Convergent Strategies in Total Syntheses of Complex Terpenoids

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Convergent Strategies in Total Syntheses of Complex Terpenoids

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Daisuke Urabe, Taro Asaba, and Masayuki Inoue* Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan exhibit higher bioactivities in comparison to their less oxidized counterparts. Therefore, these complex terpenoids are expected to serve as selective cellular probes and pharmacologically useful compounds. The impressive structural diversity of biologically active terpenoids has long served as a source of inspiration for the development of strategies and tactics in organic synthesis and as an elegant platform for exhibiting the creativity of the modern organic chemist.4,5 For instance, biosynthetic cyclization of polyenes into polycycles and postoxidation of the polycycles have inspired chemists to develop new substrates and reactions for artificially mimicking such reactions in laboratories. Scheme 1 CONTENTS illustrates the cascade C−C bond formations into the tetracyclic 1. Introduction 9207 skeleton of triterpenoids by Johnson6 and the multiple oxidation 2. Total Syntheses of Tricyclic Terpenoids 9208 reactions of the taxane skeleton by Baran.7 Since many excellent 2.1. Neodolastanes (5/7/6 Tricycle) 9208 Scheme 1. Polyene Cyclization for Construction of the 2.2. Ophiobolanes and Fusicoccane (5/8/5 TriTetracyclic Skeleton by Johnson and Co-workers (1968) and cycle) 9211 Post-Oxidation of the Taxane Skeleton by Baran and Co2.3. Taxol (6/8/6 Tricycle) 9214 workers (2014) 2.4. Limonoids (6/6/6 Tricycle) 9217 3. Total Syntheses of Tetracyclic Terpenoids 3.1. Nitidasin (5/8/6/5 Tetracycle) 3.2. Steroids (6/6/6/5 Tetracycle) 3.3. C20-Diterpene Alkaloids (6/6/6/6 Tetracycle) 4. Total Syntheses of Pentacyclic Terpenoids 4.1. Neofinaconitine (6/5/6/5/6 Pentacycle) 4.2. Daphmanidin E (5/5/6/6/7 Pentacycle) 5. Total Synthesis of Hexacyclic Terpenoid: Vannusals (5/5/6/5/5/5 Hexacycle) 6. Conclusion Author Information Corresponding Author Notes Biographies References

9217 9217 9218 9222 9223 9223 9224 9225 9226 9226 9226 9226 9227 9227

1. INTRODUCTION One of the largest classes of naturally occurring bioactive compounds, the terpenoids, is of extraordinary pharmacological importance.1,2 The sphere of activity of terpenoids covers anticancer, antiviral, antibiotic, and immunosuppressive. Terpenoids originate biosynthetically from the C5 isoprene monomers.3 The isoprene units are condensed together to form polyenes with a pyrophosphate at the end. The polyenes in turn undergo a series of enzymatic transformations including cationic cyclizations and skeletal rearrangements to generate various carboskeletons, CC and C(sp3)-H bonds of which are further oxidized to afford enormously diverse natural products with distinct oxidation levels. As the oxygen-based functional groups potentially form hydrogen bonds with biological polymers, polycyclic terpenoids with multiple oxygen functionalities often © 2015 American Chemical Society

Special Issue: 2015 Frontiers in Organic Synthesis Received: December 27, 2014 Published: March 17, 2015 9207

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reviews have been published for these biomimetic syntheses,8,9 this review focuses on the nonbiomimetic strategies for the total synthesis of terpenoids. In general, the following features of a target structure increase the challenge of a chemical synthesis: (i) the number and density of functional groups, (ii) the number of stereocenters, (iii) the number and types of rings, and (iv) the overall size of the molecule. Accordingly, the highly oxygenated and fused polycyclic structures of terpenoids pose formidable challenges and necessitate highly efficient and robust synthetic strategies. Both linear and convergent strategies have been applied for the total syntheses of polycyclic terpenoids. The linear strategy includes the one-by-one ring formations from the terminus of a target compound (B → C, D → E) and functionalizations of the carbon framework of all the intermediates (A, C, E) en route to the target (Scheme 2). On the other hand, the convergent strategy involves preparation of the functionalized fragments (F

functionalities of the intermediates H, I, and J. Executing the subsequent reactions from K to the target compound also heightens the synthetic challenge, because the specific steric or electronic effects that arise from the unique three-dimensional structures of complex intermediates present additional difficulties in controlling the outcomes of chemo- and/or stereoselective reactions. This review focuses on various convergent strategies for the assembly of the highly oxygenated terpenoids. Our goal in writing this review is not to provide a comprehensive collection of the literature related to the convergent syntheses of complex terpenoids. Rather, we emphasize the diversity of routes that have culminated in the fused structures of terpenoids. Accordingly, the total syntheses were selected on the basis of the following criteria: (i) the core framework of the target terpenoids was composed of three or more fused carbocycles (e.g., x/y/z-tricycle, where x, y, and z denote the number of carbon atoms of each ring), (ii) the terpenoids possessed two or more heteroatoms, (iii) fragment coupling and subsequent ring formation were utilized, and (iv) the syntheses were published from 1989 to 2014. Figure 1 illustrates representative complex terpenoids whose total satisfy the above-mentioned criteria.10 Among them, we summarize 20 convergent total syntheses, placing particular emphasis on assembly of the fragments, cyclization of the ring between them, and functional group transformations at the last stage (H + I → J → K → target compound, Scheme 2). In this manner, we hope to foster appreciation and show comparative analyses of the various convergent total syntheses.

Scheme 2. Illustration of the Linear and Convergent Strategies for Synthesis of the Fused Polycyclic Terpenoids

2. TOTAL SYNTHESES OF TRICYCLIC TERPENOIDS 2.1. Neodolastanes (5/7/6 Tricycle)

A 5/7/6-fused tricyclic ring system is found in the core framework of a family of neodolastane diterpenes (Figure 2).11 Over 40 compounds belong to this family, and they possess an oxygenated tricyclic structure with two angular methyl groups (C8 and 11) and an isopropyl group (C12). Biological studies of this class of diterpenes revealed their potent antibacterial activities against methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium, although the therapeutic development of these diterpenes has been hampered due to their negative side effects, e.g., hemolytic activity against human red blood cells.12 To date, a number of synthetic approaches to the unique carbon framework of the neodolastane diterpenes have been developed, culminating in several total and formal syntheses.13 Here, the total syntheses of the diterpenes from Overman’s (guanacastepene N, 1),14 Carreira’s (guanacastepenes N and O, 1 and 2),15 Sorensen’s (guanacastepene E, 3),16 and Trauner’s (ent-heptemerone B, ent-4, and entguanacastepene E, ent-3)17 groups are summarized. In 2006, Overman and co-workers reported the total synthesis of (+)-guanacastepene N (1) by using conjugate addition and subsequent 7-endo Heck cyclization for assembly of the 5membered A- and 6-membered C-rings. Optically active (S)-iodide 6 was prepared from 5 using Ireland-Claisen rearrangement to set the quaternary carbon (Scheme 3). (R)-Cyclopentenone 9 was synthesized from 8 in 3 steps including optical resolution by attachment of (+)-menthol. Next, cyanocuprate reagent 7 was generated from 6 by sequential treatment with t-BuLi and CuCN. This metalated C-ring was subjected to TMSBr and A-ring 9 to promote the desired conjugate addition, affording silyl enol ether 10. After the

→ H, G → I), coupling of two or more carbocycles (H + I → J), subsequent cyclization (J → K), and functionalizations (K → target compound). Since the stepwise nature of the linear strategy results in a large number of steps, the convergent strategy is more advantageous in designing shorter synthetic routes to these complex terpenoids. To take maximum advantage of the convergent strategy, multiple polar functional groups need to be implemented in the coupling partners H and I, and the subsequent functional group manipulations after the cyclization must be minimized. Furthermore, it is important that the coupling and cyclization reactions are selected in order not to damage the preexisting 9208

