Rac-Jungermannenones B and C. Angew. Chem., Int. Ed. 2016, 55, 3112−3116. (86) Zhao, X.; Li, W.; Wang, J.; Ma, D. Convergent Route to EntKaurane Diterpenoids: Total Synthesis of Lungshengenin D and 1α,6α-Diacetoxy-Ent-Kaura-9(11),16-Dien-12,15-Dione. J. Am. Chem. Soc. 2017, 139, 2932−2935. (87) He, C.; Hu, J.; Wu, Y.; Ding, H. Total Syntheses of Highly Oxidized Ent-Kaurenoids Pharicin A, Pharicinin B, 7-O-Acetylpseurata C, and Pseurata C: A [5 + 2] Cascade Approach. J. Am. Chem. Soc. 2017, 139, 6098−6101. (88) Deng, J.; Li, R.; Luo, Y.; Li, J.; Zhou, S.; Li, Y.; Hu, J.; Li, A. Divergent Total Synthesis of Taiwaniaquinones A and F and Taiwaniaquinols B and D. Org. Lett. 2013, 15, 2022−2025. (89) Thommen, C.; Neuburger, M.; Gademann, K. Collective Syntheses of Icetexane Natural Products Based on Biogenetic Hypotheses. Chem. - Eur. J. 2017, 23, 120−127. (90) Wang, C.; Wang, D.; Gao, S. Total Synthesis of Cyanthiwigins A, C, G, and H. Org. Lett. 2013, 15, 4402−4405. (91) Nagatomo, M.; Koshimizu, M.; Masuda, K.; Tabuchi, T.; Urabe, D.; Inoue, M. Total Synthesis of Ryanodol. J. Am. Chem. Soc. 2014, 136, 5916−5919. BZ


Chemical Reviews

Review

(92) Koshimizu, M.; Nagatomo, M.; Inoue, M. Unified Total Synthesis of 3-Epi-Ryanodol, Cinnzeylanol, Cinncassiols A and B, and Structural Revision of Natural Ryanodol and Cinnacasol. Angew. Chem., Int. Ed. 2016, 55, 2493−2497. (93) Müller, D. S.; Untiedt, N. L.; Dieskau, A. P.; Lackner, G. L.; Overman, L. E. Constructing Quaternary Stereogenic Centers Using Tertiary Organocuprates and Tertiary Radicals. Total Synthesis of Trans-Clerodane Natural Products. J. Am. Chem. Soc. 2015, 137, 660− 663. (94) Yue, G.; Zhang, Y.; Fang, L.; Li, C.-C.; Luo, T.; Yang, Z. Collective Synthesis of Cladiellins Based on the Gold-Catalyzed Cascade Reaction of 1,7-Diynes. Angew. Chem., Int. Ed. 2014, 53, 1837−1840. (95) Hugelshofer, C. L.; Magauer, T. A General Entry to Antifeedant Sesterterpenoids: Total Synthesis of (+)-Norleucosceptroid A, (−)-Norleucosceptroid B, and (−)-Leucosceptroid K. Angew. Chem., Int. Ed. 2014, 53, 11351−11355. (96) Hugelshofer, C. L.; Magauer, T. Total Synthesis of the Leucosceptroid Family of Natural Products. J. Am. Chem. Soc. 2015, 137, 3807−3810. (97) Klotter, F.; Studer, A. Short and Divergent Total Synthesis of (+)-Machaeriol B, (+)-Machaeriol D, (+)-Δ8-THC, and Analogues. Angew. Chem., Int. Ed. 2015, 54, 8547−8550. (98) Sulake, R. S.; Chen, C. Total Synthesis of (+)-Antroquinonol and (+)-Antroquinonol D. Org. Lett. 2015, 17, 1138−1141. (99) Kobayashi, S.; Tamanoi, H.; Hasegawa, Y.; Segawa, Y.; Masuyama, A. Divergent Synthesis of Bioactive Resorcinols Isolated from the Fruiting Bodies of Hericium Erinaceum: Total Syntheses of Hericenones A, B, and I, Hericenols B−D, and Erinacerins A and B. J. Org. Chem. 2014, 79, 5227−5238. (100) Trotta, A. H. Total Synthesis of Oridamycins A and B. Org. Lett. 2015, 17, 3358−3361. (101) Kamo, S.; Yoshioka, K.; Kuramochi, K.; Tsubaki, K. Total Syntheses of Juglorescein and Juglocombins A and B. Angew. Chem., Int. Ed. 2016, 55, 10317−10320. (102) Zhang, Y.; Ye, Q.; Wang, X.; She, Q.