Letter Cite This: Org. Lett. 2019, 21, 252−255
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Asymmetric Total Synthesis of (+)-Strychnine Liping He,† Xiaobei Wang,† Xiaoqing Wu, Zhaoxiang Meng, Xin Peng, Xiao-Yu Liu, and Yong Qin* Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
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S Supporting Information *
ABSTRACT: A synthetic strategy for the catalytic asymmetric total synthesis of (+)-strychnine is disclosed. Key features of this synthesis include an organocatalytic enantioselective Michael addition to establish the chirality of the starting building block, a photoinduced radical cascade reaction to access the Corynanthe alkaloid intermediate, and a bioinspired cascade rearrangement to generate the core of the Strychnos alkaloids.
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trychnine (1; Figure 1), first isolated in 18181 and fully characterized in 1946,2−4 is one of the most well-known
(Scheme 1).8d,g Pentacycle 4 could be synthesized via functional group transformations from 5, and the latter Scheme 1. Retrosynthetic Analysis of (+)-Strychnine
Figure 1. Chemical structures of strychnine (1) and its related biosynthetic precursors (2 and 3).
molecules in the history of alkaloid natural products. As a representative member of the large family of monoterpenoid indole alkaloids, the heptacyclic strychnine is biogenetically related to its simpler congener norfluorocurarine (2)5 and the Corynanthe alkaloid geissoschizine (3).6 Specifically, biosynthetic transformations including skeletal reorganization (3 to 2) followed by subsequent oxidation and cyclization events (2 to 1) would deliver the Strychnos alkaloid strychnine.7 The intriguing chemical structure of strychnine has made this legendary molecule an attractive target in the organic synthetic community.8 Since the pioneering work accomplished by Woodward and co-workers in 1954,8a the synthesis of strychnine has long challenged chemists and continued to stimulate interest in recent years, resulting in the development of many creative methodologies and strategies toward this compound.8,9 On the basis of our recent studies on the development of radical cascade reactions to form tetrahydrocarbolinone systems and related alkaloids,10 herein we report the utilization of two cascade reactions as key steps to achieve a new and concise catalytic asymmetric total synthesis of (+)-strychnine, the enantiomer of the natural molecule. Retrosynthetically, the target strychnine could be accessed from the known ester 4 according to Overman’s protocol © 2018 American Chemical Society
would be achieved through a bioinspired cascade of the Corynanthe alkaloid intermediate 7 involving an oxidative rearrangement and subsequent intramolecular condensation.8l Compound 7 could be traced back to lactam 8 via functional group manipulations. In turn, the tetracyclic 8 could be assembled by a key photocatalytic radical cascade reaction between enamide 10 and Michael acceptor 11 via the pathway depicted (9; Scheme 1). Finally, 10 could be prepared by condensation of the known chiral aldehyde ester 1210,11 and the propargylamine derivative 13.12 Received: November 19, 2018 Published: December 18, 2018 252
DOI: 10.1021/acs.orglett.8b03686 Org. Lett. 2019, 21, 252−255
Letter
Organic Letters
respectively. The major isomer 25b was confirmed to possess the desired stereochemistry at C15,14 and this compound was carried forward in subsequent synthetic steps. With the tetracyclic intermediate 25b in hand, we sought to complete the total synthesis of (+)-strychnine. As shown in Scheme 3, facile oxidation of the indoline moiety in 25b to the
To implement the above-mentioned strategy, we started our synthesis with the preparation of the substrates for the photocatalytic radical cascade reaction (Scheme 2). The Scheme 2. Substrate Preparation and Exploration of the Photocatalytic Radical Cascade Reaction
Scheme 3. Completion of the Total Synthesis of (+)-Strychnine [(+)-1]
known chiral aldehyde ester 1210,11 was condensed with propargylamine 1412 in the presence of AcOH in PhMe at 80 °C to afford enamide 15 (75% yield). Conversion of 15 into sulfonamide 16 was realized in 64% overall yield through zinc reduction of the nitro group followed by tosyl (Ts) protection of the resulting amine. Removal of the t-butyldimethylsilyl (TBS) group in 16 with TBAF gave alcohol 17 in 89% yield. Thus, the stage was set for the key photoinduced radical cascade reaction. Formation of the E-alkene between C19 and C20 in the radical cascade process was required to generate the target strychnine. However, our previous studies showed poor Z/E selectivities with radical precursors possessing an internal alkyne side chain on the enamide nitrogen atom.10a In order to access the desired geometry of the C19−C20 double bond, both 16 and 17 were used as substrates to investigate the photoredox radical cascade reactions with different Michael acceptors 18−20. Specifically, the reaction of enamide 16 and benzyl acrylate (18) in the presence of Ir(dtbbpy)(ppy)2PF6 and KHCO3 under the irradiation with blue LEDs afforded compound 21 as a mixture of diastereomers at C15 and geometrical isomers at C19 in 70% overall yield (5:2:3:2 d.r.). The reaction of alcohol 17 and methyl acrylate (19) under the same reaction