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Figure 1. Reported convergent total syntheses of representative polycyclic terpenoids.

of the delocalized radical derived from bromide 20 with nBu3SnH in air, followed by in situ reduction of the allylic peroxide intermediate with Ph3P,19 yielded the correct C5-stereoisomer, and thus the total synthesis of (+)-guanacastepene N (1) was completed. In 2011, Carreira and co-worker reported the total synthesis of (±)-guanacastepenes N (1) and O (2) by utilizing cyclohexyne cycloinsertion and ring expansion reactions as the key steps.20 This novel methodology converted the 5/5-fused ring system 22 and the 6-membered ring 24 to the 5/7/6-framework of the guanacastepenes. Bicyclic ketone 22, a substrate of the crucial annulation, was prepared from 21 in 7 steps as a racemate (Scheme 4). Treatment of iodonium salt 23 with KOCEt3 generated cyclohexyne 24, which underwent syn-addition with the potassium enolate derived from 22 to afford tetracycle 25. The A- and C-rings were successfully joined in a highly diastereoselective manner by this annulation. Thus, the obtained 5/4-ring system of 25 was expanded to the 7-membered ring of 26 by the action of Fe2(CO)9 at 90 °C.21 Interestingly, it was proposed that Fe(CO)4 promoted the disrotatory opening of the cyclobutene in the formation of the dienol-Fe(CO)3 complex 26.22 The subsequent demetalation of 26 and tautomerization were induced by DBU, leading to the requisite 5/7/6-tricycle 27. Toward the completion of the total synthesis, the angular C8methyl group of the target compounds was installed by a combination of cyclopropanation and reduction. Before doing so, the C2-ketone of 27 was stereoselectively reduced from the convex face by using a 1:1 mixture of DIBAL-H and n-BuLi, producing the α-oriented allylic alcohol. This hydroxy group directed the next cyclopropanation23 to undergo from the α-face of the molecule. After oxidation of the hydroxy group to the corresponding ketone, the cyclopropane of 28 was regioselectively opened via a single-electron transfer under Birch conditions, and the enol intermediate 29 was captured by oxygen in a single operation, yielding hydroperoxide 30. The last remaining ring was assembled by the following sequence. Enone 31 was first produced through Me2S-reduction

Figure 2. 5/7/6-Tricyclic ring system: the structures of neodolastane diterpenes.

reaction of 10 with Eschenmoser’s salt, the adduct was converted to diene 12 by N-alkylation, followed by base-promoted elimination. The C15-carbon unit was then installed on 13, which was prepared from 12 in 5 steps, by alkoxycarbonylation of the lithium enolate of 13 with benzyl formate. The 3-step sequence from 14 including formation of the enol triflate, cleavage of the TBS group, and oxidation of the resulting allylic alcohol delivered the key substrate 15 for the B-ring formation. The 7-membered B-ring was constructed by the Heck cyclization: treatment of enol triflate 15 with Pd-catalyst in the presence of KOAc gave rise to 16.18 The highly regioselective 7endo cyclization was favored over the 6-exo cyclization that would lead to an intermediate lacking an eliminating β-hydrogen. The synthesis of guanacastepene N (1) was completed from the Heck product 16. The β-oriented C13-hydroxy substituent of 17 was introduced by oxidation of the TES-enol ether derived from 16 with DMDO. After acetylation, cleavage of the benzyl group of 18 with Pd(OAc)2 and Et3SiH induced the oxy-Michael addition to form the 5-membered oxacycle of 19. Treatment of resultant 19 with NBS in the presence of (BzO)2 promoted the unsaturation and concomitant C5-bromination. Solvolysis of 20 in acetone/water in the presence of Ag(I) salt preferentially provided the incorrect C5-epimer of 1. In contrast, oxygenation 9209

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Scheme 3. Total Synthesis of (+)-Guanacastepene N (Overman, 2006)

Scheme 4. Total Synthesis of (±)-Guanacastepenes N and O (Carreira, 2011)

of peroxide 30 and subsequent SOCl2-promoted dehydration. The ethynyl group, a surrogate of carboxylic acid, was then installed at the C4 position by the stereoselective 1,4-addition of Me2AlCCTMS to 31. The triple bond of 32 was oxidatively cleaved to the carboxylic acid. The acid was then converted to the corresponding acid chloride, which was intramolecularly attacked by the C2-ketone, generating the lactone ring of 33 with concomitant C4-epimerization. For the total synthesis of the targeted guanacastepenes, the common intermediate bis-enol ether 34 was prepared by exposure of 33 to TBSOTf/Et3N. Osmylation of 34 generated the hydroxylated diene 36 along with diene 35. These products were transformed into the two guanacastepenes as follows. The β-configured C13-acetate was introduced by treating 35 with Mn(OAc)3.24 The C5-position was hydroxylated according to the procedure developed by Overman, yielding (±)-guanacastepene N (1). (±)-Guanacastepene O (2) was synthesized from 36 by C13-acetylation and two-step C5-hydroxylation.

Sorensen and co-worker reported the synthesis of both natural (+)- and unnatural (−)-guanacastepenes E (3) from (S)- and 9210

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the C14-ketone of 44, (iii) C13-hydroxylation by epoxidation of the enol ether, (iv) attachment of the Ac group, (v) removal of the PMP acetal, and (vi) SiO2-promoted oxy-Michael addition. Trauner and co-workers reported the total synthesis of (−)-heptemerone B (ent-4) and (−)-guanacastepene E (ent-3), both of which are unnatural enantiomers. Conjugate addition using a cyanocuprate reagent and anodic oxidative cyclization were employed for construction of the B-ring from the A- and Cring fragments. Enantiomerically enriched building blocks 4829 and 51 were synthesized from 47 in 7 steps and 50 in 6 steps, respectively (Scheme 6). The two carbocycles were coupled by utilizing the conditions developed by Lipshutz and Yamamoto.30 Specifically, iodine−lithium exchange of 48 with t-BuLi, followed by addition of lithium 2-thienylcyanocuprate, gave the mixed cyanocuprate 49, which then underwent the conjugate addition to 51 in the presence of BF3·OEt2 to afford product 52 as a single stereoisomer. Although attempts to trap the copper enolate with TMSCl in situ were unsuccessful, silylation of 52 realized regioselective deprotonation of the ketone, resulting in formation of TBS-enol ether 53. The next key cyclization of the B-ring from 53 via C1−2 bond formation necessitated the umpolung, since both positions were inherently nucleophilic. The authors achieved this challenging transformation by application of an anodic oxidation,31 resulting in formation of tetracycle 57 as a single isomer. The mechanism of the intriguing cyclization was proposed as follows.32 Oxidation of the silyl enol ether 53 to the corresponding radical cation 54 and the following intramolecular Friedel−Crafts cyclization provide intermediate 55. Capture of carboxonium radical cation 55 by MeOH and a second anodic oxidation form 56, TBS-elimination from which affords 57. The 7-step functional group manipulation from thus obtained tetracycle 57 furnished (−)-heptemerone B (ent-4), which was further converted to (−)-guanacastepene E (ent-3) by site-selective C5-deacetylation. Through the present total synthesis, the absolute configuration of natural heptemerone B (4) was established to be the antipode of that shown in Scheme 6.

