Article Cite This: Acc. Chem. Res. XXXX, XXX, XXX−XXX
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The Journey of Schinortriterpenoid Total Syntheses Zhen Yang*
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Beijing National Laboratory for Molecular Science and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of the Ministry of Education, College of Chemistry and Molecular Engineering and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China State Key Laboratory of Chemical Oncogenomics and Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen 518055, China CONSPECTUS: Plants in the Schisandraceae family are important components of the traditional Chinese herbal medicines and are often used to treat various illnesses. Therefore, these Schisandraceae plants are valuable sources for the discovery of new chemical entities for novel therapeutic development. Considerable progress has been made in the identification of bioactive and structurally novel triterpenoids from the Schisandraceae family in the past two decades. In particular, Sun and co-workers have successfully isolated over 100 nortriterpenoids from the Schisandraceae family. Some of these nortriterpenoids have strong inhibitory activities toward hepatitis, tumors, and HIV-1. However, the natural scarcity of these nortriterpenoids in the Schisandraceae plants has hampered their isolation and further biomedical development, and their biosynthesis has not been fully elucidated. It is therefore important and urgent to develop efficient and streamlined total syntheses of these medicinally important nortriterpenoids. Such syntheses will provide sufficient materials for detailed biological studies as well as new synthetic analogues and probe molecules to improve their biological functions and elucidate their mode of actions. However, because of their structural novelty and complexity, the total syntheses of these nortriterpenoid natural products present a significant challenge for synthetic chemists, despite the progress made in organic synthesis, particularly total synthesis, in the 20th century and since the beginning of the 21st century. New synthetic methodologies and strategies therefore need to be invented and developed to facilitate the total syntheses of these nortriterpenoid natural products. With this in mind, our group has spent the last 15 years, ever since the isolation of micrandilactone A (1) by Sun and co-workers in 2003 (Sun et al. Org. Lett. 2003, 5, 1023−1026), working on synthetic studies with a view to developing methods and strategies for the total syntheses of schinortriterpenoids. Enabling methods such as a thiourea/Pd-catalyzed alkocycarbonylative annulation and a thiourea/Co-catalyzed Pauson−Khand reaction have been developed under these circumstances to form the key ring systems and stereocenters of these complex target molecules. These methodological advances have led us to the first total syntheses of schindilactone A (2), lancifodilactone G acetate (6a), 19-dehydroxyarisandilactone A (9), and propindilactone G (10) with diverse structural features via a branchingoriented strategy. The chemistry developed during our total synthesis campaign has not only helped us to deal with various challenges encountered in the syntheses of the four target molecules, but has also opened up new avenues for synthesizing other naturally occurring schinortriterpenoids and their derivatives, which will likely result in molecules with improved biological functions and tool compounds to enable elucidation of their mechanism of actions or potential cellular targets. This Account highlights the chemistry evolution of our schinortriterpenoid syntheses.
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INTRODUCTION Wuweizi, the Chinese name for Schisandraceae, literally means “five-flavor berry” and refers to the berry having all five basic flavors: salty, sweet, sour, spicy, and bitter. Traceable records show that for over 2000 years these “five-flavor berries” have been used as sedatives and tonics, and for the treatment of rheumatic lumbago and related diseases.1 In addition to their use in traditional Chinese medicines, certain Schisandraceae species have been used as additives in food, jellies, wine, and fruit juices.2 Because of their eminent status in traditional Chinese herbal medicines, plants in the Schisandraceae family have been targeted for the identification of new natural products as potential lead compounds in drug discovery. In the past two decades, considerable progress has been made in isolating bioactive and novel triterpenoids from the Schisan© XXXX American Chemical Society
draceae family. Notably, Sun and co-workers successfully isolated over 100 nortriterpenoids from Schisandraceae,3 such as those listed in Figure 1. Among these schinortriterpenoids, molecules with potent antihepatitis, antitumor, and anti-HIV activities have been identified.3 Biosynthetically, these natural products are derived from cycloartane triterpenoid schisandronic acid (A) via a series of oxidations and structural fragmentations and rearrangements (Figure 2). The key steps include a Baeyer−Villiger oxidation of the A-ring followed by rearrangement to form the 5,5-fused bicyclic lactone of certain Schinortriterpenoids and an oxidative cyclopropane fragmentation to create the center Received: November 12, 2018
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DOI: 10.1021/acs.accounts.8b00569 Acc. Chem. Res. XXXX, XXX, XXX−XXX
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Figure 1. Selected nortriterpenoid natural products and our synthetic plan.
