Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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Total Synthesis of (−)-14-Hydroxygelsenicine and Six Biogenetically Related Gelsemium Alkaloids Atsushi Saito, Noriyuki Kogure, Mariko Kitajima, and Hiromitsu Takayama* Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan
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ABSTRACT: The first concise and collective asymmetric total synthesis of six 14-hydroxygelsenicine-related Gelsemium alkaloids, i.e., 14-hydroxygelsedilam, 14-acetoxygelsedilam, gelsefuranidine, gelsemolenine A, and gelselegandines B and C, was accomplished via the facile construction of a 7azabicyclo[4.2.1]nonane skeleton by intramolecular azaMichael addition, the preparation of an oxabicyclo[3.2.2]nonane ring core with a secondary hydroxy group at C14 by an intramolecular oxymercuration−hydroxylation strategy, and divergent transformations of 14-hydroxygelsenicine into biogenetically related alkaloids.
Gelsemium elegans Benth. (Gelsemiaceae), which is native to Southeast Asia and southern China, is a toxic plant but has been used in traditional Chinese medicine for the treatment of skin ulcers and dermatitis and as a remedy for cancer-related pain. In our previous study, we were able to prove that the plant of origin of “Yakatsu”, an ancient medicine stored in The Shosoin Repository in Japan for over 1250 years, is G. elegans.1 Phytochemical studies of this plant by us and other groups have led to the isolation and structure elucidation of more than 100 monoterpenoid indole alkaloids with diverse chemical structures. Among the six classes of Gelsemium alkaloids, the so-called gelsedine-type alkaloids were found to exhibit potent cytotoxic activity against A431 epidermoid carcinoma cells.2 However, due to the small quantities of the natural products, including gelsefuranidine (1)3a and 14-hydroxygelsedilam (2) that we had identified3b (Figure 1), a comprehensive biological evaluation of these alkaloids could not be accomplished. To accelerate further investigation of pharmacological activities and SAR study, we embarked on the asymmetric total syntheses of this class of alkaloids, which possess a unique ring core consisting of fused oxabicyclo[3.2.2]nonane and pyrroline (or pyrrolidine-2-one) rings and a spiro-Namethoxyoxindole moiety. Much effort has been made to accomplish the total synthesis of gelsedine-type alkaloids.4 The first total synthesis of ent-gelsedine was completed in 21 steps by Hiemstra and co-workers in 1999, which features the construction of a 7-azabicyclo[4.2.1]nonane system by intramolecular addition of an allene to an N-acyliminium intermediate followed by the construction of an oxindole moiety by the palladium-catalyzed Heck reaction.5 Later, Fukuyama and co-workers accomplished a spectacular total synthesis of gelsemoxonine,6a the structure of which was revised by us in 2003,3c and of other gelsedine-type alkaloids by a divinylcyclopropane−cycloheptadiene rearrangement to construct an oxabicyclo[3.2.2]nonane core skeleton as one of the key steps.6b Carreira also achieved a total synthesis of gelsemoxonine through a novel ring contraction of a © XXXX American Chemical Society
Figure 1. Structure of 14-hydroxygelsedilam (2) and its biogenetically related alkaloids and a retrosynthetic plan for these alkaloids.