-B.; Thorson, J. S. A Divergent Enantioselective Strategy for the Synthesis of Griseusins. Angew. Chem., Int. Ed. 2015, 54, 11219−11222. (103) He, C.; Zhu, C.; Dai, Z.; Tseng, C.-C.; Ding, H. Divergent Total Synthesis of Indoxamycins A, C, and F. Angew. Chem., Int. Ed. 2013, 52, 13256−13260. (104) Hwang, M.-H.; Han, S.-J.; Lee, D.-H. Convergent and Enantioselective Total Synthesis of (−)-Amphidinolide O and (−)-Amphidinolide P. Org. Lett. 2013, 15, 3318−3321. (105) Feng, Z.-G.; Bai, W.-J.; Pettus, T. R. R. Unified Total Syntheses of (−)-Medicarpin, (−)-Sophoracarpan A, and (±)-Kushecarpin A with Some Structural Revisions. Angew. Chem., Int. Ed. 2015, 54, 1864−1867. (106) Sohn, T.-i.; Kim, D.; Paton, R. S. Substrate-Controlled Asymmetric Total Syntheses of Microcladallenes A, B, and C Based on the Proposed Structures. Chem. - Eur. J. 2015, 21, 15988−15997. (107) Cichowicz, N. R.; Kaplan, W.; Khomutnyk, Y.; Bhattarai, B.; Sun, Z. K.; Nagorny, P. Concise Enantioselective Synthesis of Oxygenated Steroids Via Sequential Copper(Ii)-Catalyzed Michael Addition/Intramolecular Aldol Cyclization Reactions. J. Am. Chem. Soc. 2015, 137, 14341−14348. (108) Kaplan, W.; Khatri, H. R.; Nagorny, P. Concise Enantioselective Total Synthesis of Cardiotonic Steroids 19-Hydroxysarmentogenin and Trewianin Aglycone. J. Am. Chem. Soc. 2016, 138, 7194− 7198. (109) Xu, Z.; Wang, Q.; Zhu, J. Enantioselective Total Syntheses of Leuconolam−Leuconoxine−Mersicarpine Group Monoterpene Indole Alkaloids. J. Am. Chem. Soc. 2013, 135, 19127−19130. (110) Xu, Z.; Wang, Q.; Zhu, J. Total Syntheses of (−)-Mersicarpine, (−)-Scholarisine G, (+)-Melodinine E, (−)-Leuconoxine, (−)-Leuconolam, (−)-Leuconodine A, (+)-Leuconodine F, and (−)-Leuconodine C: Self-Induced Diastereomeric Anisochronism (SIDA) Phenomenon for Scholarisine G and Leuconodines A and C. J. Am. Chem. Soc. 2015, 137, 6712−6724.

(111) Yang, Y.; Bai, Y.; Sun, S.; Dai, M. Biosynthetically Inspired Divergent Approach to Monoterpene Indole Alkaloids: Total Synthesis of Mersicarpine, Leuconodines B and D, Leuconoxine, Melodinine E, Leuconolam, and Rhazinilam. Org. Lett. 2014, 16, 6216−6219. (112) Li, Z.; Geng, Q.; Lv, Z.; Pritchett, B. P.; Baba, K.; Numajiri, Y.; Stoltz, B. M.; Liang, G. Selective Syntheses of Leuconolam, Leuconoxine, and Mersicarpine Alkaloids from a Common Intermediate through Regiocontrolled Cyclizations by Staudinger Reactions. Org. Chem. Front. 2015, 2, 236−240. (113) Dagoneau, D.; Xu, Z.; Wang, Q.; Zhu, J. Enantioselective Total Syntheses of (−)-Rhazinilam, (−)-Leucomidine B, and (+)-Leuconodine F. Angew. Chem., Int. Ed. 2016, 55, 760−763. (114) Campbell, E. L.; Zuhl, A. M.; Liu, C. M.; Boger, D. L. Total Synthesis of (+)-Fendleridine (Aspidoalbidine) and (+)-1-Acetylaspidoalbidine. J. Am. Chem. Soc. 2010, 132, 3009−3012. (115) Xie, J.; Wolfe, A. L.; Boger, D. L. Total Synthesis of Kopsinine. Org. Lett. 2013, 15, 868−870. (116) Lee, K.; Boger, D. L. Total Syntheses of (−)-Kopsifoline D and (−)-Deoxoapodine: Divergent Total Synthesis Via Late-Stage Key Strategic Bond Formation. J. Am. Chem. Soc. 2014, 136, 3312−3317. (117) Leng, L. Y.; Zhou, X. H.; Liao, Q.; Wang, F. L.; Song, H.; Zhang, D.; Liu, X. Y.; Qin, Y. Asymmetric