cycloheptane ring (A → B → C). Oxidative cleavage of C28 via the loss of CO2 resulted in the transformation of triterpene G to nortriterpene H, which was further converted to intermediate I, a schiartane member.3 The schiartanes represent the least-rearranged and most upper-stream ones among this family. Further functional group interconversions, C13−C14 bond fragmentation, and cyclopropane ring formation then led to intermediate N, a key diverging point to other skeletons, including preschisanartane P, 13,16-secopreschisanartane Q, and schisanartane U. Structurally unique and challenging natural products are always a source of inspiration for synthetic chemists to design and develop new chemistry to map out the relations among the chemical structure, reactivity, reaction pathways, and reaction mechanism.4,5 Since the isolation in 2003 of the first schinortriterpenoid, these compounds have attracted much attention from the organic synthesis community.6 To date, the total syntheses of 12 schinortriterpenoids have been reported by our research laboratory (Figure 1)7,12−14 or others including the groups of Li,8,10 Anderson,9 Tang,11,15 and Ding16 (Figure 3). In this Account, we trace the evolution of the chemistry involved in our development of methods and strategies for schinortriterpenoid synthesis. Our efforts culminated not only in the total syntheses of schindilactone A (2),7 lancifodilactone G acetate (6a),1419-dehydroxyarisandilactone A (9),13 and propindilactone G (10)12 from the corresponding intermediates 11, 12, and 13 (Figure 1) via a branching-oriented strategy, but also provided a platform for divergent synthesis17 of the other schinortriterpenoid natural products and their synthetic analogues by using 11−13 or other key intermediates as the branching points. Because of the unprecedented polycyclic scaffolds of schinortriterpenoids, we have designed and developed a series of synthetic methodologies to address these structural challenges, e.g., a thiourea/Co-catalyzed Pauson−Khand reaction18 for formation of the cyclopentanone motifs (F ring) of 2 and 6a, and a thiourea/Pd-catalyzed alkoxycarbonylative annulation19 for the stereoselective construction of the GH bicyclic core of 2.
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RETROSYNTHETIC ANALYSIS OF SCHINDILACTONE A AND TWO ENABLING SYNTHETIC METHODOLOGIES We initially chose micrandilactone A (1, Figure 1) as our target molecule right after it was discovered by Sun and co-workers in 2003. While we were on our way to micrandilactone A (1), a closely related analogue schindilactone A (2, Figures 1 and 4) was isolated and fully characterized in 2007 by Sun and coworkers.20 We redirected our synthetic efforts to schindilactone A (2) because our chemistry had evolved into a good shape to reach this target. Schindilactone A (2) contains a highly oxygenated framework bearing 12 stereogenic centers, eight of which are contiguous chiral centers accommodated within the congested FGH tricyclic ring system. It also features an oxa-bridged ketal within an unprecedented 7,8-fused carbocycle. All these structural features present formidable synthetic challenges, which were first conquered by us in 2011.7 Retrosynthetically, we proposed using a Dieckmann cyclization21 to build the A ring and a Pd-catalyzed alkoxycarbonylative annulation22 to install the fused GH ring system (Figure 4A). Use of a Pauson−Khand reaction23 was envisioned for forming the highly substituted cyclopentanone moiety (F ring). The challenging oxabicyclo[4.2.1]nonene system in 16 could potentially be constructed by a ring-closing metathesis, which could retrosynthetically lead to bicyclic lactone intermediate 18. Compound 18 could be produced by a Diels−Alder reaction of 21 and 22, followed by a one-carbon ring expansion. Each of these synthetic transformations had been reported previously, but whether or not they could be orchestrated together in such complex structural settings was uncertain prior to our synthetic studies. As we progressed in our total synthesis campaign, some of these steps turned out to be nontrivial, and new reaction conditions or catalytic systems had to be developed to solve the problems presented by the complex structures of schindilactone A and micrandilactone A. For example, a novel thiourea ligand (Ligand A, Figure 4B-1) and a thiourea/Pd catalytic system were developed to ensure installation of the fused GH ring via alkoxycarbonylative annulation22 in the presence of many other functional groups B
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Figure 2. Plausible biosynthetic pathway of the schinortriterpenoids.
