Letter pubs.acs.org/OrgLett
Total Synthesis of (±)-Grandilodine B Chunyu Wang,† Zhonglei Wang,† Xiaoni Xie, Xiaotong Yao, Guang Li, and Liansuo Zu* School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China S Supporting Information *
ABSTRACT: The first total synthesis of the opened-type Kopsia alkaloid grandilodine B is reported. Four stereocenters of this alkaloid, three of them quaternary, are stereoselectively generated by a Diels−Alder reaction, a diastereoselective cyanation of tertiary alcohol, and a facialselective nitrone 1,3-dipolar cycloaddition.
L
Scheme 1. Retrosynthetic Analysis of Grandilodine B
undurines, grandilodines, and lapidilectines are structurally and biogenetically related Kopsia alkaloids that have received the attention of synthetic chemists due to their structural complexity and interesting pharmacological activities (Figure 1).1 Remarkable progress in the chemical syntheses of
Figure 1. Representative biogenetically related Kopsia alkaloids.
this class of natural alkaloids have been achieved by synthetic efforts from the groups of Pearson,1a,b Nishida,1c−f Qin,1g,h and Echavarren,1i which have led to the elegant total syntheses of lundurines (1a, 1b), grandilodine C (2a), and lapidilectine B (2b). The notable structural features of these completed synthetic targets include the indoline core with fused cyclopropyl (1a, 1b) and γ-lactone (2a, 2b), respectively. By contrast, lapidilectam (3a) and grandilodine B (3b), isolated from the genus Kopsia,2 possess the opened-type architecture bearing two methyl esters at C7 and C16. The construction of the C7 quaternary carbon with an ester and the C16 αCOOMe in the context of total synthesis have not been realized so far. Herein, we report our strategies to assemble the polycyclic ring system and set up the C7 and C16 stereocenters, which lead to the first total synthesis of the opened-type Kopsia alkaloid grandilodine B (3b). We selected grandilodine B with C16 α-COOMe as our initial target to address the synthetic challenge in controlling the relative stereochemistry at C16. Previous strategies used in the total syntheses of 2a and 2b mainly delivered the C16 βepimer. In addition, we envisioned that the placement of the C16 ester at the bottom face would avoid its interaction with functional groups at the top face and thus would facilitate the construction of the C7 quaternary carbon center. The retrosynthetic analysis of grandilodine B is depicted in Scheme 1, highlighting our key strategies for the construction of the A/B/C rings and C7/C16 stereocenters. The C ring of © XXXX American Chemical Society
grandilodine B could be formed by the late stage SN2 alkylation of the amide-NH and an alkyl mesylate (4 to 3b). The spirolactam B ring in 4 could be constructed by the reductive cleavage of the N−O bond and subsequent amide formation from isoxazolidine 5, which in turn could be prepared by the facial- and regioselective 1,3-dipolar cycloaddition of methyl acrylate with an nitrone intermediate generated from ketone 6. The C7 quaternary carbon center in 6 could be established by the diastereoselective cyanation of the tertiary alcohol 7, which in turn could be generated from 8 through functional groups manipulations. Both the A ring and the C16 stereocenter in 8 could be assembled by the simple Diels−Alder reaction of 9 and 10. Finally, our designed synthetic route could allow for the use of indoxyl 11 as the starting material, which has been Received: February 27, 2017
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DOI: 10.1021/acs.orglett.7b00591 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
alcohol and ketal opening by CN. To our delight, using B(C6F5)3 as the catalyst, a reported condition by Kim mainly for the cyanation of secondary alcohols,6b 13 was prepared in good yield with excellent diastereoselectivity. After the C7 quaternary carbon with correct stereochemistry was set up, oxidative cleavage of the alkene 13 followed by reduction of the resulting aldehyde delivered alcohol 14, which was further transformed into ketone 6 through the removal of the ketal and protection of the primary alcohol. We next turned our attention to the construction of the B ring of grandilodine B using nitrone 1,3-dipolar cycloaddition as the key strategy.7 While the utility of this reaction has been previously demonstrated in the total syntheses of natural products,8 in our complex setting, several selectivity issues had to be considered (Scheme 3). We realized that high
previously demonstrated by us as a versatile building block for the total syntheses of indoline natural products.3 Our synthesis of grandilodine B commenced with the construction of the A ring and C16 stereocenter by the Diels−Alder reaction (Scheme 2).4 Dienophile 9 was prepared Scheme 2. Construction of the A Ring and C7/C16 Stereocenters
Scheme 3. Construction of the B/C Rings and Total Synthesis of Grandilodine B