Total Syntheses of Kopsia Indole Alkaloids. Angew. Chem., Int. Ed. 2017, 56, 3703−3707. (118) Beatty, J. W.; Stephenson, C. R. J. Synthesis of (−)-Pseudotabersonine, (−)-Pseudovincadifformine, and (+)-Coronaridine Enabled by Photoredox Catalysis in Flow. J. Am. Chem. Soc. 2014, 136, 10270−10273. (119) Mizoguchi, H.; Oikawa, H.; Oguri, H. Biogenetically Inspired Synthesis and Skeletal Diversification of Indole Alkaloids. Nat. Chem. 2014, 6, 57−64. (120) Moreno, J.; Picazo, E.; Morrill, L. A.; Smith, J. M.; Garg, N. K. Enantioselective Total Syntheses of Akuammiline Alkaloids (+)-Strictamine, (−)-2(S)-Cathafoline, and (−)-Aspidophylline A. J. Am. Chem. Soc. 2016, 138, 1162−1165. (121) Li, Y.; Zhu, S.; Li, J.; Li, A. Asymmetric Total Syntheses of Aspidodasycarpine, Lonicerine, and the Proposed Structure of Lanciferine. J. Am. Chem. Soc. 2016, 138, 3982−3985. (122) Wang, D.; Hou, M.; Ji, Y.; Gao, S. H. Total Synthesis of Scholarisine K and Alstolactine A. Org. Lett. 2017, 19, 1922−1925. (123) Li, L.; Aibibula, P.; Jia, Q.; Jia, Y. Total Syntheses of Naucleamides A−C and E, Geissoschizine, Geissoschizol, (E)Isositsirikine, and 16-Epi-(E)-Isositsirikine. Org. Lett. 2017, 19, 2642−2645. (124) Mercado-Marin, E. V.; Sarpong, R. Unified Approach to Prenylated Indole Alkaloids: Total Syntheses of (−)-17-HydroxyCitrinalin B, (+)-Stephacidin A, and (+)-Notoamide I. Chem. Sci. 2015, 6, 5048−5052. (125) Zhang, B. X.; Zheng, W. F.; Wang, X. Q.; Sun, D. Q.; Li, C. Z. Total Synthesis of Notoamides F, I, and R and Sclerotiamide. Angew. Chem., Int. Ed. 2016, 55, 10435−10438. (126) Li, H. H.; Wang, X. M.; Lei, X. G. Total Syntheses of Lycopodium Alkaloids (+)-Fawcettimine, (+)-Fawcettidine, and (−)-8-Deoxyserratinine. Angew. Chem., Int. Ed. 2012, 51, 491−495. (127) Li, H. H.; Wang, X. M.; Hong, B. K.; Lei, X. G. Collective Synthesis of Lycopodium Alkaloids and Tautomer Locking Strategy for the Total Synthesis of (−)-Lycojapodine A. J. Org. Chem. 2013, 78, 800−821. (128) Zhang, X.-M.; Tu, Y.-Q.; Zhang, F.-M.; Shao, H.; Meng, X. Total Synthesis of (±)-Alopecuridine and Its Biomimetic Transformation into (±)-Sieboldine A. Angew. Chem., Int. Ed. 2011, 50, 3916−3919. (129) Hou, S. H.; Tu, Y. Q.; Liu, L.; Zhang, F. M.; Wang, S. H.; Zhang, X. M. Divergent and Efficient Syntheses of the Lycopodium Alkaloids (−)-Lycojaponicumin C, (−)-8-Deoxyserratinine, (+)-Fawcettimine, and (+)-Fawcettidine. Angew. Chem., Int. Ed. 2013, 52, 11373−11376. CA


Chemical Reviews

Review

(130) Zaimoku, H.; Nishide, H.; Nishibata, A.; Goto, N.; Taniguchi, T.; Ishibashi, H. Syntheses of (±)-Serratine, (±)-Lycoposerramine T, and (±)-Lycopoclavamine B. Org. Lett. 2013, 15, 2140−2143. (131) Zeng, C.; Zheng, C. W.; Zhao, J. Y.; Zhao, G. Divergent Total Syntheses of (−)-Lycopladine D, (+)-Fawcettidine, and (+)-Lycoposerramine Q. Org. Lett. 2013, 15, 5846−5849. (132) Itoh, N.; Iwata, T.; Sugihara, H.; Inagaki, F.; Mukai, C. Total Syntheses of (±)-Fawcettimine, (±)-Fawcettidine, (±)-Lycoflexine, and (±)-Lycoposerramine-Q. Chem. - Eur. J. 2013, 19, 8665−8672. (133) Yang, Y.; Haskins, C. W.; Zhang, W.; Low, P. L.; Dai, M. Divergent Total Syntheses of Lyconadins