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(23 → 24, Figure 4B-1). This mild thiourea/Pd-catalyzed alkoxycarbonylative annulation has been used to synthesize other complex natural products, e.g., pallambins A and B by Carreira and Ebner,24 and pallambins C and D by Wong et al.25 To build the highly substituted cyclopentenone moiety (F ring), we developed a novel thiourea/Co catalytic system to achieve the desired intramolecular [2 + 2 + 1] cycloaddition of an acetal-containing enyne precursor (25 → 26, Figure 4B-2). Several other groups have used this catalytic version of the Pauson−Khand reaction for the total syntheses of natural products.26−31
TOTAL SYNTHESIS OF SCHINDILACTONE A (2)
As shown in Scheme 1, our synthesis began with an Et2AlClcatalyzed intermolecular Diels−Alder reaction32 of 27 and 28, which delivered cycloadduct 29 regioselectively and stereoselectively. After converting 29 to bicyclic lactone 30 via sequential chemoselective Grignard addition to the methyl ketone and lactonization, the angular oxygen functionality at C10 was introduced by α-hydroxylation with oxygen,33 followed by protection of the resulting hydroxyl group as a triethylsilyl (TES) ether. A dibromocyclopropane ring expansion34 was then used to achieve one-carbon ring expansion to convert 31 to 33 with the desired 5,7-fused BC C
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Figure 3. Total syntheses of schinortriterpenoids from other groups.
Figure 4. Retrosynthetic analysis of schindilactone A and two enabling synthetic methodologies.
the intramolecular Pauson−Khand reaction for installation of the cyclopentenone moiety in a complex structural setting. This modified Pauson−Khand reaction gave the desired [2 + 2 + 1] cycloadduct 42 in 74% yield. Notably, our computational calculation results suggested that CO insertion was the ratedetermining step for this Pauson−Khand reaction, whereas previous reports of other Pauson−Khand reaction systems stated that alkene insertion to give the cobaltacycle was the rate-determining step.42 The reduced activation free energy for the alkene insertion in this reaction can be attributed to the activating effect of the ester group and the high reactivity of the strained alkene. An eight-step sequence was then used to convert 42 to 45 for the Pd-catalyzed alkoxycarbonylative annulation to install the fused GH ring system. After converting 42 to a methyl ester, the angular methyl group at C13 was introduced by KHMDS deprotonation, and the resulting enolate was trapped with MeI from the less hindered convex face. The desired product 43 was obtained in 80% yield over three steps. The methyl ester group of 43 was then converted to an allylic
ring system. The ring expansion was accomplished by treating 31 with dibromocarbene35 and then AgClO4.36 Vinyl bromide 33 was then converted to the ring-closing metathesis precursor 39 in five steps. The vinyl bromide moiety obtained naturally by dibromocyclopropane ring expansion, served as an electrophile in the following Pdcatalyzed cross-coupling with (1-tert-butoxyvinyloxy)(tertbutyl)dimethylsilane (34)37 to yield keto ester 35, which underwent Grignard addition with but-3-enylmagnesium bromide to afford a mixture of lactones (see 36) in 88% yield. This mixture was converted to 38 by α-hydroxylation with MoOPH38 and TfOH-promoted benzylation39 of the resulting secondary alcohol. Another Grignard addition with vinylmagnesium bromide converted 38 to diene 39. Treatment of 39 with Grubbs II catalyst40 in the presence of MgBr241 gave 40 with the desired oxabicyclo[4.2.1]nonene moietyas a single diastereoisomer. After esterification of the hemiketal with but-2-ynoic pivalic anhydride, we used the novel tetramethylthiourea (TMTU)/ Co catalytic system developed in our laboratory18 to catalyze D
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Accounts of Chemical Research Scheme 1. Total Synthesis of Schindilactone A (2)
steps. The total synthesis of schindilactone A (2) also provided the platform for divergent syntheses of other schinortriterpenoids such as lancifodilactone G acetate (6a), 19-dehydroxyarisandilactone A (9), and propindilactone G (10).
