Unified Total Synthesis of Stemoamide-Type Alkaloids by

Article Cite This: J. Am. Chem. Soc. 2017, 139, 18386−18391

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Unified Total Synthesis of Stemoamide-Type Alkaloids by Chemoselective Assembly of Five-Membered Building Blocks Makoto Yoritate,† Yoshito Takahashi,†,‡ Hayato Tajima,†,‡ Chisato Ogihara,† Takashi Yokoyama,† Yasuki Soda,† Takeshi Oishi,§ Takaaki Sato,*,† and Noritaka Chida*,† †

Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan § School of Medicine, Keio University, 4-1-1 Hiyoshi, Kohoku-ku, Yokohama 223-8521, Japan S Supporting Information *

ABSTRACT: A unified total synthesis of stemoamide-type alkaloids is reported. Our synthetic approach features the chemoselective convergent assembly of five-membered building blocks via stemoamide as the common precursor to tetracyclic natural products. The synthesis consists of two successive coupling reactions of the three five-membered building blocks. The first coupling reaction is the vinylogous Michael addition/ reduction sequence, which enables the gram-scale synthesis of stemoamide. The second coupling reaction is a chemoselective nucleophilic addition to stemoamide. While the lactoneselective nucleophilic addition to stemoamide affords saxorumamide and isosaxorumamide, the lactam-selective reductive nucleophilic addition leads to the formation of stemonine. Both chemoselective nucleophilic additions enable direct modification of stemoamide, resulting in highly concise and efficient total syntheses of the stemoamide-type alkaloids.

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INTRODUCTION Chemoselectivity is a crucial concept in modern organic chemistry for the efficient syntheses of highly functionalized molecules, especially when pharmaceutical applications are taken into account.1 A high level of chemoselective control enables transformations of specific functional groups even in highly complex molecules without the use of tedious protecting group manipulations2 or redox reactions.3 In this article, we report a unified total synthesis of stemoamide-type alkaloids,4 featuring a chemoselective convergent assembly of fivemembered building blocks via stemoamide (1) as a common intermediate. The Stemona alkaloids, isolated from Stemonaceae plants, consist of over 150 natural products.4 Traditionally, extracts of these plants have been utilized in Chinese and Japanese folk medicines as antitussive and insecticidal agents. Recent studies revealed that the isolated Stemona constituents also possess diverse biological activities including antitussive, insecticidal, and anthelmintic effects.5 Most of the Stemona alkaloids consist of five-membered heterocyclic rings and an azepane ring and are structurally classified into several groups.4 The stemoamidetype alkaloids are known to compose one of the largest groups (Figure 1). Stemoamide (1), which is the representative natural product of this group, is comprised of a fused tricyclic framework including a γ-lactone and a γ-lactam.6 While saxorumamide (2) and isosaxorumamide (3) have an additional γ-lactone on the γ-lactone carbonyl group of stemoamide (1),7 stemonine (4) possesses an additional γ-lactone on the γ-lactam © 2017 American Chemical Society

Figure 1. Representative stemoamide-type alkaloids.

carbonyl group of stemoamide (1).8 More than 20 syntheses of stemoamide (1) have been reported to date due to its relatively simple structure.9,10 In contrast, the tetracyclic derivatives of stemoamide (1) drastically increase the structural complexity. Indeed, only the Williams’ group achieved a landmark total synthesis of stemonine (4) through sequential, late-stage ring closure reactions of an acyclic intermediate.11 An ideal synthetic approach to these tetracyclic natural products would be the direct installation of the γ-lactone to stemoamide (1) itself. However, such a strategy has not been realized so far because Received: October 13, 2017 Published: November 27, 2017 18386

DOI: 10.1021/jacs.7b10944 J. Am. Chem. Soc. 2017, 139, 18386−18391

Journal of the American Chemical Society

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differentiating between the γ-lactone and the γ-lactam embedded in 1 is not trivial. Our central strategy toward the unified total synthesis of stemoamide-type alkaloids is based on the highly convergent assembly of heterocyclic building blocks 5 and 6 (Scheme 1A).