Received: August 1, 2019
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DOI: 10.1021/acs.orglett.9b02703 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters spirocyclopropane-isoxazolidine to furnish an azetidine moiety.7 In 2016, Ferreira8 and Zhao,9 respectively, reported the total syntheses of (±)-gelsenicine and (±)-gelsedilam. The recent total syntheses of four gelsedine-type alkaloids, (−)-gelsedilam, (−)-gelsenicine, (−)-gelsedine, and (−)-gelsemoxonine, by Ma and co-workers were quite efficient.10 They developed an elegant strategy that involved an asymmetric Michael addition, a tandem oxidation/aldol cyclization, and a pinacol rearrangement to construct an oxabicyclo[3.2.2]nonane core and a spiro-Na-methoxyoxindole moiety. Despite these massive efforts, however, synthetic studies of gelsedinetype alkaloids having a hydroxy group at C14 were quite limited, even though some of the compounds showed potent antitumor activity, as described above. Herein, we report the first concise and collective asymmetric total synthesis of six 14hydroxygelsenicine-related alkaloids, i.e., (−)-14-hydroxygelsedilam (2),3b (−)-14-acetoxygelsedilam (3),3a (−)-gelsefuranidine (1),3a (−)-gelsemolenine A (4),11a and (−)-gelselegandines B (5)11b and C (6).11b Our retrosynthetic analysis is illustrated in Figure 1. Gelsefuranidine (1), gelsemolenine A (4), gelselegandine B (5), and gelselegandine C (6) belonging to the 14hydroxygelsedine class of alkaloids would be biosynthesized from 14-hydroxygelsenicine (7). Then we planned a collective synthesis of these natural products based on 7, which would be transformed from 14-hydroxygelsedilam (2) by installation of an ethyl group at C20. The oxabicyclo[3.2.2]nonane ring core with a secondary hydroxy group at C14 in 2 would be accessed from alcohol 8 by an intramolecular oxymercuration− hydroxylation strategy. The spiro-Na-methoxyoxindole core in 8 would be constructed from enoltriflate 10 by a carbonylative cross coupling with aniline unit 9 followed by cyclization via a stereoselective intramolecular Heck reaction. Key intermediate 10 would be obtained by a reductive enol triflation of ketone 11. The 7-azabicyclo[4.2.1]nonane skeleton in 11 would be obtained from dienone 12 by employing an intramolecular azaMichael addition. Compound 12 would be accessed by aminolysis of lactone 13 followed by oxidation of the allyl alcohol. The seven-membered ring in 13 would be synthesized from a known optically active γ-lactone (S)-1412 and alkyl iodide 1513 via stereoselective alkylation and ring-closing metathesis. According to the retrosynthetic analysis, we initially prepared cycloheptene 13 from known optically active γlactone (S)-14 and alkyl iodide 15 (Scheme 1). Lactone (S)14 was stereoselectively alkylated with iodide 15 using LiHMDS to give compound 16, which was subjected to ring-closing metathesis using Hoveyda−Grubbs II catalyst to produce cycloheptene 13 in good yield. Aminolysis of the γlactone in 13 under the PMBNH2−DIBAL conditions14 gave amide 17 in 99% yield. Protection of the primary alcohol in 17 with a TBDPS group followed by deprotection of the TBS group gave alcohol 18, and 18 was oxidized with IBX gave dienone 12 directly in moderate yield. Intramolecular azaMichael addition using LiHMDS as the base enabled the construction of the 7-azabicyclo[4.2.1]nonane skeleton in 11. 1,4-Reduction of the enone in 11 with L-Selectride and successive treatment with McMurry’s reagent15 produced enoltriflate 10 in 98% yield. With enoltriflate 10 in hand, we next investigated the installation of a spiro-N-methoxyoxindole moiety for the completion of the total synthesis of 14-hydroxygelsedilam (2) (Scheme 2). The Pd-catalyzed carbonylative cross-
Scheme 1. Construction of Key Intermediate 10
Scheme 2. Asymmetric Total Synthesis of (−)-14Hydroxygelsedilam (2)
coupling5c,16 of enoltriflate 10 with aniline derivative 9 (see the SI) produced amide 19 in 68% yield. Next, the intramolecular Heck cyclization of bromide 19 to construct 20 with 3,3-spiro-Na-methoxyoxindole was attempted. However, we were unable to realize this cyclization under various conditions. Because the steric hindrance of the bulky TBDPS group was considered to be a factor preventing the Heck reaction, we removed the protecting group in 19 to prepare 21 and again subjected it to the Heck reaction conditions. This time, the reaction proceeded smoothly to deliver spiroB
DOI: 10.1021/acs.orglett.9b02703 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