alcohol to produce 44. After removal of the TMS group with TBAF, Magnus’ procedure was used to reduce 44 to 45 with LiAlH2(OMe)2, achieving high diastereoselectivity.43 We then tested the Pd-catalyzed alkoxycarbonylative annulation strategy for installing the GH ring system and completing the total synthesis of schindilactone A (2). The commonly used annulation reaction conditions failed in this highly complex situation, but 45 underwent alkoxycarbonylative annulation with our optimized novel thiourea/Pd catalytic system19 under a balloon pressure of CO in THF. The desired lactone 46 was produced in 78% yield. The C2-symmetric thiourea Ligand A44 proved to be essential for successful alkoxycarbonylative annulation. Compound 46 was then treated with LiHMDS and MeI to introduce the α-methyl group, but convex face methylation led to undesired stereochemistry at C25. This stereochemical problem was solved via epimerization by treating the undesired epimer with a hindered base (i.e., lithium tetramethylpiperidinide)45 in THF at −78 °C and then quenching with a saturated solution of NH4Cl. Product 47 was then converted to acetate 48 via a one-pot procedure46 to remove the TES group and cap the resulting alcohol as an acetate, followed by catalytic hydrogenation to remove the benzyl group. Treatment of 48 with LiHMDS furnished the A ring via a Dieckmann-type cyclization.47 A Dess−Martin periodinane (DMP) oxidation completed the total synthesis of schindilactone A (2) in its racemic form in 29
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TOTAL SYNTHESIS OF LANCIFODILACTONE G ACETATE (3) Lancifodilactone G48,49 (6, Figure 1) was isolated from the medicinal plant Schisandra lancifolia by Sun and co-workers in 2005. It shows modest anti-HIV activity. Its structure was determined by X-ray crystallographic analysis. Unlike the other family members, lancifodilactone G (6) contains two unusual twofold anomerically stabilized bis-spiro(4,4) ketal moieties,50 one of which is an oxaspirolactone. It also contains a striking and unprecedented CDE ring system bearing a rare nonresonance-stabilized aliphatic enol51,52 (C8/C14), which, on cursory inspection, appears to be too strained to exist because of its electronic, geometric and steric constraints. However, quantum chemistry calculations indicated that the naturally occurring enol lancifodilactone G is more stable than the keto form by 2.6 kcal/mol in water. It is the only known stable aliphatic enol that is devoid of conjugative stabilization.53 Additionally, compared with schindilactone A (2), it has an oxygenated C30 (a hydroxymethyl group). These structural features render lancifodilactone G (6) an even more E
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Accounts of Chemical Research Scheme 2. Total Synthesis of Lancifodilactone G Acetate (6a)
