Total Synthesis of Isodihydrokoumine, (19Z)-Taberpsychine, and (4R

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Total Synthesis of Isodihydrokoumine, (19Z)‑Taberpsychine, and (4R)‑Isodihydroukoumine N4‑Oxide Jeff K. Kerkovius and Michael A. Kerr* Department of Chemistry, University of Western Ontario, 1151 Richmond Street, London, ON N6A 3K7, Canada

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two total syntheses of koumidine,7,8 and no total synthesis of (19Z)-taberpsychine have been published to date. We sought to develop a divergent synthetic route that could be used to prepare the cores of koumine, koumidine, and (19Z)taberpsychine from a single synthetic intermediate, which could allow for biological activity assessments of analogues of these natural products. When considering a synthetic plan, we noticed that indole 10 mapped onto the cores of koumidine/taberpsychine and koumine concisely (Scheme 1). In addition to having most of

ABSTRACT: We report the total synthesis of the natural products isodihydrokoumine and (19Z)-taberpsychine in 11 steps each and (4R)-isodihydrokoumine N4-oxide in 12 steps from commercially available starting materials. The key reactions include an intramolecular [3 + 2] nitrone cycloaddition and Lewis acid mediated cyclizations of a common intermediate to provide the core structures of either taberpsychine or isodihydrokoumine. Gelsemium is a genus of flowering plants, which includes three species: Gelsemium elegans, Gelsemium rankinii, and Gelsemium sempervirens.1 All of these species are poisonous and contain a rich variety of natural products including steroids, alkaloids, and iridoids.1,2 Alkaloids constitute the largest variety of compounds in Gelsemium making up over 120 of the nearly 200 molecules isolated from this genus, which are sorted into six general classes: sarpagine (koumidine), koumine, humantenine, gelsedine, yohimbane, and gelsemine (Figure 1).3 The

Scheme 1. Retrosynthetic Analysis

Figure 1. Six classes of Gelsemium alkaloids

the necessary carbon atoms, nearly all the oxidation states were analogous to those in the natural products. Retrosynthetically we envisioned that the carbon framework of indole 10 could be rapidly synthesized by utilizing an intramolecular [3 + 2] nitrone olefin cycloaddition. Preparation of nitrone 11 from hydroxylamine 12 and indole 13 would be advantageous because it would result in a convergent synthesis. Rapid analogue synthesis should be feasible by the addition of substituents onto either hydroxylamine 12 or aldehyde 13

biological effects of Gelsemium alkaloids include antitumor, anti-inflammatory, antianxiety, antistress, and analgesic as well as various immunoregulatory effects.3 In recognition of their unique biological effects and intricate structures, there has been synthetic work directed toward many of these compounds.4 We were interested in koumine and koumidine type scaffolds due to their unique structural features and the promising biological activity that koumine has exhibited.3 We found that several key natural products in these groups have mainly been investigated by semisynthetic studies, with a relatively small amount of total synthesis work being completed.5 For example, two total syntheses of koumine,6,7 © 2018 American Chemical Society

Received: May 15, 2018 Published: June 25, 2018 8415

DOI: 10.1021/jacs.8b05095 J. Am. Chem. Soc. 2018, 140, 8415−8419

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Scheme 2. Total Synthesis of Isodihydrokoumine, (19Z)-Taberpsychine, and (4R)-Isodihydroukoumine N4-Oxide

Initial attempts to deprotect hydroxylamine 19 resulted in complex mixtures of products by NMR. After investigating several protecting groups and deprotection conditions, we found that, upon loss of the protecting groups, hydroxylamine 12 underwent a Cope-type hydroamination to produce pyrrolidine 30 (Scheme 3). Previous reports have shown that

which would allow for the preparation of a variety of uniquely substituted scaffolds. Making use of this strategy, we have been able to synthesize the three natural products (19Z)taberpsychine,9 isodihydrokoumine, and (4R)-isodihydrokoumine-N4-oxide.10 The synthesis commenced with the hydrostannylation of alkyne 14 to yield a vinyl stannane intermediate (Scheme 2).11 The crude reaction mixture was treated with oxygen gas causing the palladium to precipitate as palladium black, which catalyzed the subsequent Stille coupling to produce 16.12 A copper-catalyzed conjugate addition of vinyl magnesium bromide onto dihydropyranone 16 furnished lactone 17. Attempts to install the vinyl group asymmetrically have yet to be successful; however, during ligand screening it was observed that an NHC ligand outperformed all the other ligands in terms of yield (see Supporting Information (SI) for details). Based on this observation we tested achiral NHC ligand L1 and found that it improved the yield and reproducibility of the reaction, particularly upon scale-up. Initial attempts at scaling the reaction utilized a stoichiometric quantity of CuBr·Me2S which led to erratic results even when using freshly purified material. Reduction of lactone 17 with LiAlH4 proceeded smoothly to yield diol 18. A regioselective substitution of the allylic alcohol in 18 provided protected hydroxylamine 19 in an 83% yield as a single regioisomer.