(R)-carvones, respectively. The key transformations in the total synthesis are the π-allyl Stille coupling of the two cyclic building blocks 38 and 40 and sequential [2 + 2]-photocycloaddition/ reductive fragmentation to access the tricyclic system of guanacastepene E (3). The synthetic route is summarized below. Chiral vinylstannane 38 was synthesized from (S)-carvone 37 through an 8-step transformation, while optically pure allylic mandelate 40, the counterpart of the coupling reaction, was derivatized from 39 in 11 steps including the resolution of the achiral intermediate by acylation with (S)-mandelic acid (Scheme 5). The two functionalized carbocycles, the A- and Crings, were effectively linked by the CuCl-accelerated π-allyl Stille reaction.25 The B-ring was constructed by combination of Scheme 5. Total Synthesis of (+)-Guanacastepene E (Sorensen, 2006)

2.2. Ophiobolanes and Fusicoccane (5/8/5 Tricycle)

Ophiobolane sesterterpenes33 and fusicoccane diterpenes34 represent natural products bearing the 5/8/5-tricyclic ring system (Figure 3). These terpenes are derived from a wide range of natural sources (e.g., fungi, liverworts, algae, and higher plants). Ophiobolanes are known to exhibit antibacterial and antifungal activities and cytotoxicity against several cancer cell lines, while fusicoccanes function as phytohormones. These classes of terpenes have been attractive synthetic targets,35 because their unique tricyclic skeleton contains a synthetically challenging 8-membered carbocycle as the central ring (Bring).36 To access the complex ring structure, distinct convergent strategies have been explored. The selected total syntheses of the terpenes from Kishi’s (ophiobolin C, 60),37 Nakada’s (ophiobolin A, 61),38 and Kato and Takeshita’s (cotylenol, 62)39 laboratories are shown below. In 1989, Kishi and co-workers reported the total synthesis of (+)-ophiobolin C (60) by utilizing a Ni(II)/Cr(II)-mediated reaction [a.k.a. Nozaki−Hiyama−Kishi (NHK) reaction] for formation of the 8-membered B-ring. Before the fragment coupling, the two functionalized 5-membered A- and C-rings were synthesized from 63 in 2 steps and 65 in 18 steps,40 respectively, in optically pure forms (Scheme 7). The lithium− bromine exchange of 64 generated the vinyl lithium species, which reacted with aldehyde 66 to afford the adduct 67.

cycloaddition and fragmentation. First, irradiation of 41 with a mercury lamp stereoselectively effected the [2 + 2] photocycloaddition between the enone and olefin moieties to form the strained cyclobutane of 42.26 Next, SmI2-mediated reductive fragmentation27 of 42 cleaved the C−C bond parallel to the πorbital of the carbonyl group, giving rise to the 7-membered ring. The putative Sm-enolate was trapped with PhSeBr in one pot, leading to 43.28 These 3 steps from 38 and 40 effectively built the requisite 5/7/6-fused ring system. Implementation of the remaining functional groups only necessitated 6 steps to deliver (+)-guanacastepene E (3): (i) oxidation of selenide 43 to the corresponding selenoxide and subsequent syn-elimination of the selenoxide to form diene 44, (ii) silyl enol ether formation from 9211

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Scheme 6. Total Synthesis of (−)-Heptemerone B and (−)-Guanacastepene E (Trauner, 2006)

Figure 3. 5/8/5-Tricyclic ring system: the structures of ophiobolane and fusicoccane terpenoids.

conditions, demonstrating high applicability of the NHK reaction to complex substrates. Only 9 transformations were required to complete the total synthesis from 70. Secondary allylic alcohol 70 was transformed to primary allylic alcohol 73 through epoxidation of the exodouble bond, thiocarbonate formation, and radical-mediated reductive opening of the epoxide. During the radical reaction, the C1-double bond was concomitantly reduced to produce 73 in a stereoselective fashion. After protection of the C21-primary alcohol of 73 as its TBS ether, the C20-methyl group was introduced, and the carbon side chain of the C-ring was extended. Finally, desilylation and Swern oxidation gave rise to (+)-ophiobolin C (60). In 2011, Nakada and co-workers reported the total synthesis of (+)-ophiobolin A (61), which possesses an additional spirofused tetrahydrofuran moiety on the C-ring of ophiobolin C (60). In the authors’ strategy, the C-ring was cyclized by the Hosomi−Sakurai reaction, and the B-ring was constructed by boron enolate-mediated aldol reaction and ring-closing metathesis. The C-ring fragment was synthesized from enantiopure 75 and 77 (Scheme 8).43 Compounds 75 and 77 were derivatized into iodide 76 in 15 steps and lactone 78 in 3 steps, respectively. Lithiation of 76 with t-BuLi, followed by addition of lactone 78, yielded the coupled adduct 79 as the hemiacetal. The BF3·Et2Opromoted Hosomi−Sakurai alkylation44 of 79 cyclized the 5membered carbocycle stereoselectively, providing 80 as a major product. The obtained 80 was further transformed into the spirofused C-ring fragment 81 via a 4-step sequence. C-ring 81 was next coupled with A-ring 83, which was prepared from optically pure 82 in 6 steps (Scheme 9). αBromoketone 83 was regioselectively transformed to the corresponding boron enolate by application of n-Bu3SnH and Et3B.45 The enolate attacked the aldehyde of 81, resulting in formation of the aldol adduct 84 in a diastereoselective fashion. The next 10 steps from 84 to 85 involved manipulations of the peripheral functional groups. The methyl ketone moiety of 85 was transformed into the allyl alcohol of 86 in 3 steps: (i) formation of the vinyl triflate with Comins’ reagent,46 (ii) Pdmediated carbomethoxylation, and (iii) DIBAL-H reduction of

Construction of the α,β-unsaturated ketone and functional group manipulations of the two carbon chains converted 67 to 69. Compound 69 was then subjected to the key intramolecular Ni(II)/Cr(II)-mediated coupling reaction.41,42 Specifically, treatment of 69 with excess CrCl2 and catalytic NiCl2 in a mixture of DMSO and Me2S cyclized the 8-membered B-ring, affording 70 as a single diastereomer. Noteworthily, the baselabile functional groups, including the enone, β-hydroxy ketone, and pivaloate groups, were unaffected under the reaction 9212

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Scheme 7. Total Synthesis of (+)-Ophiobolin C (Kishi, 1989)

Scheme 8. Synthesis of the C-Ring Fragment Using Nucleophilic Addition and Hosomi−Sakurai Cyclization

In 1994, Kato and Takeshita’s group reported the total synthesis of (−)-cotylenol (62). The strategy employed the Crmediated allylation for coupling of the A- and C-rings, and the ene reaction for cyclization of the B-ring. Compounds 90 and 91 were converted to the racemic carboxylic acid, which was derivatized into the diastereomeric menthol esters 3(S)-92a and 3(R)-92b (6 steps, Scheme 10). The resultant enantiopure 3(S)-92a and 3(R)-92b were utilized for syntheses of A-ring 93 (12 steps) and C-ring 94 (5 steps), respectively.50 The two fragments were then linked by the Crmediated allylation.51 Namely, treatment of C-ring 94 with the low-valent Cr species generated the corresponding organochromium compound, which then attacked the aldehyde of Aring 93, giving rise to bicyclic intermediate 95 after TMS protection. Next, the substrate for the key ene reaction was prepared. Hydroboration/oxidation of the C7-olefin of 95 generated the C8-primary hydroxy group of 96. The C1-double bond of 98 was constructed from 96 by the following sequence: removal of the TMS group at the C1-oxygen atom, introduction of the TBS group at the C8-oxygen atom, mesylation of the C1-hydroxy group, and reductive olefination from the epoxy mesylate under Birch conditions.52 The protective group manipulations from 98 afforded 99 in 3 steps, and oxidation of the alcohol of 99 generated the aldehyde of 100. Significantly, the ene reaction of 100 occurred only by heating 100 to 160 °C, producing the 8membered B-ring of 101. Thus, this reaction completed the stereoselective assembly of the tricyclic framework of cotylenol (62). The final stage of the synthesis involved construction of the C8,9-trans-diol structure. After oxidation of the C8-hydroxy group of 101 to the ketone, the C9-hydroxy group of 103 was stereoselectively installed through the enolate formation from 102 and subsequent hydroxylation with MoOPH.53 The C9hydroxy directed reduction of the C8-ketone of 103 was realized using NaBH(OAc)3,54 establishing the C8,9-trans-diol stereochemistry of 104. Finally, desilylation of 104 gave rise to (−)-cotylenol (62).

