TY - JOUR
AU - Gong, Liu-Zhu
AB - Abstract Indole and its structural analogues have been frequently found in numerous alkaloids, pharmaceutical products and related materials. The enantioselective construction of these structures allows efficient total synthesis of optically pure indole alkaloids, and hence has received worldwide interest. In the past decade, asymmetric organocatalysis has been recognized as one of the most powerful strategies to create chiral molecules with high levels of stereoselectivity. In particular, organocatalytic asymmetric cascade reactions often occur with multiple bond-breaking and forming events simultaneously or sequentially, leading to the appearance of various straightforward approaches to access core structures for asymmetric total synthesis. This review will summarize recent applications of asymmetric organocatalysis in the enantioselective synthesis of indole alkaloids. asymmetric catalysis, organocatalysis, indole alkaloids, total synthesis INTRODUCTION Indole alkaloids constitute a large family of important natural and pharmaceutical substances with a diverse range of structural complexity and biological relevance [1]. These alkaloids are often installed with complex structures that are of great challenge to be accessed. Furthermore, the issue to control stereochemistry in the synthesis of a specific target molecule has been considered particularly difficult. As such, the development of new synthetic methods to stereoselectively access core structural skeletons that allow the enantioselective total synthesis of indole alkaloids represents an ambition in chemical synthesis [2,3]. Circumventing the current challenges existing in this highly valuable field basically relies on the development of new catalytic bond-forming strategies to prepare optically pure fragments that enhance efficiency and provide concise approaches to access target molecules [4–95]. Over the past decade, organocatalysis has been included among the most successful concepts in asymmetric catalysis, and it has been used for the enantioselective formation of new chemical bonds with several advantages from an economical and environmental point of view [10–135]. In addition to methodology development, impressive advances have also been made on the organocatalytic asymmetric total synthesis. Previous elegant reviews have summarized the progress and perspective of this field [14–335]. This review will focus on recent representative examples describing asymmetric organocatalytic synthesis of core structural skeletons or intermediates that turn out to be key issues to build up indole alkaloids with excellent efficiency and stereoselectivity (Fig. 1). These examples will be described in different sections grouped on the basis of the core structures, which are accessed by using a conceptually diverse range of organocatalytic asymmetric reactions. Figure 1. Open in new tabDownload slide Representative organocatalysis for the total synthesis of indole alkaloids. (a) A crucial role of organocatalysed reactions applied in the key step of total synthesis. (b) Organocatalysts involved in total synthesis. (c) Representative indole alkaloids. Figure 1. Open in new tabDownload slide Representative organocatalysis for the total synthesis of indole alkaloids. (a) A crucial role of organocatalysed reactions applied in the key step of total synthesis. (b) Organocatalysts involved in total synthesis. (c) Representative indole alkaloids. TOTAL SYNTHESIS OF CYCLOTRYPTAMINE ALKALOIDS Cyclotryptamine alkaloids constitute a large family of natural products that show fascinating biological activities [34,35]. These molecules, such as (+)-folicanthine and (–)-chimonanthine, share an octahydro-3a,3΄a-bispyrrolo[2,3-b]indole subunit characterized by vicinal all-carbon quaternary stereogenic centers. The construction of the bispyrrolidinoindoline core is considered the key issue for total synthesis and thereby has received considerable attention [36]. However, the enantioselective catalytic synthesis of