thermore, 7 was utilized for the synthesis of new alkaloid gelsemolenine A (4). Acetylation of 7 with conventional reagents gave diacetate 25, which was treated with aqueous HCl in MeOH to generate (−)-gelsemolenine A (4) in 75% yield. Next, we synthesized (−)-gelsefuranidine (1) and (−)-gelselegandines B (5) and C (6) from (−)-14-hydroxygelsenicine (7), as follows (Scheme 4). The condensation of 7 and 2-
oxindole 8 in good yield and with high diastereoselectivity. The stereochemistry at the spiro center was confirmed from the NOE correlation between H-9 on the benzene ring and H217 of the side chain. We next focused on the formation of an oxabicyclo[3.2.2]nonane ring core with a secondary hydroxy group at C14 from alcohol 8. Treatment of 8 with Hg(TFA)2 in MeCN followed by the addition of saturated aqueous NaCl gave mercury-containing intermediate 22 in 78% yield.5c Compound 22 was converted into alcohol 23 using Whitesides’ conditions (NaBH4 under oxygen bubbling in DMF)17 in 86% yield with the requisite stereochemistry of the secondary hydroxy group at C14. The stereochemistry at C14 was confirmed from the NOE correlation between H-14 and H-6. Removal of the p-methoxybenzyl group on nitrogen in 23 by treatment with TFA in the presence of anisole led to the first asymmetric total synthesis of (−)-14-hydroxygelsedilam (2) (13 steps from known compound (S)-14, 8.5% overall yield). Synthetic 2 ([α]24D = −109 (c 0.08, MeOH)) was completely identical in all respects with the natural product (see the SI). Therefore, the structure of (−)-14-hydroxygelsedilam including the absolute configuration was established. Having obtained new alkaloid 2 in a concise manner, we next attempted to transform 2 into several biogenetically related alkaloids (Scheme 3). First, acetylation of the C14 hydroxy group in 2 under conventional conditions resulted in the first total synthesis of (−)-14-acetoxygelsedilam (3). To introduce a two-carbon unit onto C20, lactam 3 was converted into N-Boc derivative 24, which was treated with ethylmagnesium bromide and then with trifluoroacetic acid to afford natural product (−)-14-hydroxygelsenicine (7). Fur-
Scheme 4. Asymmetric Total Synthesis of (−)-Gelsefuranidine (1), (−)-Gelselegandine B (5), and (−)-Gelselegandine C (6)
Scheme 3. Asymmetric Total Synthesis of (−)-14Acetoxygelsedilam (3), (−)-14-Hydroxygelsenicine (7), and (−)-Gelsemolenine A (4) furaldehyde under acidic conditions (in the presence of trifluoroacetic acid in 1,2-dichloroethane at 50 °C) led to the first total synthesis of (−)-gelsefuranidine (1). 14Hydroxygelsenicine (7) was condensed with 3-vinylbenzaldehyde under acidic conditions to give (−)-gelselegandine B (5) in good yield. In a similar manner, the condensation of 7 and 4-ethylbenzaldehyde gave exclusively compound 26 having an E configuration at the C19−C1′ positions, as anticipated. To synthesize natural product (−)-gelselegandine C (6) having Z geometry at the C19−C1′ positions, a new procedure developed by Metternich and Gilmour18 was applied to compound 26. Irradiation of 26 with blue LED in the presence of riboflavin induced the isomerization of the olefin to afford (−)-gelselegandine C (6) in 23% yield together with 23% of the recovered starting material. In conclusion, we have succeeded in the first concise and collective asymmetric total synthesis of 14-hydroxygelsenicinerelated Gelsemium alkaloids, i.e., (−)-14-hydroxygelsedilam (2), (−)-14-acetoxygelsedilam (3), (−)-gelsefuranidine (1), (−)-gelsemolenine A (4), (−)-gelselegandine B (5), and (−)-gelselegandine C (6), via the facile construction of a 7azabicyclo[4.2.1]nonane skeleton by intramolecular azaMichael addition, the preparation of an oxabicyclo[3.2.2]nonane ring core with a secondary hydroxy group at C14 by an intramolecular oxymerculation−hydroxylation strategy, and divergent transformations of (−)-14-hydroxygelsenicine (7) into biogenetically related alkaloids. As a result of the present C
DOI: 10.1021/acs.orglett.9b02703 Org. Lett. XXXX, XXX, XXX−XXX
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asymmetric total syntheses of 1, 2, 3, 4, 5, and 6, their structures including their absolute configurations inferred by spectroscopic analyses were unambiguously established.
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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.9b02703. Experimental procedures including spectroscopic data for all new compounds (UV, IR, 1H NMR, 13C NMR, HRMS) (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Hiromitsu Takayama: 0000-0003-3155-2214 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by JSPS (Japan Society for the Promotion of Science) KAKENHI Grant Nos. 17H03993 and 16H05094.
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REFERENCES
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DOI: 10.1021/acs.orglett.9b02703 Org. Lett. XXXX, XXX, XXX−XXX