Scheme 3. Cope-Type Hydroamination Reaction

our substrate is favorably aligned to undergo this type of reaction.13 We surmised that adding an aldehyde directly to the crude reaction mixture might trap hydroxylamine 12 in situ. To test this on a model system, we treated protected hydroxylamine 19 with trifluoroacetic acid followed by 3phenylpropanal and a base, which provided us nitrone 31 in an isolated yield of 77% (Scheme 4). The diastereo- and regioselectivity of intramolecular nitrone cycloadditions can often be challenging to predict, but previous studies on similar 8416

DOI: 10.1021/jacs.8b05095 J. Am. Chem. Soc. 2018, 140, 8415−8419

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Treatment of 35 with a Swern oxidation, followed by acetal protection, worked in a 79% yield over two steps. The SmI2 reduction effected removal of the p-toluenesulfonyl protecting group and simultaneously reduced the N−O bond to yield 24.16 While this route was able to supply us with 20−100 mg quantities of acetal 24, we sought a route which would allow for the production of gram quantities of the product. We surmised that enolization of the intermediate nitrone made from 34 was the cause of the variable 2−12% yields. Therefore, for our second-generation route we employed Ntosylated indoline 20 and were met with substantially better results. Nitrone formation and subsequent cycloaddition proceeded in a 33% yield favoring the cis diastereomer 22 by a ratio of 2:1, with an inconsequential 1:1 ratio of diastereomers about the indoline. This procedure was reliably reproducible from milligram to decagram scales. Our next goal was to rearomatize indoline 22 into indole 35 to connect with our previous synthetic route. Oxidants such as MnO2, DDQ, and Mn(OAc)3 under mild conditions did not push the reaction to completion, while under more harsh conditions a complex mixture of products was formed. We reasoned that protected indoline 22 was too electron deficient to undergo oxidation efficiently and decided that an unprotected indoline should be easier to oxidize. Removal of the p-toluenesulfonyl protecting group with magnesium worked cleanly on both small and large scales to yield the unprotected indoline. A Swern oxidation was performed that transformed the primary alcohol into an aldehyde and the indoline into an indole.17 Protection of the aldehyde to yield an acetal was required to avoid reduction by SmI2. It was found that the mixture of diastereomers 22 and 23 from the cycloaddition could only be separated at this stage. The isoxazolidine ring reduction worked smoothly to yield acetal 24, which was the connection point to our first-generation route From acetal 24, our initial plan was to form koumidine via a Pictet−Spengler reaction. Being aware that this reaction would have to proceed through an anti-Bredt bridgehead iminium ion, we were apprehensive of the potential success of this transformation. A variety of Lewis and Brønsted acids were screened to try to discover one that could facilitate this reaction (see SI for details). Several Brønsted acids under aprotic conditions led to enamine 26, while Lewis acids such as Sc(OTf)3 under protic conditions led to hemiaminal ether 25. A breakthrough result occurred with the use of BF3·OEt2 in acetonitrile which formed des-N4-methyl-(19Z)-taberpsychine (27) in a 64% yield in 15 min at room temperature. Most likely the primary alcohol condensed with the acetal to form a transient cyclic carboxonium ion (36) that underwent a Friedel−Crafts reaction with the indole nucleus (Scheme 6). A reductive amination installed the methyl group to furnish the natural product (19Z)-taberpsychine in a total of 11 steps.9 During a previous semisynthetic study (19Z)-Taberpsychine had been transformed into koumine; therefore, this work constitutes a formal synthesis of koumine.5j In an attempt to synthesize koumidine (2) we screened conditions to cleave the ether bond in des-N4-methyl (19Z)taberpsychine (27). Intriguingly, TMSI formed a new product within 15 min at room temperature. After comprehensive investigation by NMR the product was identified as des-N4methyl isodihydrokoumine (28) instead of koumidine (2). It was then discovered that TMSI was able to transform acetal 24 directly into des-N4-methyl isodihydrokoumine (28) which