A and C. Angew. Chem., Int. Ed. 2014, 53, 3922−3925. (134) Azuma, M.; Yoshikawa, T.; Kogure, N.; Kitajima, M.; Takayama, H. Biogenetically Inspired Total Syntheses of Lycopodium Alkaloids, (+)-Flabellidine and (−)-Lycodine. J. Am. Chem. Soc. 2014, 136, 11618−11621. (135) Xu, K.; Cheng, B.; Li, Y.; Xu, T.; Yu, C.; Zhang, J.; Ma, Z.; Zhai, H. Stereocontrolled Total Syntheses of (±)-Fawcettimine, (±)-Lycoflexine, and (±)-Lycoflexine N-Oxide. Org. Lett. 2014, 16, 196−199. (136) Lee, A. S.; Liau, B. B.; Shair, M. D. A Unified Strategy for the Synthesis of 7-Membered-Ring-Containing Lycopodium Alkaloids. J. Am. Chem. Soc. 2014, 136, 13442−13452. (137) Zhao, X. H.; Zhang, Q.; Du, J. Y.; Lu, X. Y.; Cao, Y. X.; Deng, Y. H.; Fan, C. A. Total Synthesis of (±)-Lycojaponicumin D and Lycodoline-Type Lycopodium Alkaloids. J. Am. Chem. Soc. 2017, 139, 7095−7103. (138) Wang, F. X.; Du, J. Y.; Wang, H. B.; Zhang, P. L.; Zhang, G. B.; Yu, K. Y.; Zhang, X. Z.; An, X. T.; Cao, Y. X.; Fan, C. A. Total Synthesis of Lycopodium Alkaloids Palhinine A and Palhinine D. J. Am. Chem. Soc. 2017, 139, 4282−4285. (139) Li, X.-H.; Zhu, M.; Wang, Z.-X.; Liu, X.-Y.; Song, H.; Zhang, D.; Wang, F.-P.; Qin, Y. Synthesis of Atisine, Ajaconine, Denudatine, and Hetidine Diterpenoid Alkaloids by a Bioinspired Approach. Angew. Chem., Int. Ed. 2016, 55, 15667−15671. (140) Miyatake-Ondozabal, H.; Bannwart, L. M.; Gademann, K. Enantioselective Total Synthesis of Virosaine A and Bubbialidine. Chem. Commun. 2013, 49, 1921−1923. (141) Kwon, S. H.; Seo, H.-A.; Cheon, C.-H. Total Synthesis of Luotonin A and Rutaecarpine from an Aldimine Via the Designed Cyclization. Org. Lett. 2016, 18, 5280−5283. (142) Han, J.-C.; Li, F.; Li, C.-C. Collective Synthesis of Humulanolides Using a Metathesis Cascade Reaction. J. Am. Chem. Soc. 2014, 136, 13610−13613. (143) Cherney, E. C.; Lopchuk, J. M.; Green, J. C.; Baran, P. S. A Unified Approach to Ent-Atisane Diterpenes and Related Alkaloids: Synthesis of (−)-Methyl Atisenoate, (−)-Isoatisine, and the Hetidine Skeleton. J. Am. Chem. Soc. 2014, 136, 12592−12595. (144) Song, L.; Zhu, G.; Liu, Y.; Liu, B.; Qin, S. Total Synthesis of Atisane-Type Diterpenoids: Application of Diels−Alder Cycloadditions of Podocarpane-Type Unmasked Ortho-Benzoquinones. J. Am. Chem. Soc. 2015, 137, 13706−13714. (145) Cheng, H.; Zeng, F.-H.; Yang, X.; Meng, Y.-J.; Xu, L.; Wang, F.-P. Collective Total Syntheses of Atisane-Type Diterpenes and Atisine-Type Diterpenoid Alkaloids: (±)-Spiramilactone B, (±)-Spiraminol, (±)-Dihydroajaconine, and (±)-Spiramines C and D. Angew. Chem., Int. Ed. 2016, 55, 392−396. (146) Yeoman, J. T. S.; Mak, V. W.; Reisman, S. E. A Unified Strategy to Ent-Kauranoid Natural Products: Total Syntheses of (−)-Trichorabdal A and (−)-Longikaurin E. J. Am. Chem. Soc. 2013, 135, 11764− 11767. (147) Yeoman, J. T. S.; Cha, J. Y.; Mak, V. W.; Reisman, S. E. A Unified Strategy for the Synthesis of (−)-Maoecrystal Z, (−)-Trichorabdal A, and (−)-Longikaurin E. Tetrahedron 2014, 70, 4070−4088. (148) Kobayakawa, Y.; Nakada, M. Total Syntheses of (−)-Scabronines G and A, and (−)-Episcabronine A. Angew. Chem., Int. Ed. 2013, 52, 7569−7573.