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RESULTS AND DISCUSSION Gram-Scale Total Synthesis of Stemoamide. Our unified total synthesis commenced with the preparation of stemoamide (1) (Scheme 2). The DIBAL-H reduction of

Scheme 2. Gram-Scale Total Synthesis of Stemoamidea

Scheme 1. Synthetic Strategy for Stemoamide-Type Alkaloids

Use of these simple five-membered building blocks allows for functionalization at any position of each building block such as 1,2-addition to the carbonyl or alkylation at the α-position. The building block synthesis of natural products has been well documented, culminating in Martin’s total synthesis of croomine by the vinylogous Mannich reaction.12,13 However, the application of such strategy to the synthesis of stemoamidetype alkaloids requires the precise control of chemoselectivity. Convergent assembly is not feasible without differentiation between the γ-lactone and the γ-lactam. Our actual synthetic plan is outlined in Scheme 1B. We envisioned that stemoamide (1) could serve as a common precursor to the tetracyclic natural products and incorporated two successive coupling reactions of the five-membered building blocks. The first coupling reaction would be the vinylogous Michael addition/ reduction sequence of γ-lactam derivative 8 to chiral α,βunsaturated lactone 7. Stemoamide (1) could then be synthesized through construction of the azepane ring and methylation. The second coupling reaction is the chemoselective nucleophilic addition of the γ-lactone equivalent 10 to the resulting stemoamide (1). The γ-lactone-selective nucleophilic addition would afford both saxorumamide (2) and isosaxorumamide (3). On the other hand, the γ-lactam-selective nucleophilic addition14,15 could allow access to stemonine (4). If these chemoselective controls are successfully achieved, the tetracyclic stemoamide-type alkaloids would be supplied from relatively simple stemoamide (1) in a step-economical fashion.3b,16

Reagents and conditions: (a) DIBAL-H (1.1 equiv), CH2Cl2, −78 °C, 1 h; (b) methyl propiolate (3 equiv), ZnMe2 (3 equiv), (S,S)ProPhenol (20 mol %), toluene, 0 °C, 24 h, 78% (2 steps), 98% ee; (c) Pd/PEI (2 wt %), H2 (1 atm), MeOH/dioxane = 1:1, rt, 15 h, 72%, 98% ee; (d) 14 (1.2 equiv), SnCl4 (0.5 equiv), CH2Cl2, −78 °C to −60 °C, 12 h; then MeOH (2.5 equiv), Et3SiH (15 equiv), TiCl4 (3.0 equiv), −78 °C to rt, 24 h, 76%, 9:epi-9 = 3.7:1; (e) CAN (3 equiv), MeCN/H2O = 10:1, rt, 24 h, 94%; (f) NaH (1.5 equiv), TMSOTf (20 mol %), TBAI (10 mol %), DMF, 0 °C, 6 h, 17: 57%, epi-17: 19%; (g) LiHMDS (1.2 equiv), MeI (1.3 equiv), THF, −78 °C to rt, 2 h, 84%. a

commercially available ethyl 4-bromobutyrate 11, followed by catalytic enantioselective alkynylation under Trost’s conditions,17 afforded propargylic alcohol 13 in 78% yield over 2 steps (98% ee). The resulting alkyne group underwent partial hydrogenation with Sajiki’s catalyst (Pd/PEI: polyethylenimine)18 to give the methyl Z-enoate, which was immediately converted to γ-lactone 7 by acidic workup. The first pivotal coupling reaction of five-membered building blocks 7 and 1419 was then attempted through Mukaiyama-type vinylogous Michael addition and subsequent one-pot reduction (Scheme 2).20 Addition of SnCl4 (0.5 equiv) to the solution of γ-lactone 7 and N-PMB-2-siloxypyrrole 14 in CH2Cl2 at −78 °C initiated the carbon−carbon bond formation. After 18387