Scheme 4. Model Cycloaddition Study

systems gave us hope that an all-cis isomer would be the major product.14 We found that nitrone 31 underwent an intramolecular cycloaddition upon heating to produce a 57% yield of a 1:1 mixture of diastereomers. Isolation of one of the diastereomers (33) allowed us to obtain an X-ray structure of its hydrogen oxalate salt to verify that it was the all-cis diastereomer (Scheme 4). Subsequent NMR analysis of the analogous compound in the actual synthetic route (vide infra) implied that the other diastereomer is likely 32 (see SI for characterization). Attempts to influence the diastereoselectivity with Lewis acids and transition metal complexes has yet to be effective. In efforts directed at the target molecules we deprotected hydroxylamine 19 and treated it in situ with indole-3acetaldehyde (13); however, nitrone 11 was not formed. It was suspected that the tendency of indole-3-acetaldehyde to polymerize, especially under basic conditions, was the reason that the reaction produced a complex mixture of products.15 This reasoning led us to employ p-toluenesulfonyl protected indole-3-acetaldehyde (34) to condense with hydroxylamine 12 in situ. The intermediate nitrone was not stable to isolation, but we were able to perform the cycloaddition in a 2−12% yield by directly heating the reaction mixture (Scheme 5). Scheme 5. First Generation Synthesis of Acetal 24

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DOI: 10.1021/jacs.8b05095 J. Am. Chem. Soc. 2018, 140, 8415−8419

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Scheme 6. Friedel−Crafts and Conia-Ene Type Cyclizations

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We would like to thank the Natural Sciences and Engineering Research Council of Canada for funding. Jeff K. Kerkovius is the recipient of an NSERC CGSM award. We are grateful to Doug Hairsine of the University of Western Ontario Mass spectrometry facility for performing MS analysis. We would like to thank Dr. Paul Boyle for X-ray crystallographic analysis, and Dr. Mat Willans for NMR spectroscopy assistance. We would graciously like to thank Dr. Schmalz, and Julia Westphal for providing a sample of ligand L8 (see SI for details) for our screening studies. We are also grateful to Dr. Wang Lei for providing us a copy of the NMR spectra of natural isodihydrokoumine (8).

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(1) Dutt, V.; Thakur, S.; Dhar, V. J.; Sharma, A. Pharmacogn. Rev. 2010, 4, 185−194. (2) (a) Takayama, H.; Morohoshi, Y.; Kitajima, M.; Aimi, N.; Wongseripipatana, S.; Ponglux, D.; Sakai, S.-I. Nat. Prod. Lett. 1994, 5, 15−20. (b) Su, Y.-P.; Shen, J.; Xu, Y.; Zheng, M.; Yu, C.-X. J. Chromatogr. A 2011, 1218, 3695−3698. (c) Zhang, B.-F.; Zhang, Q.P.; Liu, H.; Chou, G.-X.; Wang, Z.-T. Phytochemistry 2011, 72, 916− 922. (3) Jin, G.-L.; Su, Y.-P.; Liu, M.; Xu, Y.; Yang, J.; Liao, K.-J.; Yu, C.X. J. Ethnopharmacol. 2014, 152, 33−52. (4) Namjoshi, O. A.; Cook, J. M. Sarpagine and related alkaloids. In the Alkaloids, Vol. 76; Knölker, H. J., Ed.; Elsevier: 2016; pp 63−169. (5) (a) Sakai, S.-I.; Takayama, H. Pure Appl. Chem. 1994, 66, 2139− 2142. (b) Sakal, S.-I.; Yamanaka, E.; Kitajima, M.; Yokota, M.; Aimi, N.; Wongseripatana, S.; Ponglux, D. Tetrahedron Lett. 1986, 27, 4585−4588. (c) Takayama, H.; Sakai, S.-I. Chem. Pharm. Bull. 1989, 37, 2256−2257. (d) Takayama, H.; Kitajima, M.; Wongseripipatana, S.; Sakai, S.-I. J. Chem. Soc., Perkin Trans. 1 1989, 0, 1075−1076. (e) Kitajima, M.; Takayama, H.; Sakai, S.-I. J. Chem. Soc., Perkin Trans. 1 1991, 0, 1773−1779. (f) Takayama, H.; Kitajima, M.; Ogata, K.; Sakai, S.-I. J. Org. Chem. 1992, 57, 4583−4584. (g) Sakai, S.-I.; Kubo, A.; Katano, K.; Shinma, N.; Sasago, K. Yakugaku Zasshi 1973, 93, 1165−1182. (h) Phisalaphong, C.; Takayama, H.; Sakai, S.-I. Tetrahedron Lett. 1993, 34, 4035−4039. (i) Takayama, H.; Tominaga, Y.; Kitajima, M.; Aimi, N.; Sakai, S.-I. J. Org. Chem. 1994, 59, 4381−4385. (j) Chu-Tsin, L.; Qian-Sheng, Y. Acta Chim. Sin. 1987, 45, 181−187. (k) Takayama, H.; Kitajima, M.; Sakai, S.-I. Heterocycles 1990, 30, 325−327. (6) Kitajima, M.; Watanabe, K.; Maeda, H.; Kogure, N.; Takayama, H. Org. Lett. 2016, 18, 1912−1915. (7) (a) Magnus, P.; Mugrage, B.; DeLuca, M.; Cain, G. A. J. Am. Chem. Soc. 1989, 111, 786−789. (b) Magnus, P.; Mugrage, B.; DeLuca, M. R.; Cain, G. A. J. Am. Chem. Soc. 1990, 112, 5220−5230. (8) Cao, H.; Yu, J.; Wearing, X. Z.; Zhang, C.; Liu, X.; Deschamps, J.; Cook, J. M. Tetrahedron Lett. 2003, 44, 8013−8017. (9) Ponglux, D.; Wongseripiatana, S.; Subhadhirasakul, S.; Takayama, H.; Yokota, M.; Ogata, K.; Phisalaphong, C.; Aimi, N.; Sakai, S.-I. Tetrahedron 1988, 44, 5075−5094. (10) (a) Zhang, W.; Zhang, S.-Y.; Wang, G.-Y.; Li, N.-P.; Chen, M.F.; Gu, J.-H.; Zhang, D.-M.; Wang, L.; Ye, W.-C. Fitoterapia 2017, 118, 112−117. (b) Ye et al. included a reference in their paper to the previous isolation of isodihydrkokoumine in 1981. See: Liu, C.-T.; Wang, Q.-W.; Wang, C.-H. J. Am. Chem. Soc. 1981, 103, 4634−4635. We found that Wang et al. in their 1981 paper synthesized isodihydrokoumine by hydrogenation and did not isolate it from a natural source. We realized that Ye et al. in their 2017 paper were the first group to isolate the natural product isodihydrokoumine even though they claim it had been isolated before. (11) Miyake, H.; Yamamura, K. Chem. Lett. 1989, 18, 981−984.