(149) Hugelshofer, C. L.; Magauer, T. A Divergent Approach to the Marine Diterpenoids (+)-Dictyoxetane and (+)-Dolabellane V. Chem. - Eur. J. 2016, 22, 15125−15136. (150) Jørgensen, L.; McKerrall, S. J.; Kuttruff, C. A.; Ungeheuer, F.; Felding, J.; Baran, P. S. 14-Step Synthesis of (+)-Ingenol from (+)-3Carene. Science 2013, 341, 878−882. (151) McKerrall, S. J.; Jørgensen, L.; Kuttruff, C. A.; Ungeheuer, F.; Baran, P. S. Development of a Concise Synthesis of (+)-Ingenol. J. Am. Chem. Soc. 2014, 136, 5799−5810. (152) Kawamura, S.; Chu, H.; Felding, J.; Baran, P. S. Nineteen-Step Total Synthesis of (+)-Phorbol. Nature 2016, 532, 90−93. (153) Tian, C.; Lei, X.; Wang, Y.; Dong, Z.; Liu, G.; Tang, Y. Total Syntheses of Periconiasins A−E. Angew. Chem., Int. Ed. 2016, 55, 6992−6996. (154) Song, L.; Liu, Y.; Tong, R. Cephalosporolide B Serving as a Versatile Synthetic Precursor: Asymmetric Biomimetic Total Syntheses of Cephalosporolides C, E, F, G, and (4-Ome-)G. Org. Lett. 2013, 15, 5850−5853. (155) Wang, X.; Zhang, H.; Yang, X.; Zhao, J.; Pan, C. Enantioselective Total Synthesis of (+)-Brazilin, (−)-Brazilein and (+)-Brazilide A. Chem. Commun. 2013, 49, 5405−5407. (156) Yang, H.; Feng, J.; Li, Y.; Tang, Y. Biomimetic Syntheses of Rubialatins A, B and Related Congeners. Org. Lett. 2015, 17, 1441− 1444. (157) Krüger, S.; Gaich, T. Enantioselective, Protecting-Group-Free Total Synthesis of Sarpagine Alkaloidsa Generalized Approach. Angew. Chem., Int. Ed. 2015, 54, 315−317. (158) Kitajima, M.; Watanabe, K.; Maeda, H.; Kogure, N.; Takayama, H. Asymmetric Total Synthesis of Sarpagine-Related Indole Alkaloids Hydroxygardnerine, Hydroxygardnutine, Gardnerine, (E)-16-EpiNormacusine B, and Koumine. Org. Lett. 2016, 18, 1912−1915. (159) Wang, N.; Du, S.; Li, D.; Jiang, X. Divergent Asymmetric Total Synthesis of (+)-Vincadifformine, (−)-Quebrachamine, (+)-Aspidospermidine, (−)-Aspidospermine, (−)-Pyrifolidine, and Related Natural Products. Org. Lett. 2017, 19, 3167−3170. (160) Gualtierotti, J.-B.; Pasche, D.; Wang, Q.; Zhu, J. Phosphoric Acid Catalyzed Desymmetrization of Bicyclic Bislactones Bearing an All-Carbon Stereogenic Center: Total Syntheses of (−)-Rhazinilam and (−)-Leucomidine B. Angew. Chem., Int. Ed. 2014, 53, 9926−9930. (161) Du, J.-Y.; Zeng, C.; Han, X.-J.; Qu, H.; Zhao, X.-H.; An, X.-T.; Fan, C.-A. Asymmetric Total Synthesis of Apocynaceae Hydrocarbazole Alkaloids (+)-Deethylibophyllidine and (+)-Limaspermidine. J. Am. Chem. Soc. 2015, 137, 4267−4273. (162) Feng, L.-W.; Ren, H.; Xiong, H.; Wang, P.; Wang, L.; Tang, Y. Reaction of Donor-Acceptor Cyclobutanes with Indoles: A General Protocol for the Formal Total Synthesis of (±)-Strychnine and the Total Synthesis of (±)-Akuammicine. Angew. Chem., Int. Ed. 2017, 56, 3055−3058. (163) Leduc, A. B.; Kerr, M. A. Total Synthesis of (−)-Allosecurinine. Angew. Chem., Int. Ed. 2008, 47, 7945−7948. (164) Wang, X.; Xia, D.; Qin, W.; Zhou, R.; Zhou, X.; Zhou, Q.; Liu, W.; Dai, X.; Wang, H.; Wang, S.; Tan, L.; Zhang, D.; Song, H.; Liu, X. − Y.; Qin, Y. A