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Scheme 3. (A) Unsuccessful Stereocontrol at C11 Carbon Center in Lactone-Selective Nucleophilic Addition and (B) Working Hypothesis in the Lactone-Selective Nucleophilic Additiona

Reagents and conditions: (a) DIBAL-H (3 equiv), CH2Cl2, −78 °C, 1 h; (b) 19 (3 equiv), BF3·Et2O (5 equiv), CH2Cl2, rt, 36 h, 2: 12%, 3: 9%, 21: 27% (dr = 1.3:1). a

a separable mixture of 17 and epi-17 in 76% combined yield (Scheme 2). Although the formation of the azepane ring by intramolecular N-alkylation was documented in previous reports,9b,o the gram-scale synthesis required an improved procedure since the γ-lactone group of 9 was prone to hydrolysis by the residual sodium hydroxide in NaH, resulting in low yield. After extensive investigation, we found that the addition of TMSOTf (20 mol %) improved the yield of the cyclization probably because premixing TMSOTf with a suspension of NaH (1.5 equiv) and TBAI (10 mol %) in DMF removed the residual sodium hydroxide. Finally, the regio- and stereoselective methylation9b,g,o of 17 afforded stemoamide (1) in 84% yield. Our enantioselective route enabled the gram-scale production22 of stemoamide (1: 1.07 g) from a single path in 7 steps and 19.2% total yield, which represents one of the most efficient enantioselective syntheses to date. Total Syntheses of Tetracyclic Stemoamide-Type Alkaloids. With stemoamide (1) in hand, we investigated the lactone-selective nucleophilic addition to give saxorumamides (2) and isosaxorumamide (3) (Scheme 3A). This chemoselectivity could be achieved with classic transformations by taking advantage of inherent electrophilicities: γ-lactone > γlactam. However, the more challenging issue in this transformation was the stereocontrol. For example, the lactone-

completion of the coupling reaction at −60 °C, the resulting compound 15 was then treated with methanol, TiCl4 (3.0 equiv), and Et3SiH to give an inseparable mixture of bicyclic compounds 9 and epi-9 in 76% combined yield. In the first Michael addition, the equivalent of SnCl4 was crucial, and use of more than 0.5 equiv provoked the unfavorable retro-Michael reaction. In the second reduction step, no bicyclic products 9 and epi-9 were obtained without the addition of methanol. TLC analysis of this reaction indicated that N,O-acetal 16 was formed probably through protonation of 15 at the C2 carbon when methanol was added and then was consumed via the Nacyliminium ion as the reaction proceeded. The first coupling reaction proceeded with complete stereocontrol at the C9 carbon center, and the subsequent reduction showed 3.7:1 diastereoselectivity at the C9a carbon center. The enantio excesses of both diastereomers were maintained at 98% ee.21 Although the mechanistic rationale controlling the stereoselectivity at the C9a carbon center is yet to be clarified, this one-pot vinylogous Michael addition/reduction process enabled quick access to the bicyclic compound from two simple five-membered building blocks on a multigram scale (4.52 g).22 After cleavage of the PMB group of the mixture of 9 and epi9, the seven-membered ring was formed with NaH in the presence of TBAI (10 mol %) and TMSOTf (20 mol %), giving 18388


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Scheme 4. Total Syntheses of Tetracyclic Stemoamide-Type Alkaloids (A) Saxorumamide and Isosaxorumamide by LactoneSelective Nucleophilic Addition and (B) Stemonine by Lactam-Selective Reductive Nucleophilic Additiona