all-carbon quaternary stereogenic centers has been considered a longstanding formidable challenge [37,38]. Thus, the construction of octahydro-3a,3΄a-bispyrrolo[2,3-b]indole skeletons basically relied on asymmetric induction [39,40] and chiral pool-strategy [41–435]. Folicanthine In 2012, Gong and coworkers established an asymmetric substitution of 3-hydroxyoxindole 1 with enamine 2 via TS-1, providing an alkylation product 4 in 82% yield and with 90% ee (Scheme 1) [44]. (E)-Oxime 5 was then obtained via a three-step routine transformations from 4. A HgCl2-promoted Beckman rearrangement selectively delivered amide 6, which was followed by a five-step reaction sequence, including oxidation of indole moiety and alkylation, to give the key diamide intermediate 7. After a known reductive cyclization of 7 [45], the first catalytic enantioselective synthesis of (+)-folicanthine was finished in 12 steps and 3.7% overall yield. Scheme 1. Open in new tabDownload slide First catalytic enantioselective total synthesis of (+)-folicanthine by Gong and coworkers. Scheme 1. Open in new tabDownload slide First catalytic enantioselective total synthesis of (+)-folicanthine by Gong and coworkers. A more concise total synthesis of folicanthine via asymmetric metal/organo relay catalysis was developed by Gong and coworkers [46]. The combination of 1.0 mol% of Rh2(OAc)4 and 5.0 mol% of chiral bifunctional squaramide 9 enabled a three-component coupling reaction of indole, diazooxindole 8 and nitroethylene, affording chiral nitroalkane 10 bearing 3,3΄-bisindole skeleton in a decent yield and with 88% ee (Scheme 2). Oxidation of indole moiety within 10 and a subsequent diastereoselective Michael addition with nitroethylene catalysed by manganese(II) acetate provided Kanai-Matsunaga intermediate 11 [47]. Finally, following Kanai/Matsunaga's [47] and Oguri's procedures [48], the synthesis of (–)-folicanthine was accomplished in seven steps and 14.5% overall yield. Scheme 2. Open in new tabDownload slide Synthesis of (–)-folicanthine via asymmetric Rh(II)/squaramide relay catalysis by Gong and coworkers. Scheme 2. Open in new tabDownload slide Synthesis of (–)-folicanthine via asymmetric Rh(II)/squaramide relay catalysis by Gong and coworkers. Chimonanthine (–)-Chimonanthine, isolated from skin extracts of the Colombian poison-dark frog phyllobates terribilis [49], also has a bispyrrolidinoindoline core. The total synthesis of this molecule has intensively been established. In 2013, Ma and coworkers reported an extremely concise synthesis of chimonanthine [50]. By virtue of chiral anion-phase transfer catalysis pioneered by Toste [51,52], gram-scale asymmetric bromocyclization reaction of protected tryptamine 12 with 13 afforded 15 in 98% yield and 95% ee (Scheme 3). A low-covalent cobalt(I) complex mediated homo-coupling reaction of 15 provided a direct access to octahydro-3a,3΄a-bispyrrolo[2,3-b]indole skeleton 16 [53–565], which could be then converted into (–)-chimonanthine after removal of the N-Boc protecting group and the reduction of methylcarbamate. Scheme 3. Open in new tabDownload slide Chiral anion-phase transfer strategy for the total synthesis of (–)-chimonathine by Ma and Xie. Scheme 3. Open in new tabDownload slide Chiral anion-phase transfer strategy for the total synthesis of (–)-chimonathine by Ma and Xie. Gliocladin C Gliocladin C was isolated from a strain of Gliocladium sp., originally separated from the sea hare exhibited cytotoxic activity against murine P388 lymphocytic leukemia cells [57]. 