Radical Cascade Enabling Collective Syntheses of Natural Products. Chem. 2017, 2, 803−816. (165) Sun, Y.; Li, R.; Zhang, W.; Li, A. Total Synthesis of Indotertine A and Drimentines A, F, and G. Angew. Chem., Int. Ed. 2013, 52, 9201−9204. (166) Guo, L.; Zhang, F.; Hu, W.; Li, L.; Jia, Y. Palladium-Catalyzed Synthesis of Benzofurans Via C-H Activation/Oxidation Tandem Reaction and Its Application to the Synthesis of Decursivine and Serotobenine. Chem. Commun. 2014, 50, 3299−3302. (167) Fine Nathel, N. F.; Shah, T. K.; Bronner, S. M.; Garg, N. K. Total Syntheses of Indolactam Alkaloids (−)-Indolactam V, (−)-Pendolmycin, (−)-Lyngbyatoxin A, and (−)-Teleocidin A-2. Chem. Sci. 2014, 5, 2184−2190. (168) Lathrop, S. P.; Movassaghi, M. Application of DiazeneDirected Fragment Assembly to the Total Synthesis and Stereochemical Assignment of (+)-Desmethyl-Meso-Chimonanthine and Related Heterodimeric Alkaloids. Chem. Sci. 2014, 5, 333−340. CB


Chemical Reviews

Review

(188) Yamano, Y.; Chary, M. V.; Wada, A. Stereocontrolled First Total Syntheses of Amarouciaxanthin A and B. Org. Lett. 2013, 15, 5310−5313. (189) Yeom, H.-S.; Li, H.; Tang, Y.; Hsung, R. P. Total Syntheses of Cannabicyclol, Clusiacyclol A and B, Iso-Eriobrucinol A and B, and Eriobrucinol. Org. Lett. 2013, 15, 3130−3133. (190) Tran, D. N.; Cramer, N. Biomimetic Synthesis of (+)-Ledene, (+)-Viridiflorol, (−)-Palustrol, (+)-Spathulenol, and Psiguadial A, C, and D Via the Platform Terpene (+)-Bicyclogermacrene. Chem. - Eur. J. 2014, 20, 10654−10660. (191) Lam, H. C.; Spence, J. T. J.; George, J. H. Biomimetic Total Synthesis of Hyperjapones A−E and Hyperjaponols A and C. Angew. Chem., Int. Ed. 2016, 55, 10368−10371. (192) Oblak, E. Z.; VanHeyst, M. D.; Li, J.; Wiemer, A. J.; Wright, D. L. Cyclopropene Cycloadditions with Annulated Furans: Total Synthesis of (+)- and (−)-Frondosin B and (+)-Frondosin A. J. Am. Chem. Soc. 2014, 136, 4309−4315. (193) Sparling, B. A.; Moebius, D. C.; Shair, M. D. Enantioselective Total Synthesis of Hyperforin. J. Am. Chem. Soc. 2013, 135, 644−647. (194) Sparling, B. A.; Tucker, J. K.; Moebius, D. C.; Shair, M. D. Total Synthesis of (−)-Nemorosone and (+)-Secohyperforin. Org. Lett. 2015, 17, 3398−3401. (195) Kusakabe, T.; Kawai, Y.; Kato, K. Total Synthesis of (+)-Gregatin B and E. Org. Lett. 2013, 15, 5102−5105. (196) Weber, F.; Brückner, R. Total Syntheses of the Dihydrofuranonecarboxylate Natural Products Gregatin B and E: Gram-Scale Synthesis of (+)-Gregatin B and Unambiguous Assignment of the Stereostructure of (+)-Gregatin E. Org. Lett. 2014, 16, 6428−6431. (197) Adachi, S.; Watanabe, K.; Iwata, Y.; Kameda, S.; Miyaoka, Y.; Onozuka, M.; Mitsui, R.; Saikawa, Y.; Nakata, M. Total Syntheses of Lactonamycin and Lactonamycin Z with Late-Stage A-Ring Formation and Glycosylation. Angew. Chem., Int. Ed. 2013, 52, 2087−2091. (198) Nicolaou, K. C.; Cai, Q.; Qin, B.; Petersen, M. T.; Mikkelsen, R. J. T.; Heretsch, P. Total Synthesis of Trioxacarcin DC-45-A2. Angew. Chem., Int. Ed. 2015, 54, 3074−3078. (199) Nicolaou, K. C.; Cai, Q.; Sun, H.; Qin, B.; Zhu, S. Total Synthesis of Trioxacarcins DC-45-A1, A, D, C, and C7″-Epi-C and Full Structural Assignment of Trioxacarcin C. J. Am. Chem. Soc. 2016, 138, 3118−3124. (200) Li, Z.; Leung, T.