avoided an extra step of having to prepare 27. Even though a significant molar excess of TMSI was employed, the ether bond in the isodihydrokoumine core remained intact. It was observed in models that the exo-cyclic alkene in 27 was oriented overtop of the indole nucleus (Scheme 6).5b We theorized that a Conia-Ene type reaction occurred transforming 27 into des-N4-methyl isodihydrokoumine (28). A reductive amination reaction furnished the natural product isodihydrokoumine (8) in a 57% yield.10 (4R)-Isodihydrokoumine N4-oxide (7) was prepared by oxidizing the N4 nitrogen in 8 with mCPBA.18 The oxidation produced a 1.8:1 mixture of diastereomers favoring the N4 epimer (29) which could be separated from the natural product (4R)-Isodihydrokoumine N4-oxide (7) by chromatography.10,19 In summary, the first total syntheses of the natural products isodihydrokoumine and (19Z)-taberpsychine were completed in 11 steps and isodihydrokoumine N4-oxide in 12 steps (longest linear sequence) from commercially available starting materials. In addition, a formal total synthesis of koumine has been realized. Modification of hydroxylamine 19 or aldehyde 20 will allow for rapid analogue preparation, which highlights the modularity of this synthesis. The brevity of these routes was made possible by an intramolecular [3 + 2] nitrone cycloaddition to set the stereochemistry of the piperidine ring central to these natural products. The ability to produce acetal 24 on a gram scale will allow us to prepare suitable quantities of these natural products for biological testing to potentially unearth new uses for these natural product scaffolds.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.8b05095. Experimental procedures, and characterization, and spectral data for all compounds (PDF) Crystallographic data for the hydrogen oxalate salt of 33 (CIF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Michael A. Kerr: 0000-0001-7239-3673 8418

DOI: 10.1021/jacs.8b05095 J. Am. Chem. Soc. 2018, 140, 8415−8419

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Journal of the American Chemical Society (12) Kratochvíl, J.; Novák, Z.; Ghavre, M.; Nováková, L.; Růzǐ čka, A.; Kuneš, J.; Pour, M. Org. Lett. 2015, 17, 520−523. (13) Beauchemin, A. M. Org. Biomol. Chem. 2013, 11, 7039−7050. (14) Collins, I.; Nadin, A.; Holmes, A. B.; Long, M. E.; Man, J.; Baker, R. J. Chem. Soc., Perkin Trans. 1 1994, 0, 2205−2215. (15) Gray, R. A. Arch. Biochem. Biophys. 1959, 81, 480−488. (16) Ankner, T.; Hilmersson, G. Org. Lett. 2009, 11, 503−506. (17) Keirs, D.; Overton, K. J. Chem. Soc., Chem. Commun. 1987, 0, 1660−1661. (18) Rao, A. S.; Mohan, H. R.; Charette, A. m-Chloroperbenzoic acid. In Encyclopedia of Reagents for Organic Synthesis; John Wiley and Sons: New York, 2005. (19) It was only until after observing the serendipitous formal Conia-Ene transformation that we realized isodihydrokoumine and its N4-oxide had recently been isolated (see ref 10).

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DOI: 10.1021/jacs.8b05095 J. Am. Chem. Soc. 2018, 140, 8415−8419