gave lactone 55 from 52 in nine steps. In this case, the C19 methyl group was introduced in the Grignard addition step. This methyl group, which requires additional steps for installation in our schindilactone A (2) synthesis, did not cause problems in the subsequent ring-closing metathesis to form the oxabicyclo[4.2.1]nonene moiety with a trisubstituted double bond (55 → 56) and the TMTU/Co-catalyzed Pauson−Khand reaction for construction of the cyclopentenone moiety (57 → 58) with an all-carbon quaternary center. The C20 and C22 chiral centers were installed stereoselectively by Pd-catalyzed hydrogenation of 58, followed by DBU-promoted epimerization of the C20 stereogenic center to produce 59 in 78% yield. We then developed a four-step procedure for constructing the oxaspirolactone moiety (59 → 60 → 61): chemo- and stereoselective vinylation, intermolecular cross-metathesis58,59 with methyl acrylate, catalyzed by the Hoveyda−Grubbs II catalyst, Pd-catalyzed hydrogenation, and NaH-promoted lactonization. The lactone A ring was built from 61 via a Dieckmann-type cyclization protocol and compound 63 was obtained in four steps. After a Martin’s sulfurane 60 dehydration, C27 was introduced as an exo-methylene group via a modified Eschenmoser procedure. Briefly, 63 was treated with LiHMDS and Eschenmoser’s reagent61 and then treated with 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT)62 in the presence of TEA to afford exo-methylene-containing 64. Subsequent oxidation of 64 with DMP gave ketone 65,which underwent Pd/C-catalyzed hydrogenation for stereoselective
challenging target for total synthesis. Lancifodilactone G (6) and schindilactone A (2) share a similar ABCDEF ring system, therefore intermediate 11 (Figure 1) could serve as a suitable branching point. Although part of the strategy for schindilactone A (2) synthesis could be adapted for the synthesis of lancifodilactone G (6), new methods for solving the aforementioned problems need to be developed. We therefore planned to develop an asymmetric synthesis of lancifodilactone G (6). Our first innovation involved the development of an asymmetric intermolecular Diels−Alder reaction of diene 50 with dienophile 49 (Scheme 2). The latter contains two activating groups, i.e., a keto group and an ester group, both of which can potentially interfere with the chiral Lewis acids or Brønsted acids used to catalyze the asymmetric cycloaddition process. The use of a ketone-based dienophile54 bearing two different electron-withdrawing groups represents a fundamental challenge in asymmetric Diels−Alder reactions. We systematically investigated this type of reaction and identified 51,55 which was derived from the Corey oxazaborolidine catalyst,56,57 as an effective catalyst for the asymmetric Diels−Alder reaction. The desired product 52 was obtained in high yield with high enantioselectivity. The CF3 groups substituted on the oxazaborolidinium core are critical for enhancing the Lewis acidity of the boron center. This reaction can also be conducted on a 100 g scale, which enabled sufficient material to be obtained for our total synthesis. The protocols used in our total synthesis of schindilactone A (2) F
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Scheme 3. Plausible Biosynthetic Transformation from 7 to 8 and Retrosynthetic Analysis of 19-Dehydroxyarisandilactone A
Scheme 4. Total Synthesis of (+)-19-Dehydroxyl Arisandilactone A (9)
reduction of the exo-methylene group and removal of the TBS protecting group.63 Ketone 66 was produced in 60% yield from
64. However, all attempts to convert ketone 64 to its enol form under various conditions failed to afford the desired G
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Figure 5. Synthetic plan toward propindilactone G.