-F.; Tong, R. Total Syntheses of (±)-Musellarins A-C. Chem. Commun. 2014, 50, 10990−10993. (201) Li, Z.; Ip, F. C. F.; Ip, N. Y.; Tong, R. Highly Trans-Selective Arylation of Achmatowicz Rearrangement Products by Reductive γDeoxygenation and Heck−Matsuda Reaction: Asymmetric Total Synthesis of (−)-Musellarins A−C and Their Analogues. Chem. Eur. J. 2015, 21, 11152−11157. (202) Ruider, S. A.; Sandmeier, T.; Carreira, E. M. Total Synthesis of (±)-Hippolachnin A. Angew. Chem., Int. Ed. 2015, 54, 2378−2382. (203) Ruider, S. A.; Carreira, E. M. A Unified Strategy to Plakortin Pentalenes: Total Syntheses of (±)-Gracilioethers E and F. Org. Lett. 2016, 18, 220−223. (204) Klotter, F.; Studer, A. Total Synthesis of Resveratrol-Based Natural Products Using a Palladium-Catalyzed Decarboxylative Arylation and an Oxidative Heck Reaction. Angew. Chem., Int. Ed. 2014, 53, 2473−2476. (205) Tang, M.-L.; Peng, P.; Liu, Z.-Y.; Zhang, J.; Yu, J.-M.; Sun, X. Sulfoxide-Based Enantioselective Nazarov Cyclization: Divergent Syntheses of (+)-Isopaucifloral F, (+)-Quadrangularin A, and (+)-Pallidol. Chem. - Eur. J. 2016, 22, 14535−14539. (206) Takeuchi, H.; Mishiro, K.; Ueda, Y.; Fujimori, Y.; Furuta, T.; Kawabata, T. Total Synthesis of Ellagitannins through Regioselective Sequential Functionalization of Unprotected Glucose. Angew. Chem., Int. Ed. 2015, 54, 6177−6180. (207) Drew, S. L.; Lawrence, A. L.; Sherburn, M. S. Unified Total Synthesis of the Natural Products Endiandric Acid A, Kingianic Acid E, and Kingianins A, D, and F. Chem. Sci. 2015, 6, 3886−3890. (208) Drew, S. L.; Lawrence, A. L.; Sherburn, M. S. Total Synthesis of Kingianins A, D, and F. Angew. Chem., Int. Ed. 2013, 52, 4221− 4224.

(169) Li, H.; Chen, Q.; Lu, Z.; Li, A. Total Syntheses of Aflavazole and 14-Hydroxyaflavinine. J. Am. Chem. Soc. 2016, 138, 15555−15558. (170) Hesse, R.; Gruner, K. K.; Kataeva, O.; Schmidt, A. W.; Knölker, H.-J. Efficient Construction of Pyrano[3,2-a]Carbazoles: Application to a Biomimetic Total Synthesis of Cyclized Monoterpenoid Pyrano[3,2-a]Carbazole Alkaloids. Chem. - Eur. J. 2013, 19, 14098− 14111. (171) Kumar, V. P.; Gruner, K. K.; Kataeva, O.; Knölker, H.-J. Total Synthesis of the Biscarbazole Alkaloids Murrafoline A−D by a Domino Sonogashira Coupling/Claisen Rearrangement/Electrocyclization Reaction. Angew. Chem., Int. Ed. 2013, 52, 11073−11077. (172) Kutz, S. K.; Börger, C.; Schmidt, A. W.; Knölker, H.