3-Functionalized indolyloxindole skeleton, commonly existing in a wide selection of alkaloids, including Gliocladin C, has been commonly used as a key intermediate in the total synthesis of natural products [58]. The hexahydropyrrolo indole skeleton, in particular a quaternary stereogenic center at its C3 position, is a signature structural element. In 2011, Overman and coworkers reported a highly efficient Steglich-type rearrangement of bisindole 18, in the presence of 5% Fu's catalyst 19, to give 3,3΄-disubstituted oxindole 20 in 96% yield and 96% ee on a 15-gram scale (Scheme 4) [59]. The carbonyl of oxindole in 20 was easily reduced by NaBH4, and then underwent a highly yielding methylation reaction with trimethyl orthoformate under acidic conditions. Subsequent Soai reduction and Dess-Martin oxidation provided aldehyde intermediate 22, which was able to couple with a trioxopiperazine analogue 23 to furnish compound 24. Finally, (+)-gliocladin C was obtained by the treatment of 24 with Sc(OTf)3. Starting from (+)-di-Boc-gliocladin C, Overman and coworkers accomplished the total synthesis of (+)-gliocladine C, (+)-Leptosin D, (+)-T988C, (+)-Bionectin A and Plectosphaeroic Acid B [60,61]. Scheme 4. Open in new tabDownload slide Steglich-type rearrangement for total synthesis of (+)-gliocladin C by Overman and coworkers. Scheme 4. Open in new tabDownload slide Steglich-type rearrangement for total synthesis of (+)-gliocladin C by Overman and coworkers. In 2013, the Gong group described a primary amine-catalysed highly enantioselective alkylation reaction of 3-hydroxyoxindoles with aldehydes, which allows the asymmetric catalytic total synthesis of (+)-gliocladin C (Scheme 5) [62]. The combined catalysts of primary amine 26 and chiral phosphoric acid 27 provided an efficient approach to access disubstituted oxindoles in 80% yield and 94% ee. Interestingly, the addition of ethanol gave relatively higher enantioselectivity, showing that the alcohol indeed plays an important role in the formation of new carbon–carbon bond. The reduction of the chiral aldehyde 28 to corresponding alcohol and protection with the tert-butyldimethylsilyl (TBS) group gave 29. Oxindole carbonyl turned out to be more reactive after protecting with (Boc)2O and was thereby reduced with NaBH4 in MeOH to give a hemiaminal 30. A subsequent methylation and deprotection reaction sequence provided diol 31, which was then transformed into Overman intermediate [59] by NaIO4 oxidation. From the chiral alkylation adduct 28, the enantioselective total synthesis of (+)-gliocladin C was successfully accomplished in 12 steps and 19% overall yield. Scheme 5. Open in new tabDownload slide Synthesis of (+)-gliocladin C by Gong and coworkers. Scheme 5. Open in new tabDownload slide Synthesis of (+)-gliocladin C by Gong and coworkers. TOTAL SYNTHESIS OF POLYCYCLIC TERPENE INDOLE ALKALOIDS Translating new methodology in total synthesis and building up large collections of natural product families are two fundamental challenges in target molecule synthesis. The MacMillan group recently sought to develop an asymmetric strategy for the collective total synthesis by preparing an advanced core structure based on organocascade catalysis (Fig. 2). The strategy of collective natural product synthesis via chiral imidazolidinone catalysis has been demonstrated through the asymmetric total syntheses of six alkaloid natural products: (–)-strychnine, (+)-aspidospermidine, (+)-vincadifformine, (–)-akuammicine, (–)-kopsinine and (–)-kopsanone [63]. Figure 2. Open in new tabDownload slide Organocascade catalysis developed by MacMillan and coworkers. Figure 2. Open in new tabDownload slide Organocascade catalysis developed by MacMillan and coworkers. The detailed catalytic cycles of this fascinating cascade reaction are shown in Fig. 2 [63]. Under the catalysis of 1-naphthyl-substituted imidazolidinone 32, the tryptamine derivative 33 and propynal underwent an endo-selective Diels-Alder reaction, followed by a methyl selenide-triggered β-elimination, to give a transient intermediate 35. The author proposed a reversible cyclization/ring-opening process of 35. In the second catalytic cycle, both iminium and Brønsted acid catalysis were possible to lower the Lowest Unoccupied Molecular Orbital (LUMO) energy of 38, thus rendered a conjugate addition reaction to generate the common intermediate 39. (–)-Strychnine and (–)-akuammicine Strychnine is the most well-known member of the strychnos alkaloid family. Akuammicine is an alkaloid found in