the methyl ester. The crucial 8-membered B-ring formation was realized by ring-closing metathesis.47 Although the protecting groups of the four hydroxy groups dramatically influenced the cyclization efficiency, the authors found 87 to be the best substrate. Accordingly, treating 87 with the second-generation Hoveyda−Grubbs catalyst L 48 in the presence of 1,4benzoquinone49 at 110 °C generated 88. Finally, a 6-step sequence converted 88 to (+)-ophiobolin A (61). 9213

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Scheme 9. Total Synthesis of (+)-Ophiobolin A (Nakada, 2011)

Scheme 10. Total Synthesis of (−)-Cotylenol (Kato and Takeshita, 1994)

2.3. Taxol (6/8/6 Tricycle)

One of the most important families of tricarbocycles containing 8-membered rings is that of the taxane diterpenes (Figure 4). The taxane family is mainly derived from yew trees, and the genus Taxus produces over 300 related compounds.55 Among these, taxol (105) has attracted special attention in natural product chemistry because of its potent anticancer activity. Taxol (105) has in fact been used as an anticancer drug for treatment of a wide range of human cancers.56,57 In addition, the fused 6/8/6tricyclic structure, which is densely functionalized by hydroxy, acetyl, benzoyl, and oxetane groups, poses a synthetic challenge, and numerous creative synthetic studies have been reported over the years.58,59 In this review, three convergent total syntheses reported by Nicolaou’s,60 Danishefsky’s,61 and Kuwajima’s62 groups are presented.

In 1994, Nicolaou and co-workers reported the total synthesis of (−)-taxol (105) based on two coupling reactions, Li-anionmediated coupling of two 6-membered ring fragments (Shapiro reaction) and low-valent Ti-mediated ketyl radical coupling (McMurry reaction) (Scheme 11). As substrates for the Shapiro reaction, the two functionalized 6-membered fragments 10863 (A-ring) and 11164 (C-ring) were prepared from four simple building blocks (106 and 107 for 108 and 109 and 110 for 111) by using the Diels−Alder cycloaddition as the key process. The vinyl lithium species that was generated by treatment of 108 with n-BuLi attacked the aldehyde of 111.65 The reaction effectively 9214

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generated the adduct 112, which had all of the necessary carbons of the taxane framework. Hydroxy-directed epoxidation of the C1-olefin of 112 with VO(acac)2/t-BuOOH,66 followed by reductive opening of the epoxide and protection of the diol, led to carbonate 113. After the bis-desilylation of 113, the resultant hydroxy groups were simultaneously oxidized with TPAP/ NMO.67 Construction of the 8-membered B-ring was extensively optimized.68 Thus, treating 114 with TiCl3·DME1.5 and Zn−Cu at 70 °C resulted in formation of the desired 116 together with three other products. The mechanism of the cyclization was proposed to involve coupling of the two ketyl radical species generated by the low-valent Ti (0) reagent. For the total synthesis of enantiopure taxol (105), resolution was carried out by acylation of racemic diol 116 with (1S)-camphanic chloride M, leading to diastereomeric 117a and 117b, which were separated by silica gel column chromatography. The 9 steps of oxidations and protecting group manipulations from 117a provided 118 (Scheme 12). TMS-protection of the

Figure 4. 6/8/6-Tricyclic ring system: the structure of taxol.

Scheme 11. Construction of the Taxane Framework through Shapiro and McMurry Couplings

Scheme 12. Total Synthesis of (−)-Taxol (Nicolaou, 1994)

C20-hydroxy group, triflation of the C5-hydroxy group, cleavage of the TMS group, and SiO2-induced SN2-type cyclization constructed the oxetane structure of 120. After acetylation, the authors completed the total synthesis of (−)-taxol (105) by the following transformations from 121:69 (i) regioselective opening of the carbonate with PhLi, (ii) C13-allylic oxidation with PCC, (iii) stereoselective reduction of the C13-ketone, (iv) attachment of the side chain with β-lactam N,70 and (v) removal of the TES groups. Danishefsky and co-workers reported the total synthesis of (−)-taxol (105) in 1995. The synthesis features nucleophilic 9215

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alized C-ring fragment with the reactive oxetane structure was successfully utilized in the anionic coupling reaction, and this contributed to increase the convergency of the total synthesis. After the C11-ketone of 129 was unmasked by removal of the TMS group, the C2-hydroxy-directed epoxidation of the C1olefin and reductive opening of the epoxide gave rise to 130. The diol of 130 was protected as its carbonate, and the enone was subjected to 1,4-reduction conditions to afford ketone 131. Triflation of the potassium enolate of 131 with PhNTf2, followed by hydrolysis of the acetal to the aldehyde and Wittig olefination, constructed the requisite functional groups for the key cyclization. When 132 was treated with a stoichiometric amount of Pd(PPh3)4, the highly strained 8-membered B-ring with the bridgehead olefin was cyclized to generate tetracycle 133. Success of the cyclization showed the power of the Heck reaction in constructing highly functionalized systems. After exchanging the TBS of 133 to the TES of 134, the C11olefin was temporarily protected as the corresponding epoxide to afford 135. The following 5-step sequence, including reductive cleavage of the benzyl group and oxidative cleavage of the exomethylene, converted 135 to 136. The C11-olefin was regenerated by treating 136 with SmI2 in the presence of Ac2O, leading to 137. The C9-hydroxylation of 137 with (PhSeO)2O, followed by an α-ketol interchange and acetylation, provided 122. Finally, 122 was transformed to (−)-taxol (105) through C13-allylic oxidation and installation of the side chain using lactam N. Kuwajima’s total synthesis of (−)-taxol (105) in 1998 is summarized in Schemes 14 and 15. The key reactions for

addition of the A-ring to the highly functionalized C-ring and intramolecular Heck reaction for cyclization of the 8-membered B-ring. The A- and C-ring fragments were prepared from 125 in 4 steps and (S)-Wieland Miescher ketone 12771 in 23 steps, respectively (Scheme 13). Lithium−iodine exchange of A-ring 126 with t-BuLi generated the vinyl lithium species, which was coupled with aldehyde 128 to afford 129. The fully functionScheme 13. Total Synthesis of (−)-Taxol (Danishefsky, 1995)

Scheme 14. Construction of the Tricyclic Framework of Taxol via Anion-Promoted Coupling and Vinylogous Mukaiyama Aldol Reactions

constructing the taxane skeleton are the carbanion-promoted coupling reaction between the A- and C-rings and the vinylogous Mukaiyama aldol reaction for the B-ring formation. The anionic coupling was applied to connect the 6-membered A-ring 141 and C-ring 143, which were prepared from 140 in 12 steps and 142 in 7 steps, respectively (Scheme 14).72 The coupling product 144 was stereoselectively produced by nucleophilic addition of the vinyl lithium, prepared from 143 and t-BuLi, to aldehyde 141 in the presence of chelating Mg(II) ion. The 1,2-diol of 144 was protected as the corresponding boronate of 145. When 145 was exposed to TiCl2(Oi-Pr)2, the oxocarbenium cation was produced from the dibenzyl acetal and 9216