a Reagents and conditions: (a) 22 (1.5 equiv), THF, −78 °C, 2 h, 87%; (b) NaBH3CN (5 equiv), CCl2HCO2H (5 equiv), CH2Cl2, −78 °C, 14 h, 95%, single diastereomer; (c) mCPBA (1.2 equiv), CH2Cl2, rt, 2 h; (d) TBAF (3 equiv), THF, −40 °C, 30 min; then NaBH4 (5 equiv), AcOH (3 equiv), −40 °C, 30 min, 2: 46%, 3: 39%; (e) IrCl(CO)(PPh3)2 (1 mol %), (Me2HSi)2H (1.5 equiv), toluene, rt, 1 h; then 19 (2.8 equiv), 2NO2C6H4CO2H (5 equiv), MeCN, rt, 24 h, 29: 43%, epi-29: 30%; (f) DBU (2 equiv), CH2Cl2, rt, 3 h, 29: 52%, epi-29: 43%; (g) Rh/Al2O3 (5 wt %), H2 (1 atm), EtOH, rt, 3 h, 98%, single diastereomer.

subsequent hydride-reduction. Therefore, we planned to employ 2-silyl-3-methyl furan as the γ-lactone equivalent. The lactone-selective nucleophilic addition of lithiated furan 22 to stemoamide (1) would give lactol 23. Then, acid-mediated reduction of 23 would provide tetrahydrofuran 25 with the correct stereochemistry at C11 because the sterically small hydride group could approach the generated oxocarbenium ion 2423 from the stereoelectronically favored β-face by the Woerpel model, not the sterically favored α-face. To prove our working hypothesis, lithiated furan 2225 was added to a solution of stemoamide (1) in THF at −78 °C (Scheme 4A). The nucleophilic addition of 22 proceeded with complete lactone selectivity. The reaction did not provide lactol 23 (Scheme 3B), but led to the isolation of enol ether 26 in 87% yield through concomitant elimination probably with the assistance of the adjacent furan ring. Gratifyingly, stereoselective reduction of enol ether 26 was achieved with NaBH3CN in the presence of CCl2HCO2H at −78 °C. Two consecutive stereocenters (C10 and C11) were established by stereoselective protonation of the enol ether26 and subsequent reduction of the resulting oxocarbenium ion, giving 25 in 95% yield as a single diastereomer. Finally, saxorumamide (2) and isosaxorumamide (3) were obtained by transformation of the 2silylfuran to the γ-lactone in 85% yield by epoxidation of 25 with mCPBA and desilylation with TBAF accompanied by onepot reduction with NaBH4 (dr = 1.2:1 at C12). In this reaction, monoepoxidation of 25 with mCPBA and subsequent

selective DIBAL-H reduction of stemoamide (1) provided lactol 18, which underwent the BF3·Et2O-mediated vinylogous Mukaiyama reaction with 2-siloxyfuran 19. Unfortunately, although saxorumamide (2) and isosaxorumamide (3) were obtained in 12% and 9% yields, respectively, the major products were two diastereomers 21 with the incorrect stereochemistry at the C11 carbon center. The poor diastereoselectivity at the C11 carbon center in the vinylogous Mukaiyama reaction was rationalized based on the lowest energy conformation of the transient oxocarbenium ion 20.23 The stereochemical outcome could be defined by balance between stereoelectronic and steric factors. The stereoelectronic effect preferred the approach of 2siloxyfuran 19 from the β-side (path A) through the insideattack model proposed by Woerpel,24 leading to incorrect stereochemistry at C11. On the other hand, the steric factor favored the approach from the α-side (path B) due to the steric repulsion with the adjacent methyl group, affording saxorumamide (2) and isosaxorumamide (3). We believe that these two pathways competed in the vinylogous Mukaiyama reaction of lactol 18, resulting in the poor diastereoselectivity at the C11 carbon center. A practical feature of our synthetic strategy taking advantage of the nucleophilic addition to a carbonyl group is the stereodivergency by simply changing the order of addition related to the hydride and carbon unit (Scheme 3B). In other words, the correct stereochemistry at C11 could presumably be installed by addition of the carbon unit first and then 18389


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total synthesis also demonstrated the utility of our nucleophilic addition to amides, which enables the use of easily available and stable amides as multisubstituted amine equivalents even in highly complex molecules.