as a mixture of E/Z isomers (4:5) by the condensation of indoxyl 11 and commercially available ethyl glyoxylate.5 The Diels−Alder reaction of 9 and diene 10 proceeded smoothly in excellent yield, affording spirocycle 8 as the major epimer (C16 α/β = 4:1). The C16 α/β selectivity of the reaction was presumably due to the equilibrium between the E/Z isomers of 9 and the faster reaction rate of the Z isomer. Thus, both the A ring and the C16 α-ester of grandilodine B were successfully assembled by the two-step approach in multigram scale. While previous works for the installation of the ester-type functionality at C16 (2a, 2b) relied on an indirect strategy involving the introduction of a vinyl group and subsequent functional group transformations,1a,f our strategy demonstrated the power and brevity of a simple Diels−Alder reaction in addressing this synthetic problem. Deprotection of 8 with TBAF and ketal formation afforded ketone 12, which underwent diastereoselective 1,2-addition with allyl Grignard reagent to generate the tertiary alcohol 7 (Scheme 2). At this stage, another key reaction would be the construction of the all-carbon C7 quaternary center with inversion of the stereochemistry of the tertiary alcohol. A cyano group was identified as a suitable carbanion equivalent because of its demonstrated reactivity in the cyanation of tertiary alcohols6 and its capability of being a surrogate to a methyl ester. Among the metal Lewis acids screened, InBr36a was able to promote the conversion of 7 to 13, albeit with a significant amount of side products that were formed by elimination of the
regioselectivity could be expected based on the elegant works from the group of Snider,8a,b and the stereochemistry at C14 was inconsequential as it would be removed upon alkene formation in the late stage of the synthesis. The facial selectivity was then the key concern and essential to build the correct stereochemistry at C20. We envisioned that this could be achieved by using the designed substrate 6 with the placement B
DOI: 10.1021/acs.orglett.7b00591 Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters
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of a bulky TIPS protecting group at the top face. With these concerns in mind, the 1,3-dipolar cycloaddition was carried out. Treatment of ketone 6 with benzylhydroxylamine generated the nitrone intermediate, which was reacted with methyl acrylate immediately to generate isoxazolidine 5 as a mixture of two isomers (C14). To our delight, the reaction proceeded with excellent facial- and regioselectivity as expected. Subsequent cascade reaction involving cleavage of the N−O bond, debenzylation, and amide formation was achieved under hydrogenation condition,9 affording spirolactam 15. Thus, the B ring of grandilodine B was successfully assembled by the twostep reactions. Removal of the TIPS group of 15 followed by the mesylation of the both alcohols furnished key intermediate 4, the precursor for the formation of C ring of grandilodine B via SN2 alkylation (Scheme 3). While similar bond disconnection has been creatively conceived by Pearson in the total synthesis of lapidilectine B (2b),1a,b the transformation of 4 to 16 turned out to be very challenging presumably due to the poor nucleophilicity of the amide NH (Pearson’s synthesis using amine for the alkylation). Under strong basic conditions, such as DBU or NaH, the desired C ring formation was not observed, instead, 19 (C16 alkylation) and 20 (elimination/Nalkylation) were isolated as the major products, indicating that the C16−H was very easy to be deprotonated. The structures of these side products were determined by the single-crystal Xray analysis of their derivatives.10 After extensive optimization, we were able to identify suitable conditions for the formation of C ring via SN2 alkylation of the amide-NH. Using Cs2CO3 as the base and toluene as the nonpolar solvent, the conversion of 4 to 16 was successfully achieved in modest yield. Subsequent elimination of the mesylate afforded alkene 17. The direct hydrolyze of the cyano group to carboxylic acid or ester under acidic conditions proved to be very challenging, and thus a 2step approach was adopted. 17 was first converted to an amide intermediate (CONH2) using K2CO3 and H2O2,11 which was subsequently transformed to the methyl ester 18 using Meerwein’s reagent.12 Finally, ester exchange with MeOH produced natural product grandilodine B (3b). The characterization data of synthetic 3b matched those reported for the natural sample.2b In summary, we have achieved the first total synthesis of the opened-type Kopsia alkaloid grandilodine B. Key synthetic strategies include a Diels−Alder reaction to directly construct the A ring and C16 stereocenter, a diastereoselective cyanation of tertiary alcohol to establish the C7 quaternary carbon center, a facial- and regioselective nitrone 1,3-dipolar cycloaddition to assemble the B ring, and a late-stage SN2 alkylation to form the C ring. Our synthesis of grandilodine B allows access to this natural product and provides the basis for the total syntheses of other structurally related Kopsia alkaloids.