Vinca minor and Aspidosperma. Importantly, strychnine is believed to share a key precursor of these structurally diverse alkaloids. Thus, a common intermediate 39 is exploited in the construction of a diverse collection of target complex molecules. The crucial asymmetric reaction was accomplished by using catalyst 32 and tribromoacetic acid as co-catalyst, giving the tetracyclic spiroindoline 39a in a good yield and with excellent enantioselectivity (82% yield, 97% ee, Scheme 6). Decarbonylation of 39a mediated with Wilkinson's catalyst (Rh(PPH3)3Cl) followed by the introduction of a carbomethoxy group and reduction with DIBAL-H resulted in an isomeric mixture of unsaturated ester 40. An allylation/reduction reaction sequence that occurred with 40 afforded compound 41. As a second key step, a cascade Jeffery-Heck cyclization/lactol formation was initiated. The insertion of palladium into the vinyl iodide and a subsequent carbopalladation would forge the six-membered ring and produce an alkyl palladium intermediate. The following β-hydride elimination step provided an enol that would rapidly engage in lactol cyclization and gave intermediate 42. The removal of the p-methoxybenzyl (PMB) group with trifluoroacetic acid (TFA)/PhSH followed by treatment with malonic acid delivered enantioenriched (–)-strychnine. A three-step reaction sequence starting from 40, including removal of the PMB protecting group, an allylation reaction and a Heck cyclization finally furnished (–)-akuammicine (Scheme 6) [63]. Scheme 6. Open in new tabDownload slide Synthesis of (–)-strychnine and (–)-akuammicine by MacMillan and coworkers. Scheme 6. Open in new tabDownload slide Synthesis of (–)-strychnine and (–)-akuammicine by MacMillan and coworkers. The broad utility of these organocatalytic enantioselective cascade reactions for constructing polycyclic rings is illustrated by total syntheses of several related natural products, such as (+)-aspidospermidine, (+)-vincadifformine, (–)-kopsinine and (–)-kopsanone (Scheme 7) [63]. Scheme 7. Open in new tabDownload slide (a) Application of organocascade catalysis to total synthesis of (+)-vincadifformine. (b) Total synthesis of (–)-kopsinine and (–)-kopsanone. Scheme 7. Open in new tabDownload slide (a) Application of organocascade catalysis to total synthesis of (+)-vincadifformine. (b) Total synthesis of (–)-kopsinine and (–)-kopsanone. Minovincine (–)-Minovincine was first isolated from Vinca minor in 1962 [64]. In 2013, the MacMillan group disclosed an organocatalytic cascade reaction of 2-vinyl indole 33a with but-3-yn-2-one, providing direct access to the key tetracycle skeleton of (–)-minovincine (Scheme 8). The vinyl selenide system was crucial for the cascade enantioselective Diels-Alder cycloaddition, β-elimination and conjugate addition reactions. A palladium-catalysed carbomethoxylation of the dienylogous amide converted the enantioenriched tetracyclic intermediate 52 into a vinylogous carbamate 53 in 92% yield. After a subsequent four-step reaction sequence, (–)-minovincine was accessed in 13% overall yield [65]. Scheme 8. Open in new tabDownload slide Organocascade catalysis for synthesis of (–)-minovincine by MacMillan and coworkers. Scheme 8. Open in new tabDownload slide Organocascade catalysis for synthesis of (–)-minovincine by MacMillan and coworkers. Vincorine (–)-Vincornie, which belongs to the Akuammiline-type alkaloids, has been found to exhibit interesting biological activity and holds an inspiring architecture [66]. In 2013, the MacMillan group reported a concise enantioselective total synthesis of (–)-vincornie based on an organocatalytic Diels-Alder reaction, elimination and conjugate cascade addition (Scheme 9a) [67]. Chiral secondary amine catalyst 55 could give the tetracyclic core structure 56 in 73% yield and 95% ee. Notably, the challenging seven-membered azepanyl ring system was built up by means of a radical cyclization initiated from an acyl telluride precursor 58. This transformation was believed to proceed through carbon-Te