desilylation with TBAF provided 2 and 3. However, we also observed the formation of γ-hydroxybutenolides probably due to the competing bisepoxidation of 25. Addition of NaBH4 was essential for the reduction of the partially formed γhydroxybutenolides, which were merged to natural products 2 and 3. Thus, we achieved the first total syntheses of saxorumamide (2) and isosaxorumamide (3) in 11 steps in 7.3% and 6.2% total yields, respectively. The lactam-selective reductive nucleophilic addition is much more challenging than the lactone-selective reaction because, in general, a γ-lactam is less electrophilic than a γ-lactone.15 The γlactone in stemoamide (1) proved to be highly reactive due to the ring strain derived from the trans-fused 5−7 ring system (Scheme 4B). For example, reduction of 1 with the Schwartz reagent [Cp2ZrHCl],27,28 which is known to be a promising reducing agent for the amide-selective reduction in the presence of an ester, showed unexpected γ-lactone selectivity. Other attempted reductions of 1 did not promote the γ-lactamselective partial reduction in the presence of the γ-lactone29{e.g., Buchwald reduction with Ti(OiPr)4 and Ph2SiH2,30 Brookhart method with cat. [Ir(COE)2Cl]2 and Et2SiH2,31 Tinnis/Adolfsson reduction with cat. Mo(CO) 6 and (Me2HSi)2O32}. However, we solved this problem by utilizing Nagashima’s conditions for an iridium-catalyzed hydrosilylation.33,34 Treatment of stemoamide (1) with the Vaska complex [IrCl(CO)(PPh3)2] (1 mol %) and (Me2HSi)2O (1.5 equiv)35 initiated hydrosilylation of the γ-lactam carbonyl and subsequent elimination of the siloxy group to form enamine 27. Next, addition of 2-siloxyfuran 19 and 2-nitrobenzoic acid in a one-pot process generated the transient iminium ion 28, which underwent the vinylogous Mannich reaction to give tetracyclic compounds 29 and epi-29. Both reduction of the γlactam and the subsequent addition of 19 took place in highly chemoselective fashion without affecting the reactive γ-lactone, giving the products 29 and epi-29 in 73% combined yield. 2Siloxyfuran 19 approached from the convex side of iminium ion 28, resulting in complete stereocontrol at the C3 carbon center. In contrast, a slight diastereoselectivity at C13 (dr = 1.4:1)12,36 was observed favoring desired β-H product 29 over α-H product epi-29, which could be isomerized to 29 with DBU in CH2Cl2. Thus, we achieved the first direct installation of the γlactone to stemoamide (1) at the late stage of the synthesis. Finally, stereoselective hydrogenation of 29 with Rh/Al2O3 completed the highly concise and efficient total synthesis of stemonine (4) in 9 steps with an overall yield of 8.1% from commercially available ethyl 4-bromobutyrate 11 (10 steps and 11.0% total yield including isomerization of epi-29).

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b10944. Procedures and characterization data (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*[email protected] *[email protected] ORCID

Takaaki Sato: 0000-0001-5769-3408 Author Contributions ‡

These authors contributed equally in this manuscript.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This research was supported by a Grant-in-Aid for Scientific Research (C) from MEXT (15K05436), the Tobe Maki Foundation, and a JSPS fellowship to M.Y. (15J05926).

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REFERENCES

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CONCLUSION We accomplished a unified total synthesis of stemoamide-type alkaloids through convergent assembly of three five-membered building blocks. The key to success was the chemoselective nucleophilic addition to stemoamide (1) as the common precursor to the tetracyclic natural products. While a lactoneselective nucleophilic addition resulted in the first total syntheses of saxorumamide (2) and isosaxorumamide (3), a lactam-selective reductive nucleophilic addition led to the most concise and efficient total synthesis of stemonine (4) to date. The lactam-selective reductive nucleophilic addition was especially useful because it did not require protection of the more electrophilic γ-lactone. We believe that our chemoselective assembly of five-membered building blocks could be a general platform for other classes of Stemona alkaloids.37 Our 18390