-J. Synthesis of Methylene-Bridged Biscarbazole Alkaloids by Using an Ullmann-Type Coupling: First Total Synthesis of Murrastifoline-C and Murrafoline-E. Chem. - Eur. J. 2016, 22, 2487−2500. (173) Matsuoka, J.; Matsuda, Y.; Kawada, Y.; Oishi, S.; Ohno, H. Total Synthesis of Dictyodendrins by the Gold-Catalyzed Cascade Cyclization of Conjugated Diynes with Pyrroles. Angew. Chem., Int. Ed. 2017, 56, 7444−7448. (174) Okano, K.; Fujiwara, H.; Noji, T.; Fukuyama, T.; Tokuyama, H. Total Synthesis of Dictyodendrin A and B. Angew. Chem., Int. Ed. 2010, 49, 5925−5929. (175) Tokuyama, H.; Okano, K.; Fujiwara, H.; Noji, T.; Fukuyama, T. Total Synthesis of Dictyodendrins A-E. Chem. - Asian J. 2011, 6, 560−572. (176) Lee, S.; Kim, K.-H.; Cheon, C.-H. Total Syntheses of Arcyriaflavin A and Calothrixin B Using 2,2′-Bisindole-3-Acetic Acid Derivative as a Common Intermediate. Org. Lett. 2017, 19, 2785− 2788. (177) Marth, C. J.; Gallego, G. M.; Lee, J. C.; Lebold, T. P.; Kulyk, S.; Kou, K. G. M.; Qin, J.; Lilien, R.; Sarpong, R. Network-AnalysisGuided Synthesis of Weisaconitine D and Liljestrandinine. Nature 2015, 528, 493−498. (178) Kou, K. G. M.; Li, B. X.; Lee, J. C.; Gallego, G. M.; Lebold, T. P.; DiPasquale, A. G.; Sarpong, R. Syntheses of Denudatine Diterpenoid Alkaloids: Cochlearenine, N-Ethyl-1α-Hydroxy-17-Veratroyldictyzine, and Paniculamine. J. Am. Chem. Soc. 2016, 138, 10830− 10833. (179) Ding, F.; Leow, M. L.; Ma, J.; William, R.; Liao, H.; Liu, X.-W. Collective Synthesis of 4-Hydroxy-2-Pyridone Alkaloids and Their Antiproliferation Activities. Chem. - Asian J. 2014, 9, 2548−2554. (180) Song, D.; Wang, Z.; Mei, R.; Zhang, W.; Ma, D.; Xu, D.; Xie, X.; She, X. Short and Scalable Total Synthesis of Myrioneuron Alkaloids (±)-A,B-Myrifabral A and B. Org. Lett. 2016, 18, 669−671. (181) Suto, T.; Yanagita, Y.; Nagashima, Y.; Takikawa, S.; Kurosu, Y.; Matsuo, N.; Sato, T.; Chida, N. Unified Total Synthesis of Madangamines A, C, and E. J. Am. Chem. Soc. 2017, 139, 2952−2955. (182) Chen, D.; Evans, P. A. A Concise, Efficient and Scalable Total Synthesis of Thapsigargin and Nortrilobolide from (R)-(−)-Carvone. J. Am. Chem. Soc. 2017, 139, 6046−6049. (183) Dattelbaum, J. D.; Singh, A. J.; Field, J. J.; Miller, J. H.; Northcote, P. T. The Nitrogenous Hamigerans: Unusual Amino AcidDerivatized Aromatic Diterpenoid Metabolites from the New Zealand Marine Sponge Hamigera Tarangaensis. J. Org. Chem. 2015, 80, 304− 312. (184) Li, X.; Xue, D.; Wang, C.; Gao, S. Total Synthesis of the Hamigerans. Angew. Chem., Int. Ed. 2016, 55, 9942−9946. (185) Yang, M.; Yang, X.; Sun, H.; Li, A. Total Synthesis of Ileabethoxazole, Pseudopteroxazole, and Seco-Pseudopteroxazole. Angew. Chem., Int. Ed. 2016, 55, 2851−2855. (186) Yu, X.; Su, F.; Liu, C.; Yuan, H.; Zhao, S.; Zhou, Z.; Quan, T.; Luo, T. Enantioselective Total Syntheses of Various Amphilectane and Serrulatane Diterpenoids Via Cope Rearrangements. J. Am. Chem. Soc. 2016, 138, 6261−6270. (187) Slutskyy, Y.; Jamison, C. R.; Zhao, P.; Lee, J.; Rhee, Y. H.; Overman, L. E. Versatile Construction of 6-Substituted Cis-2,8Dioxabicyclo[3.3.0]Octan-3-Ones: Short Enantioselective Total Syntheses of Cheloviolenes A and B and Dendrillolide C. J. Am. Chem. Soc. 2017, 139, 7192−7195. CC


Divergent Strategy in Natural Product Total Synthesis - Chemical

Recommend Documents