bond hemolysis, followed by releasing carbon monoxide to generate an alkyl radical. The challenging seven-membered azepanyl ring was then accomplished through a radical cyclization reaction. Finally, the total synthesis of (–)-vincorine was achieved in nine steps and 9% overall yield from commercially available starting materials. Scheme 9. Open in new tabDownload slide (a) Synthesis of (–)-vincorine by MacMillan and coworkers. (b) Synthesis of (–)-vincorine by Ma and coworkers. Scheme 9. Open in new tabDownload slide (a) Synthesis of (–)-vincorine by MacMillan and coworkers. (b) Synthesis of (–)-vincorine by Ma and coworkers. Alternatively, the Ma group reported the total synthesis of (–)-vincorine via an organocatalysed asymmetric Michael addition reaction (Scheme 9b) [68]. The combination of alkylidene malonate 60, aldehyde 61 and 20 mol% of TMS-protected diphenylprolinol 62 would lead to the Michael adduct 63 in 75% yield as a 5:1 diastereomeric mixture. Subsequently, a sequential process involving oxidation of the aryl selenide moiety of 63 and Et3N-mediated elimination produced olefin 64. E-64 was then treated with strong base LiHMDS and I2 to undergo an oxidative coupling reaction to give 65 in 67% isolated yield [69–71]. (–)-Vincorine was finally furnished in 5% overall yield after additional five-step routine manipulation. Deethylibophyllidine and limaspermidine (+)-Deethylibophyllidine was originally isolated from the bark of Tabernaemontana albif lora and Anacampta disticha in 1980 [72] and (+)-limaspermidine was initially isolated from the trunk bark of a small Venezuelan tree A. rhombeosignatum MARKGRAF in 1979 [73]. Both of these two natural products belong to the family of Apocynaceae alkaloids, and thus commonly have a hydrocarbazole nucleus as core structure. This functionalized hydrocarbazole unit, which contains an all-carbon quaternary stereocenter, poses a particular challenge in organic synthesis. In 2015, Fan and coworkers reported a total synthesis of these two natural products (Scheme 10) [74]. The routes involved a key tandem reaction of aminolysis and aza-Michael addition reaction of spirocyclic para-dienoneimides 66 through organocatalytic enantioselective desymmetrization. The chiral tertiary amine thiourea 67 was identified to be the optimal catalyst in terms of the yield and selectivity (45% yield and 90% ee) in the model reaction of 66 with allyl amine. The syntheses of natural products commenced with a base-promoted intramolecular aza-Michael addition of desymmetrization product 68, affording the versatile tetracyclic precursor 69 in 85% yield. The ozonolysis and palladium-catalysed anti-Markovnikov oxidation of 69 respectively gave the aldehydes 70 and 72, which then underwent an intramolecular aldol reaction to furnish the pentacyclic building block 71 and 73, respectively. Starting from the intermediate 71, an assembly of (+)-deethylibophyllidine was achieved after six additional transformations, while 10 steps were still needed from intermediate 73 to access (+)-limaspermidine. Scheme 10. Open in new tabDownload slide Synthesis of (+)-deethylibophyllidine and (+)-limaspermidine by Fan and coworkers. Scheme 10. Open in new tabDownload slide Synthesis of (+)-deethylibophyllidine and (+)-limaspermidine by Fan and coworkers. Ibophyllidine (+)-Ibophyllidine, originally isolated in 1976 from the plants Taberanthe iboga and T. subsessilis, contains an all-syn-pyrrolidine nucleus, thus holding an uncommon synthetic challenge [75]. In 2012, the Kwon group reported the first enantioselective total synthesis of (+)-ibophyllidine by using the key asymmetric [3 + 2] annulation (Scheme 11) [76]. Based on the concept pioneered by Lu and coworkers [77], catalytic amounts of chiral phosphine 76 was able to attack the β-carbon atom of allenoate 75 to generate a reactive dipole intermediate that could participate in an asymmetric [3 + 2] cycloaddition with imine 74 to afford dihydropyrrole 77 in 93% yield and with 99% ee. A hydrogenation of the pyrroline double