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(20) The detailed optimization of the vinylogous Michael addition is shown in the Supporting Information. (21) The enantio excesses of bicyclic compounds 9 and epi-9 were determined by chiral HPLC after cleavage of the MPM group, see the Supporting Information for details. (22) For a review on the scalability, see: Kuttruff, C. A.; Eastgate, M. D.; Baran, P. S. Nat. Prod. Rep. 2014, 31, 419−432. (23) The lowest energy conformations of oxocarbenium ions 20 and 24 were calculated by geometry optimizations using B3LYP/6-31G** implemented in Jaguar, version 9.1, Schrödinger, Inc., New York, NY, 2016, see the Supporting Information for details. (24) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A. J. Am. Chem. Soc. 1999, 121, 12208−12209. (25) Mace, L. H.; Shanmugham, M. S.; White, J. D.; Drew, M. G. B. Org. Biomol. Chem. 2006, 4, 1020−1031. (26) The mechanistic rationale for the stereoselective protonation of enol ether 26 was not elucidated. (27) (a) Wailes, P. C.; Weigold, H. J. Organomet. Chem. 1970, 24, 405−411. (b) Hart, D. W.; Schwartz, J. J. Am. Chem. Soc. 1974, 96, 8115−8116. (28) (a) White, J. M.; Tunoori, A. R.; Georg, G. I. J. Am. Chem. Soc. 2000, 122, 11995−11996. (b) Spletstoser, J. T.; White, J. M.; Tunoori, A. R.; Georg, G. I. J. Am. Chem. Soc. 2007, 129, 3408−3419. (29) The results of attempted lactam-selective reduction are shown in the Supporting Information in details. (30) (a) Bower, S.; Kreutzer, K. A.; Buchwald, S. L. Angew. Chem., Int. Ed. Engl. 1996, 35, 1515−1516. (31) Cheng, C.; Brookhart, M. J. Am. Chem. Soc. 2012, 134, 11304− 11307. (32) (a) Tinnis, F.; Volkov, A.; Slagbrand, T.; Adolfsson, H. Angew. Chem., Int. Ed. 2016, 55, 4562−4566. (b) Slagbrand, T.; Kervefors, G.; Tinnis, F.; Adolfsson, H. Adv. Synth. Catal. 2017, 359, 1990−1995. (c) Trillo, P.; Slagbrand, T.; Tinnis, F.; Adolfsson, H. Chem. Commun. 2017, 53, 9159−9162. (33) Motoyama, Y.; Aoki, M.; Takaoka, N.; Aoto, R.; Nagashima, H. Chem. Commun. 2009, 1574−1576. (34) Our group reported iridium-catalyzed reductive nucleophilic additions to N-hydroxyamide derivatives, see: (a) Nakajima, M.; Sato, T.; Chida, N. Org. Lett. 2015, 17, 1696−1699. (b) Katahara, S.; Kobayashi, S.; Fujita, K.; Matsumoto, T.; Sato, T.; Chida, N. J. Am. Chem. Soc. 2016, 138, 5246−5249. (c) Katahara, S.; Kobayashi, S.; Fujita, K.; Matsumoto, T.; Sato, T.; Chida, N. Bull. Chem. Soc. Jpn. 2017, 90, 893−904. For elegant reductive nucleophilic additions from other groups, see: (d) Gregory, A. W.; Chambers, A.; Hawkins, A.; Jakubec, P.; Dixon, D. J. Chem. - Eur. J. 2015, 21, 111−114. (e) Huang, P.-Q.; Ou, W.; Han, F. Chem. Commun. 2016, 52, 11967−11970. (f) Tan, P. W.; Seayad, J.; Dixon, D. J. Angew. Chem., Int. Ed. 2016, 55, 13436−13440. (g) Fuentes de Arriba, Á . L.; Lenci, E.; Sonawane, M.; Formery, O.; Dixon, D. J. Angew. Chem., Int. Ed. 2017, 56, 3655−3659. (h) Xie, L.-G.; Dixon, D. J. Chem. Sci. 2017, 8, 7492−7497. (35) Greene, J.; Curtis, M. D. J. Am. Chem. Soc. 1977, 99, 5176− 5177. (36) The Williams group reported that I2-mediated double cyclization of amino ester iv established two consecutive stereoceners with highly stereoselective manner in the total synthesis of (+)-croomine, see: Williams, D. R.; Brown, D. L.; Benbow, J. W. J. Am. Chem. Soc. 1989, 111, 1923−1925.