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Letter
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Liansuo Zu: 0000-0001-7747-2979 Author Contributions †
C.W. and Z.W. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful to Tsinghua University, the “1000 Talents Recruitment Program”, and the National Natural Science Foundation of China (21672123) for financial support. We thank Professor Mei-Xiang Wang (Tsinghua University) for helpful discussions.
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REFERENCES
(1) For total syntheses of lundurines, grandilodines, and lapidilectines, see: (a) Pearson, W. H.; Mi, Y.; Lee, Y., III; Stoy, P. J. Am. Chem. Soc. 2001, 123, 6724. (b) Pearson, W. H.; Mi, Y.; Lee, Y., III; Stoy, P. J. Org. Chem. 2004, 69, 9109. (c) Hoshi, M.; Kaneko, O.; Nakajima, M.; Arai, S.; Nishida, A. Org. Lett. 2014, 16, 768. (d) Arai, S.; Nakajima, M.; Nishida, A. Angew. Chem., Int. Ed. 2014, 53, 5569. (e) Nakajima, M.; Arai, S.; Nishida, A. Chem. - Asian J. 2015, 10, 1065. (f) Nakajima, M.; Arai, S.; Nishida, A. Angew. Chem., Int. Ed. 2016, 55, 3473. (g) Jin, S.; Gong, J.; Qin, Y. Angew. Chem., Int. Ed. 2015, 54, 2228. (h) Huang, H.; Jin, S.; Gong, J.; Zhang, D.; Song, H.; Qin, Y. Chem. - Eur. J. 2015, 21, 13284. (i) Kirillova, M. S.; Muratore, M. E.; Dorel, R.; Echavarren, A. M. J. Am. Chem. Soc. 2016, 138, 3671. For an elegant synthetic study, see: (j) Schultz, E. E.; Pujanauski, B. G.; Sarpong, R. Org. Lett. 2012, 14, 648. (2) (a) Awang, K.; Sevenet, T.; Pais, M.; Hadi, A. H. A. J. Nat. Prod. 1993, 56, 1134. (b) Yap, W.-S.; Gan, C.-Y.; Low, Y.-Y.; Choo, Y.-M.; Etoh, T.; Hayashi, M.; Komiyama, K.; Kam, T.-S. J. Nat. Prod. 2011, 74, 1309. (3) (a) Yu, Y.; Li, G.; Jiang, L.; Zu, L. Angew. Chem., Int. Ed. 2015, 54, 12627. (b) Li, G.; Xie, X.; Zu, L. Angew. Chem., Int. Ed. 2016, 55, 10483. (4) For a related example, see: Merour, J.; Chichereau, L.; Desarbre, E.; Gadonneix, P. Synthesis 1996, 1996, 519. (5) The methyl glyoxylate is much more expensive to purchase, so we chose to start with ethyl glyoxylate and perform the ester exchange later. (6) For selected examples, see: (a) Chen, G.; Wang, Z.; Wu, J.; Ding, K. Org. Lett. 2008, 10, 4573. (b) Rajagopal, G.; Kim, S. S. Tetrahedron 2009, 65, 4351. (c) Wang, J.; Masui, Y.; Onaka, M. ACS Catal. 2011, 1, 446. (7) For selected reviews, see: (a) Gothelf, K. V.; Jorgensen, K. A. Chem. Commun. 2000, 1449. (b) Brandi, A.; Cardona, F.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem. - Eur. J. 2009, 15, 7808. (c) Anderson, L. L. Asian J. Org. Chem. 2016, 5, 9. (8) For selected examples, see: (a) Snider, B. B.; Lin, H. J. Am. Chem. Soc. 1999, 121, 7778. (b) Snider, B. B.; Lin, H. Org. Lett. 2000, 2, 643. (c) Wilson, M. S.; Padwa, A. J. Org. Chem. 2008, 73, 9601. (9) For an example, see: Goti, A.; Cacciarini, M.; Cardona, F.; Cordero, F. M.; Brandi, A. Org. Lett. 2001, 3, 1367. (10) Compounds 19 and 20 were converted to the alkenes via elimination of the mesylate for single-crystal X-ray analysis. (11) Katritzky, A. R.; Pilarski, B.; Urogdi, L. Synthesis 1989, 1989, 949. (12) Kiessling, A. J.; McClure, C. K. Synth. Commun. 1997, 27, 923.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00591. Detailed experimental procedures, characterization data, and 1H and 13C spectra of all products (PDF) X-ray data for 19 (CIF) X-ray data for 20 (CIF) C
DOI: 10.1021/acs.orglett.7b00591 Org. Lett. XXXX, XXX, XXX−XXX