bond in 77 catalysed by Raney Ni led to the isolation of an all-syn pyrrolidine derivative 78 in 80% yield. Further transformations, including reduction, Swern oxidation and Wittig reaction, provided the intermediate 80. Silver(I)-catalysed sequential spirocyclization and aza-Morita-Baylis-Hillman reactions provided access to the pentacyclic framework in 81. After a subsequent three-step transformation, (+)-ibophyllidine was obtained in 13% overall yield. Scheme 11. Open in new tabDownload slide Phosphine-catalysed [3 + 2] cycloaddition for total synthesis of (+)-lbophyllidine. Scheme 11. Open in new tabDownload slide Phosphine-catalysed [3 + 2] cycloaddition for total synthesis of (+)-lbophyllidine. TOTAL SYNTHESIS OF TETRAHYDRO-β-CARBOLINE ALKALOIDS The 1,2,3,4-tetrahydro-β-carboline (THBC) ring has been frequently found in a wide range of indole alkaloids and biologically active compounds [78,79]. A catalytic enantioselective Pictet-Spengler reaction of tryptamine and its derivative 83 with aldehyde or ketone 84 is the most straightforward method to access enantiopure 1,2,3,4-tetrahydro-β-carboline skeleton 85 (Scheme 12a) [80,81], which is the core structural element of numerous indole alkaloids. Chiral small molecules, especially chiral Brønsted acids, have been the privileged catalysts for asymmetric Pictet-Spengler reactions [82–87], thus enabling asymmetric catalytic total synthesis of tetrahydro-β-carboline alkaloids, such as (+)-yohimbine by the Maarseceen and Hiemstra group (Scheme 12b) [84] and (–)-arboricine by Jacobsen and coworkers (Scheme 12c) [85]. Recently, the total synthesis of more complex indole alkaloids was also accomplished by using the asymmetric Pictet-Spengler reaction as the key step. Scheme 12. Open in new tabDownload slide (a) Access to 1,2,3,4-tetrahydro-β-carboline via asymmetric Pictet-Spengler reaction. (b) Synthesis of (+)-yohimbine. (c) Synthesis of (–)-arboricine. Scheme 12. Open in new tabDownload slide (a) Access to 1,2,3,4-tetrahydro-β-carboline via asymmetric Pictet-Spengler reaction. (b) Synthesis of (+)-yohimbine. (c) Synthesis of (–)-arboricine. Mitragynine Mitragynine, a potent analgesic reagent [88], was isolated from tropical tree Mitragyna speciosa (Rubiaceae) native to Thailand and Malaysia [89]. In 2012, the Maarseveen and Hiemstra group established a total synthesis of (–)-mitragynine and its congeners, (+)-paynantheine and (+)-speciogynine (Scheme 13) [90]. This synthetic approach commenced with an asymmetric Pictet-Spengler reaction catalysed by quinine-derived thiourea catalyst 90. A reaction sequence involving protection/hydrolysis of dithoacetal gave rise to the α-ketoester 92 in 73% yield. A subsequent intramolecular Tsuji-Trost allylic alkylation reaction of 92 delivered the tetracyclic intermediate as a 4:1 mixture of epimers. The intermediate 93b was treated with ylide in situ generated from methoxymethylene triphenylphosphonium chloride and then with TFA to provide (+)-paynantheine, which was finally converted to (–)-speciogynine via a simple hydrogenation. Following a similar procedure, (–)-mitragynine was also synthesized in 60% yield. Scheme 13. Open in new tabDownload slide Synthesis of (–)-mitragynine, (+)-paynantheine and (+)-speciogynine by Maarseveen and Hiemstra group. Scheme 13. Open in new tabDownload slide Synthesis of (–)-mitragynine, (+)-paynantheine and (+)-speciogynine by Maarseveen and Hiemstra group. Peganumine A Peganumine A, first isolated from the seeds of Peganum harmala L. in 2014 [91], possesses a unique octacyclic architecture and shows significant cytotoxic activity against MCF-7, PC-3, HepG2 cells. Very recently, Zhu and coworkers accomplished the first total synthesis of (+)-Peganumine A by using a catalytic enantioselective Pictet-Spengler reaction as one of the key steps (Scheme 14) [92]. The thioesterification and ozonolysis of commercially available 3,3-dimethyl-pen-4-enoic acid 94 gave 95. Starting from 6-methoxyl-tryptamine 96, a three-step synthetic sequence provided organotin intermediate 