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singlet oxygen to generate 149. Subsequent treatment of 149 with n-Bu3SnH and AIBN simultaneously reduced the O−O and C−S bonds to provide 150. Removal of the benzyl group of 150 and subsequent protection of the 1,3-diol as the benzylidene acetal yielded 151. The β-oriented C8-methyl group was then introduced as the β-configured cyclopropane. Thus, hydroxydirected cyclopropanation of 151 with Et2Zn/ClCH2I afforded 152, which was converted to 153 in 15 steps including the reductive C−C bond cleavage of the cyclopropane. Next, the oxetane moiety was constructed. The vinyl triflate of 153 was coupled with TMSCH2MgBr in the presence of Pd(PPh3)4 to produce the allylsilane, chlorination of which with NCS led to allyl chloride 154. After reprotection of the concomitantly liberated C7-hydroxy group of 154 as the acetal, the β-oriented C10-acetate was installed. The enolate derived from 155 with LDA was treated with MoOPH to generate the C10-hydroxy group, whose configuration was opposite to that of taxol (105). After the acetylation, epimerization of the oxygen functionality was induced by the action of DBN, resulting in formation of 156 with the thermodynamically more favored βconfigured acetoxy group. Dihydroxylation of 156 with OsO4 selectively occurred at the C4-exo-olefin without touching the C11-olefin to afford diol 157. The oxetane was then formed by heating 157 with DBU in toluene, giving rise to tetracycle 158. Finally, an additional 11 transformations from 158 completed the total synthesis of (−)-taxol (105).

Scheme 15. Total Synthesis of (−)-Taxol (Kuwajima, 1998)

2.4. Limonoids (6/6/6 Tricycle)

In 2012, Williams and co-workers reported the convergent total synthesis 75 of cipadonoid B (167, Scheme 16) 76 and derivatization of 167 to the three other limonoids, proceranolide (159),77 mexicanolide (160),78 and khayasin (161, Figure 5).79 The authors combined the Claisen rearrangement and 1,6conjugate addition toward construction of the 6/6/6-tricyclic structure of the limonoids.80 Enantiomerically enriched 163 and 165 were readily synthesized from 162 in 4 steps and 164 in 3 steps, respectively (Scheme 16). The two carbocycles 163 and 165 were O-tethered under acidic conditions, giving rise to vinyl ether 166. The thermal Claisen rearrangement of 166 connected the fragments by forming the C−C bond, affording (−)-cipadonoid B (167) as the major product, along with its diastereomer (dr = 7:3). Thus, the reaction established the two stereocenters in the required configurations of 167, albeit in modest yield. After nucleophilic epoxidation of the obtained 167 with H2O2, the 6-membered ring was constructed by the 1,6-conjugate addition from 168. The epoxide of 168 was reductively opened using Al/Hg to generate enolate 169, which underwent 6-endo cyclization to afford (−)-proceranolide (159). Furthermore, Jones oxidation of 159 led to (−)-mexicanolide (160), while the isobutyrate formation from 159 delivered (−)-khayasin (161). The unified total synthesis of the four natural products demonstrated high utility of the convergent approach for the divergent syntheses of natural products and related compounds.

attacked by the electron-rich vinyl ether, leading to the C9−10 bond formation.73 Thus, this successful cyclization of the 8membered B-ring of 146 demonstrated the utility of the vinylogous Mukaiyama aldol reaction in construction of a medium-sized carbocycle. Subsequent removal of the boronate from 146 produced 1,2-diol 147. The target natural product was synthesized from 147 (Scheme 15). Protection of the 1,2-diol of 147 as its silylene acetal,74 followed by reduction of the C13-ketone and TBS-introduction of the C13-hydroxy group, gave rise to 148. The conjugated diene of 148 then participated in the Diels−Alder reaction with

3. TOTAL SYNTHESES OF TETRACYCLIC TERPENOIDS 3.1. Nitidasin (5/8/6/5 Tetracycle)

In 2014, Trauner and co-workers reported the total synthesis of nitidasin (170, Figure 6),81 which was isolated from the plant Gentianella nitida.82 The structure of nitidasin (170) is characterized by the unusual 5/8/6/5 tetracyclic carbon framework with 10 stereocenters. Coupling of the bicyclic and monocyclic fragments and cyclization of the 8-membered ring by 9217

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Scheme 16. Asymmetric Total Synthesis of the Four Limonoids (Williams, 2012)

Figure 5. 6/6/6-Tricyclic ring system: the structures of limonoids.

Figure 6. 5/8/6/5-Tetracyclic ring system: the structure of nitidasin.

of the C17-hydroxy group by a combination of TPAP/NMO, furnished (−)-nitidasin (170). 3.2. Steroids (6/6/6/5 Tetracycle)

The steroid framework including the 6/6/6/5 tetracyclic ring system is an extremely important structural motif from both the chemical and biological points of view (Figure 7). A considerable number of steroid derivatives have been identified from a wide range of natural sources, and their diverse and profound bioactivities have been explored for applications to pharmaceuticals and life science research.86 Consequently, total and semi syntheses of the steroids and related compounds have been pursued for many years.87 Among the steroid natural products, cardenolide glycosides are one of the most attractive subgroups because of their potent Na+/K+-ATPase inhibiting activities.88 Recent studies have disclosed that the binding of the cardenolides to Na+/K+ATPase regulates various important cellular processes.89 Aside from the bioactivity, the structure of the cardenolides is characterized by its unusual steroid framework, in which both of the AB- and CD-rings are cis fused. Furthermore, the presence of the hydroxy groups and the butenolide heightens the synthetic challenges.90,91 Here, the total synthesis of ouabain (179) from Deslongchamps’ group,92 rhodexin A (180) from Jung’s group,93 and 19-hydroxysarmentogenin (181) from our group94 are summarized. In 2008, Deslongchamps and co-workers reported the total synthesis of the highly oxygenated cardenolide glycoside, (−)-ouabain (179). The key C−C bond formations for assembly of the functionalized steroid framework are the double Michael

the ring-closing metathesis were utilized for the convergent synthesis of 170. The two fragments 172 and 174 were synthesized from the optically active building blocks 171 in 9 steps and Hajos-Parrish ketone 17383 in 29 steps, respectively (Scheme 17). Treatment of iodide 172 with t-BuLi, followed by the addition of ketone 174, afforded 175 as a major isomer. In this particular coupling reaction, the tetrasubstituted alkenyl lithium, which has been rarely used, effectively attacked the sterically hindered C12ketone of 174. After epoxidation of the C10-tetrasubstituted double bond of 175, diene 176 was cyclized into the 8-membered ring 177 by the action of the Grubbs second-generation catalyst O.84 TASF85 in HMPA then removed the SEM group of 177. The hydrogenation of olefin 178, and the subsequent oxidation 9218

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While A-ring 183 was prepared from enantiopure 182 in 3 steps, D-ring 18495 was synthesized from Hajos-Parrish ketone 173 in 14 steps (Scheme 18). A tandem Michael addition under

Scheme 17. Total Synthesis of (−)-Nitidasin (Trauner, 2014)