(13) For a review on vinylogous Mannich reactions using the γlactones, see: Bur, S. K.; Martin, S. F. Tetrahedron 2001, 57, 3221− 3242. (14) For reviews on nucleophilic addition to amides, see: (a) Seebach, D. Angew. Chem., Int. Ed. 2011, 50, 96−101. (b) Murai, T.; Mutoh, Y. Chem. Lett. 2012, 41, 2−8. (c) Pace, V.; Holzer, W. Aust. J. Chem. 2013, 66, 507−510. (d) Sato, T.; Chida, N. Org. Biomol. Chem. 2014, 12, 3147−3150. (e) Pace, V.; Holzer, W.; Olofsson, B. Adv. Synth. Catal. 2014, 356, 3697−3736. (f) Volkov, A.; Tinnis, F.; Slagbrand, T.; Trillo, P.; Adolfsson, H. Chem. Soc. Rev. 2016, 45, 6685−6697. (15) For selected examples on chemoselective nucleophilic addition to amides, see: (a) Xia, Q.; Ganem, B. Org. Lett. 2001, 3, 485−487. (b) Bechara, W. S.; Pelletier, G.; Charette, A. B. Nat. Chem. 2012, 4, 228−234. (c) Xiao, K.-J.; Wang, A.-E.; Huang, Y.-H.; Huang, P.-Q. Asian J. Org. Chem. 2012, 1, 130−132. (d) Oda, Y.; Sato, T.; Chida, N. Org. Lett. 2012, 14, 950−953. (e) Shirokane, K.; Wada, T.; Yoritate, M.; Minamikawa, R.; Takayama, N.; Sato, T.; Chida, N. Angew. Chem., Int. Ed. 2014, 53, 512−516. (f) Huang, P.-Q.; Ou, W.; Xiao, K.-J Chem. Commun. 2014, 50, 8761−8763. (g) Huang, P.-Q.; Lang, Q.-W.; Wang, A.-E.; Zheng, J.-F. Chem. Commun. 2015, 51, 1096−1099. (h) Huang, P.-Q.; Huang, Y.-H.; Xiao, K.-J.; Wang, Y.; Xia, X.-E. J. Org. Chem. 2015, 80, 2861−2868. (i) Zheng, J.-F.; Hu, X.-N.; Xu, Z.; Cai, D.-C.; Shen, T.-L.; Huang, P.-Q. J. Org. Chem. 2017, 82, 9693−9703 For a complete list of references, see the Supporting information.. (16) Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc. Chem. Res. 2008, 41, 40−49. (17) (a) Trost, B. M.; Weiss, A. H.; von Wangelin, A. J. J. Am. Chem. Soc. 2006, 128, 8−9. (b) Trost, B. M.; Quintard, A. Angew. Chem., Int. Ed. 2012, 51, 6704−6708. (18) Sajiki, H.; Mori, S.; Ohkubo, T.; Ikawa, T.; Kume, A.; Maegawa, T.; Monguchi, Y. Chem. - Eur. J. 2008, 14, 5109−5111. (19) 2-Siloxypyrrole 14 was prepared from 4-methoxybenzylamine in two steps, see the Supporting Information for details.

(37) The lactam-selective reductive nucleophilic addition was potentially applicable to a number of the Stemona alkaloids, see a list of these natural products in the Supporting Information.

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Unified Total Synthesis of Stemoamide-Type Alkaloids by

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