conditions provided 22 (74% overall yield and 2:2:1:2 d.r.), and the reaction outcome in terms of the geometric selectivity of the C19−C20 alkene was not improved. In contrast, when propargyl alcohol 17 and acrolein (20) were employed in the photocatalytic reaction, hemiacetal 23 was formed as a mixture of four diastereomers at C15 and C16. After Ts deprotection of aniline of 23 with Mg/MeOH followed by NaBH4 reduction of the hemiacetal, diol 24 was obtained as a pair of inseparable diastereomers with 50% overall yield and 2.5:1 d.r. at C15. Thus, the E-alkene was selectively prepared using 17 and 20 as the reaction partners in the crucial radical cascade reaction.13 Notably, the key photocatalytic reaction was conducted on a decagram scale. Subsequently, selective protection of the allylic alcohol in 24 with a triisopropylsilyl (TIPS) group furnished a pair of separable diastereomers, 25a (20% yield) and 25b (50% yield),
corresponding indole with (PhSeO)2 O,15 followed by mesylation of the C16 primary hydroxyl group, gave 26 in 77% yield in two steps. Replacement of the resulting mesylate in 26 by a cyano group proceeded efficiently with n-Bu4NCN in THF and toluene (1:10) at 55 °C, affording 27 in 90% yield. Next, reduction of the amide in 27 was carried out with [Rh(H)(CO)(PPh3)3]/PhSiH3 to provide amine 28 (88% yield).16 The latter possessed the entire carbon skeleton of a Corynanthe alkaloid, which was ready for a bioinspired oxidation-rearrangement transformation to generate the core of a Strychnos alkaloid. Thus, according to Martin’s protocol,8l subjection of 28 to SnCl4 and tert-butyl hypochlorite, followed by treatment of the resulting chloroindolenines with LiHMDS, furnished the pentacyclic Strychnos intermediate 29 (30% yield). Selective reduction of the C2−C16 double bond of 29 in the presence of NaBH3CN in AcOH yielded 30 as a single diastereomer in 60% yield. Subjecting compound 30 to the conditions of HCl (g)/MeOH resulted in deprotection of the TIPS group and conversion of the cyano group into the corresponding methyl ester, giving the known intermediate 4 (61% yield).8d,g−j,o,q,s,t,x The spectroscopic data of our synthetic compound 4 were identical to those reported in the literature.8f,j Interestingly, we realized that the stereochemistry of C16 was inverted from β-nitrile 30 to α-ester 4 using the HCl (g)/MeOH conditions. The proton NMR data of the adjacent C2 position in compounds 30 (δH 3.62, d, J = 6.0 Hz) and 4 (δH 3.93, d, J = 9.6 Hz) confirmed this assignment. The coupling constant (J = 6.0 Hz) of H2 with H16 in compound 30 revealed that the dihedral angle between these two protons was approximately 120°, which implied that H16 was in an α-orientation. In contrast, the large coupling constant (J = 9.6 Hz) between H2 and H16 in 4 indicated a 253
DOI: 10.1021/acs.orglett.8b03686 Org. Lett. 2019, 21, 252−255
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Organic Letters 1,2-diaxial relationship of them, implying that H16 was βoriented. We speculated that compound 30 would first undergo cleavage of the TIPS protection of the allylic hydroxyl group under the reaction conditions to yield 31.17 After hydrolysis of the cyano group in 31 to ester 32, the formation of lactone 33 might serve as a driving force for the epimerization of the ester, which led to the desired intermediate 4 via alcoholysis of the lactone moiety with methanol. Finally, total synthesis of (+)-strychnine [(+)-1, the unnatural enantiomer] was realized in 38% overall yield from 4 according to the conditions reported in the literature.8d,g−j,o,q,s,t,x In conclusion, we have achieved a catalytic asymmetric total synthesis of the indole alkaloid (+)-strychnine. Strategically, the synthesis relies on two cascade processes: (1) a photoredox catalytic nitrogen-centered radical cascade reaction to efficiently assemble the tetracyclic Corynanthe alkaloid intermediate 28, and (2) a bioinspired oxidation-rearrangement sequence to convert 28 into the Strychnos alkaloid core 29. Notably, the combination of propargyl alcohol 17 and acrolein (20) in the photocatalytic cascade reaction secured the requisite E geometry of the key C19−C20 alkene. While strychnine represents a famous and important testing ground for synthetic methodologies and strategies, the present study provides a new and catalytic asymmetric total synthesis of the enantiomer of this natural molecule.
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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/acs.orglett.8b03686. Detailed experimental procedures and spectral data (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Yong Qin: 0000-0003-3434-5747 Author Contributions †
L. He and X. Wang contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This paper is dedicated to the memory of Professor Martin E. Kuehne. Financial support was provided by National Natural Science Foundation of China (21732005) and the National Science and Technology Major Projects for “Major New Drugs Innovation and Development” (2018ZX09711003-015).
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REFERENCES
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DOI: 10.1021/acs.orglett.8b03686 Org. Lett. 2019, 21, 252−255
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DOI: 10.1021/acs.orglett.8b03686 Org. Lett. 2019, 21, 252−255