Scheme 18. Double Michael Addition for Construction of the Tricyclic Structure

basic conditions was initiated by the intermolecular Michael addition of the deprotonated 184 to cyclohexenone 183, leading to 185. The intramolecular Michael addition from 185 proceeded in situ to produce tricycle 186. This highly efficient reaction formed the two C−C bonds (C5−6, C9−10) while establishing the three correct stereocenters (C5, 9, and 10). Deallylation from 186 and concomitant decarboxylation, followed by conversion of the aldehyde to the PMB-protected hydroxymethyl group, furnished 187 (Scheme 19). The C-ring was stereoselectively closed from 187 by using KN(TMS)2 in refluxing THF, giving rise to tetracycle 188. The rational design of the fragments and two anionic key reactions established the oxygenated steroid framework of 188 in convergent fashion. After the 5-step transformation from 188, the β-oriented C5oxygen functionality was introduced through the reduction of the C7-ketone and hydroxy-directed epoxidation of the C5-double bond. Mesylation of the C7-hydroxy group and subsequent reduction with LiBH4 simultaneously reduced the mesylate and the epoxide, resulting in 192 after hydrolysis of the unstable orthoester on silica gel. Protection of the C19-hydroxy group of 192 as the acetate and removal of the C20O-TBDPS group gave 193. The PhMe2Si group was then transformed to the C3hydroxy group by Tamao-Fleming oxidation96 to furnish 194. The butenolide moiety was constructed next. Before doing so, 194 was transformed to 195 (4 steps), the C20-aldehyde of which was homologated by Rh-catalyzed methylenation to afford 196.97 After dihydroxylation of olefin 196, chemoselective

Figure 7. 6/6/6/5-Tetracyclic ring system: the structures of cardenolides.

addition for coupling of the A- and D-rings and formation of the B-ring, and subsequent aldol reaction for cyclization of the Cring. 9219

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Scheme 19. Total Synthesis of (−)-Ouabain (Deslongchamps, 2008)

catalyzed intramolecular aldol condensation of 208 in turn formed the A-ring of 209. Stereoselective hydrogenation of the C4-double bond of 209, followed by stepwise reductions of the C3-ketone with LiBH(s-Bu)3 and the C11-ketone with Li/NH3 afforded the fully functionalized tetracycle 210. After the 5-step manipulation from 210, formation of the butenolide and attachment of L-rhamnose were performed. The butenolide was effectively synthesized by treating the hydroxy ketone 211 with triphenyl phosphoranylidene ketene. Selective removal of the C3-acetyl group and ZnCl2-promoted glycosylation of 212 with R gave rise to 213. The basic hydrolysis of the ester groups and acidic reconstruction of the butenolide delivered rhodexin A (180). In 2013, our group reported the convergent total synthesis of (+)-19-hydroxysarmentogenin (181) from the AB-ring, D-ring, and butenolide fragments by using intermolecular acetalization, intramolecular radical reaction, intramolecular aldol reaction, and Stille coupling. The cis-decalin structure of AB-ring 216 was constructed from (S)-perillaldehyde 214 and Rawal’s diene 215 in 9 steps including the stereoselective Diels−Alder reaction (Scheme 21). Meanwhile, meso-D-ring 218 was prepared from meso-217 in 6 steps by utilizing pairwise functionalizations102 and then was brominated to afford 219. Prior to the first radical cyclization, the acetal tether of 220 was formed in the presence of PhNMe2 by nucleophilic displacement of the bromine atom of 219 adjacent to the methoxy group with the C19-oxygen of 216.103 The remaining C11-bromine atom of 220 was in turn homolytically cleaved by treatment with (TMS)3SiH and Et3B,104 and the resultant C11-carbon radical 221 was reacted with the C9-olefin from the top face of the molecule due to the constraint of the

oxidation of the secondary hydroxy group was realized by NBS treatment of the corresponding tin acetal.98 Reaction of hydroxyketone 197 with triphenyl phosphoranylidene ketene formed the desired butenolide in a single operation, affording 198.99 Saponification of 198 led to the total synthesis of ouabagenin (199), the aglycone of the targeted ouabain (179). Ouabain was synthesized from aglycone 199 through installation of the L-rhamnose derivative as follows. After masking the C1, C11, and C19-hydroxy groups, the most reactive C3-hydroxy group of triol 200 was selectively glycosylated with P to furnish the β-oriented rhamnoside. Two more operations, including deprotection, led to completion of the first total synthesis of (−)-ouabain (179). In 2011, Jung and co-workers reported the total synthesis of rhodexin A (180). The BCD-tricyclic framework of 180 was assembled by application of the inverse-electron-demand Diels− Alder reaction at the early stage of the synthesis. Diene 202 was synthesized from 201 by enyne metathesis using the Grubbs catalyst Q100 (Scheme 20). Upon exposure of (±)-diene 202 (the B-ring) and (±)-vinyl ether 203 (the D-ring) to acidic conditions (10 mol % of Tf2NH), the Diels−Alder reaction occurred to give tricycle 205.101 The annulation effectively realized the coupling of the B- and D-rings and the formation of the central C-ring with introduction of three new stereocenters (C8, 13, and 14). The 6-step transformation from 205 produced enedione 206, which was further converted to 207 through reductive enolization with Li/NH3 and in situ capture of the enolate with allyl bromide. Ru-catalyzed cross-metathesis with isopropenyl (pinacolato)boronate transformed the terminal alkene of 207 to the corresponding alkenyl borate, which was then treated with NaBO3 to afford ketone 208. The base9220

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Scheme 20. Total Synthesis of Rhodexin A (Jung, 2011)

Scheme 21. Total Synthesis of (+)-19-Hydroxysarmentogenin (Inoue, 2013)

and subsequent regioselective attack on the C14-ketone in the presence of the C17-ketone. It was noteworthy that this single operation established the C8-, C13-, and C14-stereocenters through desymmetrization of the meso-D-ring substructure. The total synthesis was completed from 224 through adjustment of the functional groups and attachment of the butenolide moiety. The C7-ketone of 224 was first removed by

acetal linkage. Consequently, the C9−11 bond of the fused tricycle 222 was stereoselectively formed. After conversion of 222 to 223 in 4 steps, the stereoselective C-ring formation was attained by applying the aldol reaction. Treatment of 223 with catalytic KN(TMS)2 in refluxing THF delivered the desired 224 as the major product through site-selective C8-enolate formation 9221

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site-selective reduction to the hydroxy group, followed by xanthate formation and radical-mediated deoxygenation.105 Ozonolysis of the vinyl ether of 225 liberated the C11-oxygen functional group and the C19-formate, which was then deformylated with NH4OH. Upon treatment of the resultant compound with TBSOTf, Et3N, and LiN(TMS)2, the C19primary alcohol and the C17-ketone were protected. The remaining C11-ketone of 226 was stereoselectively reduced under Birch reduction conditions. The C17-ketone was then regenerated and converted to the vinyl iodide of 227 with (NH2)2 and I2.106 The copper-accelerated Stille coupling between 227 and butenolide S gave rise to 228. Masking the C14-tertiary alcohol of 228 with a bulky TMS group resulted in kinetic protection of the β-face of the C16-olefin. As a result, hydrogenation occurred from the α-face of 229, constructing the β-oriented butenolide of 230. Finally, removal of the four silyl groups in a single step furnished (+)-19-hydroxysarmentogenin (181).