As illustrated in Scheme 4, our synthesis commenced with conversion of (R)-carvone to cycloheptenone 70 via the Zercher β-keto ester homologation protocol.68 After hydrolysis of the methyl ester, an AgOTf-catalyzed lactonization69 gave 72, which was converted to 73 in two steps. Allylic oxidation mediated by SeO2 in the presence of AcOH,70 followed by a sequence consisting of Appel bromination,71 Pd-catalyzed carboxylation of the resulting allylic bromide, and PPTSpromoted ketal deprotection delivered 74, a close analogue of 35. Although the synthesis of 74 is two steps longer than that of 35, which is based on the Diels−Alder cycloaddition, it relies on the abundant and sustainable chiral pool molecule (R)-carvone and offers an asymmetric approach to the largescale synthesis of 74. Compound 74 was then converted to 76 with the desired BCDE ring system in six steps via our previously established procedures, which included the key ringclosing metathesis for building the hemiketal-containing oxabicyclo[4.2.1]nonene. We next needed to prepare α-diazo ester 68 for the synthesis of 77 by intramolecular cyclopropanation. The use of the House procedure and Corey’s modified procedure, which employs glyoxylic acid chloride ptoluenesulfonylhydrazone,72 was not fruitful, but a modified Regitz diazo transfer reaction73 furnished α-diazo ester 68 in three steps from 76. A subsequent copper-catalyzed intramolecular cyclopropanation74 delivered 77 in good yield. A few functional group manipulations, namely a Weinreb ketone synthesis,75 Peterson olefination76 of the resulting ketone, and removal of the TES group, converted 77 to 78. Compound 79 was obtained from 78 in six steps, including a Dieckmann-type cyclization to form the A ring. Subsequent stereoselective hydroboration/oxidation, followed by Ley oxidation77 of the primary alcohol, gave aldehyde 80 in good yield. With aldehyde 80 in hand, we investigated a biomimetic approach to complete the total synthesis of (+)-19dehydroxyarisandilactone A (9). A BF3-etherate-promoted vinylogous Mukaiyama aldol reaction78 of aldehyde 80 gave secondary alcohol 67, which under the same Lewis acidic condition smoothly underwent the proposed formal SN2′-type cyclopropane-ring-opening substitution to afford 81 in good yield, but with undesired stereochemical outcomes at both C22 and C23. However, these two stereocenters were isomerized to the desired ones by treatment of 81 with DBU in toluene at high temperature, presumably via a tandem retro-oxa-Michael addition and oxa-Michael addition.79 To complete the total synthesis, the α,β-unsaturated γ-butyrolactone was reduced with a combination of NiCl2 and NaBH4,80 but again with undesired stereochemistry at the α-carbon. This was corrected by treatment with NaOMe in MeOH to provide 83. Removal of the benzyl group with Raney Ni, followed by DMP oxidation, concluded our 37-step asymmetric total synthesis of (+)-19-dehydroxyarisandilactone A (9).
lancifodilactone G (3); in most cases, substrate 64 decomposed. Site-specific activation of the C14 ketone was therefore needed to facilitate this conversion. To this end, ketone 65 was first treated with Ac2O/Et3N, and the resulting enol acetate then underwent Pd/C-catalyzed hydrogenation to afford lancifodilactone G acetate (6a); its structure was confirmed by X-ray crystallography. However, the conversion of lancifodilactone G acetate (6a) to lancifodilactone G (3) was unsuccessful. Our synthetic efforts concluded with the first asymmetric total synthesis of lancifodilactone G acetate (6a)14 and how nature produces lancifodilactone G in its nonconjugated enol form remains a myth.