98, which underwent a Liebeskind−Srogl cross-coupling reaction with 95 to give 99. The dehydration of 99 followed by a 4-center-3-component Ugi reaction afforded tetracyclic 101. Under the catalysis of chiral thiourea 102, the asymmetric Pictet-Spengler reaction of 101 with 6-methoxyl-tryptamine 96 gave (+)-peganumine in 69% yield and with 92% ee. Scheme 14. Open in new tabDownload slide Synthesis of (+)-peganumine by Zhu and coworkers. Scheme 14. Open in new tabDownload slide Synthesis of (+)-peganumine by Zhu and coworkers. OTHER INDOLE ALKALOIDS Trigonoliimine A Trigonoliimine A with a unique polycyclic skeleton was isolated from the extract of the leaves of Trigonostemon. Lii Y. T. Chang collected in Yunnan province of China [93]. The structure features a tricylic core with a quaternary carbon center [94]. In 2013, Zhu reported an organoctalytic enantioselective Michael addition of α-aryl-isocyanoacetates 103 to vinyl phenyl selenone, which turned out to be the key step for the total synthesis of (+)-trigonoliimine A (Scheme 15a) [95]. A nucleophilic substitution of the phenylselenone 105, obtained from the asymmetric Michael addition, with sodium azide and followed by hydrolysis of nitrile functionality gave intermediate 106, which underwent a reductive alkyla-tion with 2-(1H-indole-3-yl)acetaldehydealdehyde 107 in the presence of NaBH(OAc)3 to afford complex quaternary α-amino ester 108. An efficient Staudinger reduction directly produced the lactam 109 in 78% yield. A subsequent three-step reaction sequence involving reduction of a nitro group and the Bischler-Napieralski reaction furnished (+)-trigonoliimine in 7.5% overall yield. It is noteworthy that employing quinidine-derived similar bifunctional catalyst 111 under identical conditions and following exactly the same synthetic sequence, (–)-trigonoliimine A could be obtained in 6.8% overall yield (Scheme 15b). Scheme 15. Open in new tabDownload slide (a) Synthesis of (+)-trigonoliimine A by Zhu and coworkers. (b) Synthesis of (–)-trigonoliimine A. Scheme 15. Open in new tabDownload slide (a) Synthesis of (+)-trigonoliimine A by Zhu and coworkers. (b) Synthesis of (–)-trigonoliimine A. Anhydronium alkaloids The first isolation of alstonine (from Alstonia constricta [96]) and serpentine (from Rauvolfia serpentine [97]) dates back to about 80 years ago. Biologically, alstonine and serpentine are able to treat psychotic disorders. They are pentacyclic indole alkaloids containing a zwitterionic indolo[2,3-a]quinolizidine motif and three contiguous stereogenic centers. In 2015, Scheidt and coworkers described an enamine-catalysed Michael addition reaction for the enantioselective total syntheses of these natural products (Scheme 16a) [98]. The combination of chiral primary amine 113 (30 mol%) and catechol rendered a highly efficient reaction to deliver piperidine derivative 114 in 78% yield and with 98% ee. Starting from 114, dihydropyran 115 was obtained through several routine manipulations and a key Korte rearrangement. After a highly yielding deprotection reaction, the intermediate 115 underwent a reductive alkylation with indole-3-acetaldehyde to give intermediate 116. Then an oxidative iminium ion cyclization of 116 promoted by mercuric acetate and ethylenediaminetetraacetic acid (EDTA) furnished a heteroyohimbine alkaloid ajmalicine in 41% yield. Dehydrogenation of ajmalicine by using Pd/C as catalyst in aqueous conditions followed by alkoxylation provided serpentine methoxide in 26% yield. Similarly, the synthesis of alstonine hydrogen maleate could be accomplished within four steps from 118 (Scheme 16b). Scheme 16. Open in new tabDownload slide (a) Organocatalytic asymmetric intramolecular Michael addition reaction. (b) Synthesis of ajmalicine and related natural products by Scheidt and coworkers. Scheme 16. Open in new tabDownload slide (a) Organocatalytic asymmetric intramolecular Michael addition reaction. (b) Synthesis of ajmalicine and related natural products by Scheidt and coworkers. Actinophyllic acid (–)-Actinophyllic acid was isolated in 2005 from the leaves of the tree Alstonia actinophylla growing in Cape York Peninsula, Far North Queensland, Australia [99]. (–)-Actinophyllic acid contains the cage-like scaffold, with five contiguous stereogenic centers, one of which is a quaternary carbon, bridged by a tetrahydrofuran lactol. In 2016, the Kwon group reported a catalytic asymmetric total synthesis of (–)-actinophyllic acid by using a [3 + 2] annulation strategy between imine 119 and benzyl allenoate 120 under catalysis of chiral phosphine 121 (Scheme 17) [100]. S-BINOL or R-BINOL was used as an additive to facilitate the proton-transfer steps and to rigidify the transition-state assembly, thereby improving the enantioselectivity without sacrificing the yield (99% yield and 94% ee). The annulation product 122 was converted to 123 by a C-2 selective iodination/deprotection/aza-Michael addition sequence, followed by an intramolecular CuI-catalysed cross-coupling reaction [101] to allow a C(sp2)-C(sp3) bond formation to give tetracyclic product 124. It is noteworthy that the enantiomeric excess of 124 could be 99% by one single recrystallization operation. Further transformations involving a hydrogenolysis over Pd/C to remove the benzyl group, esterification reaction with chloroiodomethane and nucleophilic substitution were performed to furnish the lactone 126. SmI2-mediated intramolecular ketone-lactone pinacol coupling provided diol product 127 in almost quantitative yield. A key radical dehydroxylation along with the removal of the Boc group provided (–)-actinophyllic acid hydrochloride. Scheme 17. Open in new tabDownload slide Synthesis of (–)-actinophyllic acid hydrochloride by Kwon and coworkers. Scheme 17. Open in new tabDownload slide Synthesis of (–)-actinophyllic acid hydrochloride by Kwon and coworkers. Leucomidine B (–)-Leucomidine B was isolated from the barks of Leuconotis griffithii in 2012 by Morita et al. [102]. Recently, the Zhu group reported a formal synthesis of (–)-leucomidine B [103], wherein asymmetric desymmetrization of prochiral synthon represented the key step (Scheme 18) [104]. A chiral imidodiphosphoric acid 130-catalzyed asymmetric desymmetrization reaction of bicyclic bislactone 129 provided monoacid 131 (95% yield and with 84% ee), which was then converted to protected azide intermediate 132 after five-step derivatization. A Staudinger reduction and subsequent aza-Wittig reaction of the deprotected azide from 132 delivered cyclic imine 133. The condensation of methyl 3-(2-nitrophenyl)-2-oxo-propanoate 134 with 133 afforded [3 + 2] annulation product 135 as a 1:1 mixture of diastereomers in 80% yield. Hydrogenative condensation of 135 gave natural product (–)-leucomidine B in 40% yield and its C21 epimer in 40% yield as well. Scheme 18. Open in new tabDownload slide Formal synthesis of (–)-leucomidine B by Zhu and coworkers. Scheme 18. Open in new tabDownload slide Formal synthesis of (–)-leucomidine B by Zhu and coworkers. CONCLUSION This review has briefly illustrated synthetic applications of organocatalytic reactions in the synthesis of relevant indole alkaloids, which have enabled rapid construction of molecular complexity with excellent levels of stereocontrol. Various approaches towards making these natural products have been reported. It is certain that organocatalysis can be therefore considered an additional tool for asymmetric synthesis, besides other kinds of well-established catalytic methods. Hopefully, this review will inspire more efforts devoted to applying organocatalytic transformations to the total synthesis of complex natural products. 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TI - Recent progress in organocatalytic asymmetric total syntheses of complex indole alkaloids
JF - National Science Review
DO - 10.1093/nsr/nwx028
DA - 2017-05-01
UR - https://www.deepdyve.com/lp/oxford-university-press/recent-progress-in-organocatalytic-asymmetric-total-syntheses-of-47JrbkH9ox
SP - 381
EP - 396
VL - 4
IS - 3
DP - DeepDyve
ER -