Scheme 22. Formal Total Synthesis of (+)-Atisine (Ihara and Fukumoto, 1990)

3.3. C20-Diterpene Alkaloids (6/6/6/6 Tetracycle)

The 6/6/6-tricyclic system is a common structural motif of diterpenes. Among such diterpenes, the structure of the entatisane-type C20-diterpene alkaloids107 is characterized by an additional 6-membered ring (Figure 8). The 6/6/6/6

α,β-unsaturated ester by a 2-step manipulation. Treatment of 239 with LiN(TMS)2112 in a mixture of hexane and Et2O generated the lithium enolate 240, which then underwent the lithium-chelated double Michael reaction to form 241 as the major product. This annulation realized the simultaneous construction of the central B-ring and the C-ring of 241. An additional 6 transformations afforded Pelletier’s intermediate 242,113 which was derivatized into (+)-atisine (231) in 10 steps. In 2006, a creative total synthesis of (±)-nominine (232) was reported by Gin and co-worker. The polycyclic structure of nominine (232) was constructed via a multiple cycloaddition process including aza-1,3-dipolar cycloaddition and Diels−Alder reaction. A-ring fragment 243 and D-ring fragment 245 were prepared from cyclohexenone 39 and protected p-anisaldehyde 244, respectively, in 3 steps each (Scheme 23). Staudinger-aza-Wittig reaction114 and following reduction of the resultant imine tethered 243 and 245, providing secondary amine 246. Acidic conditions then converted 246 to 4-oxidoisoquinolinium betaine 247 via MeOH extrusion and isomerization.115 When betaine 247 was heated to 180 °C, the intramolecular 1,3-cycloaddition occurred between the A- and D-rings, producing a 1:3.6 mixture of the facial isomers 248 and 249. Although the desired cycloadduct 248 was formed as the minor component, the authors found that the undesired cycloadduct 249 could be thermally re-equilibrated to a mixture of 248 and 249, thereby increasing the total yield of 248. To prepare for the next key reaction, the Diels−Alder cycloaddition, the benzylic oxygen functionality was removed, and the terminal alkene was constructed through a 5-step sequence from 248. Birch reduction of the aromatic ring of 250,

Figure 8. 6/6/6/6-Tetracyclic ring system: the structures of C20diterpene alkaloid.

tetracarbocyclic system with the bicyclo[2.2.2]octane structure of these natural products has attracted significant attention from synthetic chemists.108 Ihara and Fukumoto group’s formal total synthesis of atisine (231)109 and Gin group’s total synthesis of nominine (232)110 are described below. From the early 1960s, a great deal of effort has been devoted to the total synthesis of C20-diterpene alkaloids.111 Most of the synthetic routes to the compact compounds were developed based on a linear strategy. In 1990, Ihara and Fukumoto reported the efficient convergent approach to the C20-diterpene alkaloid (+)-atisine (231). The authors utilized the Wittig reaction to connect the functionalized A- and D-rings and the subsequent intramolecular double Michael annulation to form the B- and Crings. Optically pure azabicyclo[3.3.1]nonane 234, the A-ring fragment, was prepared from cyclohexanone derivative 233 through a double Mannich reaction and a lipase-catalyzed kinetic resolution over 12 steps (Scheme 22). Aldehyde 234 was then coupled with the phosphonium ylide 235 corresponding to the D-ring to furnish 236. After the MOM-removal, the methoxybenzene and olefin moieties of 237 were reduced to produce α,β-unsaturated ketone 238. Ketone 238 was converted to 239, the substrate of the key Michael reaction, by attachment of the 9222

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4. TOTAL SYNTHESES OF PENTACYCLIC TERPENOIDS

Scheme 23. Total Synthesis of (±)-Nominine (Gin, 2006)

4.1. Neofinaconitine (6/5/6/5/6 Pentacycle)

In 2013, the group of Tan and Gin reported the total synthesis of neofinaconitine (255, Figure 9).116 Compound 255 belongs to

Figure 9. 6/5/6/5/6-Pentacyclic ring system: the structure of neofinaconitine.

the family of C18-norditerpenoid alkaloids, which have been mostly isolated from plants of the genera Aconitum and Delphinium.117 The authors’ strategy toward the hexacyclic architecture including 6/5/6/5/6-pentacarbocyclic system of neofinaconitine (255) featured cyclopropene/cyclopentadiene and azepinone/siloxydiene Diels−Alder reactions and sequential Mannich-type and radical cyclizations. Scheme 24 illustrates the first cycloaddition for construction of the CD-ring. Cyclopropene 259, which was prepared from Scheme 24. Synthesis of the CD-Ring with the Diene Moiety Using the Cyclopropene/Cyclopentadiene Diels−Alder Reaction

followed by acidic workup, provided β,γ-cyclohexenone 251. Pyrrolidine in turn converted 251 to diene 252, which underwent the Diels−Alder cycloaddition with the terminal alkene, forming the BC-ring of 253. Thus, the two intramolecular cycloaddition processes effectively constructed the heptacyclic skeleton of 232. Finally, Wittig methylenation of ketone 253 and diastereoselective C15-allylic hydroxylation delivered (±)-nominine (232). The asymmetric route to (+)-nominine (232) was also developed by employing enantiopure 243, which was accessible from 39 through asymmetric 1,4-addition.

methyl acrylate 258 in 6 steps,118 reacted with cyclopentadiene 257, generating a mixture of cycloadduct 260 and its regioisomer 261 (1.6:1). CD-ring 262 was prepared from 260 through cyclopropane fragmentation for D-ring formation and side chain manipulations for construction of the diene moiety. Azepanone 264, the coupling partner of diene 262, was prepared from ε-caprolactone 263 in 6 steps (Scheme 25). These 9223

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Osmylation, followed by Pb(OAc)4-treatment, transformed exo-olefin 265 to the ketone, the bromide of which was eliminated with DBU to provide enone 266. Treatment of 266 with Tf2NH effected the following 3 transformations: the conjugate addition of the C1-oxygen atom to the enone, the C11−17 bond formation by Mannich-type N-acyliminium cyclization, and vinyl ether formation. Remarkably, these onepot sequential reactions realized the simultaneous construction of the E- and F-rings. The last remaining 6-membered B-ring was cyclized by a radical reaction. Allylic oxidation of enol ether 268, followed by mesylation of the allylic alcohol, resulted in formation of bisenone 269. When 269 was treated with AIBN and Bu3SnH, the resultant C7-radical added to the C8-olefin, thereby forming the requisite ring in 270. The total synthesis was completed via 11 additional steps from 270. The C8-hydroxy group of 272 was installed in 3 steps from 270. Regioselective silyl enol ether formation of the C16 ketone of 270 was followed by selenylation of the enol ether, oxidation of the selenide for introduction of the strained bridgehead C8olefin of 271, and in situ conjugate addition of water at C8. After the hydrogenation of the C2-double bond of 272, the two ketones (C1 and 16) were simultaneously reduced to the hydroxy groups, which were methylated to produce 273. Oxidative one-carbon truncation of the C4 methyl ester to the tertiary alcohol (LiBH4; CrO3),119 reduction of the amide of 274, o-nitrobenzoate formation, and Zn-reduction of the nitro group to the amine group provided (±)-neofinaconitine (255).