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TOTAL SYNTHESIS OF 19-DEHYDROXYARISANDILACTONE A (8) Arisanlactone C (7)64 and arisandilactone A (8)65 were isolated from S. arisanensis in Taiwan by Shen and co-workers in 2010 (Scheme 3). Structurally, arisanlactone C (7) has a similar ABCDE ring system to those of schindilactone A (2) and lancifodilactone G (3), but it features a unique highly substituted cyclopropane ring fused with the oxabicyclo[4.2.1]nonane moiety. The cyclopropane ring also serves as a linker to append the C20− C27 moiety on the hexacyclic core of arisanlactone C (7). More strikingly, the cyclopropane moiety is adjacent to a hemiketal, which renders it highly labile for ring-opening or ring-expansion rearrangement.66,67 This idea was validated by the isolation of arisandilactone A (8), which differs from arisanlactone C (7) mainly at the bridged DEF ring system by having an oxa-bridged 7−9−5 tricyclic carbon core with a strained bridge-headed double bond. Biosynthetically, arisandilactone A (8) could be derived from arisanlactone C (7) via a formal SN2′-type cyclopropane-ring-opening substitution by using the C22 alcohol to attack the C13 carbon and expel the activated hydroxyl group of the hemiketal (7 → V → 8, Scheme 3). In addition to a one-step process to form the tetrahydrofuran ring, a hydroxy ketone intermediate (i.e., W, Scheme 3) could be involved. Our computational results favor the hydroxy ketone process via a homo-Michael addition.16 Inspired by this plausible biosynthetic pathway, we designed and executed a biomimetic total synthesis of (+)-19-dehydroxyarisandilactone A (9). Retrosynthetically, (+)-19-dehydroxyarisandilactone A (9) could be synthesized from intermediate 67. Intermediate 67 could be derived from α-diazoacetate 68 via an intramolecular cyclopropanation followed by further structural elaborations. α-Diazoacetate 68 could be synthesized from 69. While we had developed a reliable approach to access closely related analogues of 69 (Schemes 1 and 2) via the Diels−Alder strategies, we envisioned a new approach to access 69 from the sustainable chiral pool molecule (R)-carvone (71). In this case, a one-carbon ring expansion is required to advanced (R)carvone (71) to cycloheptenone 70. H
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Accounts of Chemical Research Scheme 5. Total Synthesis of Propindilactone G (10)
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we developed previously. Sonogashira cross-coupling85 between 33 and ethynyltrimethylsilane, followed by CeCl3mediated86 1,2-addition, gave enyne 92 for the subsequent Pauson−Khand reaction,23 which proceeded smoothly on treatment with Co2(CO)8 to afford the tetracyclic compound 93 with the desired all-carbon quaternary center in 67% yield. Having successfully used a Pauson−Khand reaction to build the DE ring system, we next used AgF to remove the two silyl groups.87 In our attempt to reduce the extra double bond in the seven-membered ring by catalytic hydrogenation, subsequent dehydration also occurred to give dienone 94, which underwent C9-hydroxyl-group-directed chemo- and stereoselective oxidation to give epoxide 95. At this stage, we used the Dieckmann condensation to close the A ring and obtained 96 in three steps. A Pd-catalyzed double-bond reduction and epoxide ring opening88 converted 96 to 97, but as a mixture of epimers. The minor and undesired epimer 97b can be recycled into the total synthesis via a DBU-promoted epimerization. The desired epimer 97a was then converted to silyl enol ether 98 for subsequent oxidative hetero-cross-coupling with silyl enol ether 99. Coupling with ceric ammonium nitrate89 as the oxidant effectively formed the desired C−C bond in 92% yield, but it gave a mixture of four diastereoisomers (102a−d). Compounds 102c and 102d were inseparable. A mixture of 102c and 102d was therefore used in the next OsO4-catalyzed dihydroxylation. Compound 102d underwent dihydroxylation followed by in situ lactonization to afford propindilactone G (10) in 81% yield, but compound 102c led to the formation of some unidentifiable products. Overall, propindilactone G (10)
TOTAL SYNTHESIS OF PROPINDILACTONE G (10) Propindilactone G,81 which was isolated by Sun et al. in 2008, contains a unique 5/5/7/6/5 pentacyclic core and an α,βunsaturated γ-butyrolactone appended on C17 (Figure 5). The original structural assignment (Scheme 5, 10a) was established based on comprehensive NMR analysis. It shares the same 5/ 5/7 ABC ring system as all the schinortriterpenoids listed in Figure 1. Intermediate 13 (Figure 1) could therefore serve as a branching point for the total synthesis of propindilactone G (10). The enyne compound 87 was envisioned to undergo an intramolecular Pauson−Khand [2 + 2 + 1] cycloaddition23 to give the 6,5-fused DE ring system with a challenging all-carbon quaternary center82 (87 → 86). Attachment of the α,βunsaturated γ-butyrolactone at C17 was not a straightforward task and we eventually used an enolate−enolate oxidative cross-coupling83 between 85 and 84 to form the desired C17− C20 bond. The coupling product was then converted to propindilactone G (10) via a few functional group interconversions. Our synthesis has led to revision of the stereochemistry at C17. Intermediate 33 in our schindilactone A (2) synthesis (Scheme 1) could be used in the propindilactone G (10) synthesis, but it was prepared in racemic form. We therefore developed an asymmetric approach to the synthesis of 33 in an enantioenriched form. As illustrated in Scheme 5, the asymmetric approach relied on a Diels−Alder reaction between 88 and 50, which was catalyzed by the chiral amine 89,84 to furnish cycloadduct 90 in high yield and with high enantioselectivity on a 100 g scale. Compound 90 was then converted to 33 in six steps by using protocols similar to those I
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Accounts of Chemical Research was synthesized in 20 steps (longest linear sequence) in an enantioenriched form.