Scheme 25. Total Synthesis of (±)-Neofinaconitine (Tan and Gin, 2013)

4.2. Daphmanidin E (5/5/6/6/7 Pentacycle)

In 2011, Carreira and co-worker reported the total synthesis of daphmanidin E (276, Figure 10),120 which belongs to the family

Figure 10. 5/5/6/6/7-Pentacyclic ring system: the structure of daphmanidin E.

of Daphniphyllum alkaloids.121 Biosynthetically, the Daphniphyllum alkaloids are considered to be derived from a squalene-like intermediate through repetitive ring constructions and fragmentations. The 5/5/6/6/7-pentacyclic system in hexacyclic daphmanidin E (276) is structurally characterized by a bicyclo[2.2.2]octane with three quaternary carbons (C2, 5, and 8). The authors applied two Claisen rearrangements and the alkyl Heck coupling reaction to assemble the complex architecture. Optically active bicyclo[2.2.2]octanone 278 with the C2- and C5-quaternary centers, which was synthesized from 277 in 5 steps, was tethered to 279 by O-alkylation (Scheme 26). The Claisen rearrangement at 155 °C realized the connection of the cyclopentene moiety at the hindered position, affording ketone 281. The second Claisen rearrangement was performed in the

two cyclic fragments were effectively connected under judiciously optimized conditions. Namely, the Diels−Alder reaction between 262 and 264 was promoted by catalytic SnCl4, giving rise to cycloadduct 265 as a single isomer. Thus, three stereocenters were properly controlled in this single reaction. 9224

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Scheme 26. Total Synthesis of (+)-Daphmanidin E (Carreira, 2011)

subsequent 2 steps from 281 to stereoselectively introduce the C8-quaternary carbon of 282. A 6-step manipulation of the side chains on 282 produced aldehyde 283, which was then subjected to the Henry condensation with MeNO2 to form nitro olefin 284. Treatment of 284 with Me2Zn and the chiral copper catalyst122 afforded 285 as the major product. After 4 steps from 285, the formation of the 7-membered carbocycle was then explored using 286. Although several metal-mediated reactions (Pd, Cr, and Sm) failed to cyclize 286, the authors found that cobaloxime U123 effectively promoted the desired cyclization.124 Namely, treatment of 286 with U under irradiation with a sun lamp closed the strained 7-membered ring to afford 287. Moreover, the authors demonstrated the catalytic version of the alkyl Heck-type cyclization by employing U (25 mol %) and i-Pr2NEt (1.5 equiv) under irradiation with a blue LED. The last remaining 5membered carbocycle was constructed from 287 via a 4-step transformation to generate 288. Finally, TFA induced removal of the N-Boc group of 288 and imine formation, and Ph2BBr detached the MOM group, giving rise to (+)-daphmanidin E (276).

Figure 11. 5/5/6/5/5/5-Hexacyclic ring system: the structures of vannusals.

structure. The total synthesis of the revised structure of (+)-vannusal B (290) is described below. Enantiopure vinyl iodide 292 was synthesized from meso-diol 291 in 16 steps including desymmetrization of meso-building block 291 by an enzymatic kinetic resolution, while racemic aldehyde 296 was synthesized from 294 in 24 steps (Scheme 27). Lithiation of 292 with t-BuLi, followed by addition of aldehyde 296, connected the AB- and DE-rings. Upon removal of the C28OTIPS group with TBAF, the diastereomeric adducts 297a and 297b (dr = 1:1) were separated. After 4 steps, the central 6membered C-ring was cyclized from 298. Specifically, treatment of 298 with SmI2 and HMPA effected the cyclization to afford 300. The authors proposed that the ketyl radical generated from aldehyde 298 reacted with the C10-olefin, and the further single-

5. TOTAL SYNTHESIS OF HEXACYCLIC TERPENOID: VANNUSALS (5/5/6/5/5/5 HEXACYCLE) In 2009, Nicolaou and co-workers reported the total synthesis of vannusals A and B (289 and 290, Figure 11),125 which were isolated from marine ciliate Euplotes vannus.126 The natural products consist of 30 carbons and possess an unprecedented 5/ 5/6/5/5/5-hexacyclic framework. The authors’ convergent approach to the vannusals featured the anionic coupling of the two densely functionalized AB- and DE-ring fragments and a SmI2-induced radical cyclization. Their convergent strategy enabled the unified syntheses of the various stereoisomers of vannusals and allowed them to revise the originally proposed 9225

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hydroxy group of which was chemoselectively oxidized with 1Me-AZADO127 to furnish 302. Acetylation of the remaining C29-secondary hydroxy group of 302 and removal of three SEM groups and the C28O-TES group with aqueous HF afforded (+)-vannusal B (290).

Scheme 27. Total Synthesis of (+)-Vannusal B (Nicolaou, 2009)

6. CONCLUSION The foregoing work demonstrates the progress that has been made in the field of convergent syntheses of highly oxygenated and polycyclic terpenoids at the cutting edge of contemporary organic chemistry. In support of these efforts, synthetic chemists have invented novel synthetic methods to overcome the formidable chemical challenges posed by these complex terpenoids. The proper design of the coupling fragments, as well as optimized selection of the key coupling and cyclization reactions, enabled assembly of fused tri-, tetra-, penta-, and hexacyclic carbon frameworks with multiple functional groups. However, the chemical synthesis of the polycyclic terpenoids typically requires more than 30 overall steps and has not yet become a routine preparative method for obtaining natural products and their analogues. There is still no universal convergent strategy that is applicable to all the structural units with their diverse functional group patterns. Further expanding the scope of the fragment coupling and cyclization reactions permits these reactions to be performed at the very last stage of the total synthesis using the multiply functionalized fragments. Therefore, it is essential that even more mild, robust, and powerful reactions and methodologies continue to be developed for maximizing the convergency and minimizing the overall functional group transformations. Practical, concise, and general convergent strategies not only make sufficient synthetic material available for clinical evaluation in cases where the natural supply is inadequate but also allow preparation of structurally related compounds in a unified fashion simply by switching the structures of the fragments. Such modified synthetic variants of the natural terpenoids are extremely important, enabling structure−activity relationship determinations and providing tools for chemical biology and insight into the manner by which natural products interact with their target biomolecules.128 These studies will lead to discovery and development of novel therapeutic agents based on these highly complex natural terpenoids. In this regard, advances in the convergent strategies that are suitable for generation of analogues are imperative in both the chemical and pharmaceutical sciences.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected].

electron transfer from SmI2 generated carbanion 299, which eliminated the C12-oxygen functionality. The 2-step protective group manipulation converted 300 to diol 301, the primary

Notes

The authors declare no competing financial interest. 9226

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Biographies

Masayuki Inoue was born in Tokyo in 1971. He received a B.Sc. degree in Chemistry from the University of Tokyo in 1993. In 1998, he obtained his Ph.D. from the same university, working under the supervision of Prof. Kazuo Tachibana. After spending two years with Prof. Samuel. J. Danishefsky at the Sloan-Kettering Institute for Cancer Research (1998−2000), he joined the Graduate School of Science at Tohoku University as an assistant professor in the research group of Prof. Masahiro Hirama. At Tohoku University, he was promoted to lecturer in 2003 and then to associate professor in 2004. In 2007, he moved to the Graduate School of Pharmaceutical Sciences, The University of Tokyo as a full professor. He has been honored with the Young Scientist’s Research Award in Natural Product Chemistry (2001), the First Merck-Banyu Lectureship Award (2004), The Chemical Society of Japan Award for Young Chemists (2004), Novartis Chemistry Lectureship 2008/2009, fifth JSPS Prize (2008), and the Mukaiyama Award 2014. His research interests include the synthesis, design, and study of biologically important molecules, with particular emphasis on the total synthesis of structurally complex natural products.

Daisuke Urabe was born in 1978 in Hiroshima, Japan, and received his B.S. degree in 2001 from Nagoya University. He earned his Ph.D. degree in 2006 from Nagoya University, where he worked on the natural product synthesis under the supervision of Professors Minoru Isobe and Toshio Nishikawa. He then carried out postdoctoral research with Professor Yoshito Kishi at Harvard University (2006−2007). In 2008, he was appointed as Assistant Professor in the Graduate School of Pharmaceutical Sciences at the University of Tokyo and promoted to Lecturer in 2013. His research interests include the development of synthetic methodology and total synthesis of densely functionalized natural products.

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Taro Asaba was born in Osaka, Japan in 1988 and received his B.S. degree in 2011 and M.S. degree in 2013 from the University of Tokyo. He is currently working on his Ph.D. under the supervision of Professor Masayuki Inoue at the same university. His research interest is total synthesis of natural products.

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DOI: 10.1021/cr500716f Chem. Rev. 2015, 115, 9207−9231