Notes
CONCLUSION Since we started our campaign to achieve the total syntheses of schinortriterpenoids 15 years ago, we have completed the total syntheses of schindilactone A (2), lancifodilactone G acetate (6a), (+)-19-dehydroxyarisandilactone A (9), and propindilactone G (10). During the development of these total syntheses, novel and enabling synthetic methodologies such as the thiourea/Co-catalyzed Pauson−Khand reaction and the thiourea/Pd-catalyzed alkoxycarbonylative lactonization have been developed to facilitate the syntheses of these challenging target molecules. A branching-oriented synthetic strategy has also been developed, which fully uses several key intermediates in the synthesis to enable a unified approach to the syntheses of multiple members of this fascinating family of natural products. This strategy also offers a high degree of flexibility for future syntheses of schinortriterpenoid analogues. However, although we were able to accomplish the syntheses of these four complex molecules, it took us about 15 years to reach this stage. This long journey has made us ponder what we should do to improve these synthetic methods and what the next steps should be. Obviously, the synthetic efficiency needs to be significantly improved; this includes decreasing the total number of synthetic steps, developing more convergent strategies, and reducing the overall time and resources invested, the number of students and postdocs involved, and the waste generated. New enabling synthetic capabilities and strategies are needed to achieve these goals. For the long-term development of therapies centered on these medicinally important schinortriterpenoids or other complex natural products, synthetic approaches need to be more flexible and efficient to create (1) new synthetic analogues to improve their on-target potency and selectivity, and to optimize the ADMET pharmacokinetics and pharmacology, (2) and chemical probe molecules to elucidate their modes of action and help us to understand the related biological and disease processes. We have started on an adventurous and enjoyable voyage, and have reached a few stops, but the final destination of an ideal synthesis has still to be reached. I would like to thank my co-workers for championing our synthetic campaign. Meanwhile, the training they have obtained during achievement of the total syntheses of these complex schinortriterpenoids is invaluable and unparalleled, and prepares them for any challenges in their future career. I would like to conclude this Account by quoting a comment made by Prof. Corey in his review article “Retrosynthetic Thinking − Essentials and Examples”: “the frontiers and the progress of organic synthesis are limited only by the creative abilities and the vision of those who work in the field. Organic synthesis is the essence of organic chemistry, just as organic chemistry is the fundamental language of life”.90
Biography
The author declares no competing financial interest.
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Zhen Yang was born in Shenyang, China, in 1959. He obtained his B.Sc. and M.Sc from Shenyang College of Pharmacy in 1982 and 1986, respectively. He earned a Ph.D. at The Chinese University of Hong Kong in 1992 under the guidance of H. N. C. Wong. He carried out postdoctoral research on natural product synthesis with K. C. Nicolaou at The Scripps Research Institute in La Jolla, CA and joined its faculty as an assistant professor in 1995. In 1998, he moved to the Institute of Chemistry and Cell Biology at Harvard Medical School as an institute fellow before returning to China as a professor at Peking University in 2001. He actively pursues the total syntheses of bioactive natural products and chemical biology research.
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ACKNOWLEDGMENTS We would like to gratefully acknowledge support from the National Science Foundation of China (21472006, 21572009, 21632002 and 21772004) for support of this research.
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