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Catalytic Antibody Route to the Naturally Occurring Epothilones: Total Synthesis of Epothilones A-F

2001; Wiley; Volume: 7; Issue: 8 Linguagem: Inglês

10.1002/1521-3765(20010417)7

1521-3765

Subhash C. Sinha, Jian Sun, Grover P. Miller, Markus Wartmann, Richard A. Lerner,

Advanced Synthetic Organic Chemistry

Chemistry – A European JournalVolume 7, Issue 8 p. 1691-1702 Full Paper Catalytic Antibody Route to the Naturally Occurring Epothilones: Total Synthesis of Epothilones A–F Subhash C. Sinha Prof., Subhash C. Sinha Prof. [email protected] Department of Molecular Biology and the Skaggs Institute for Chemical Biology The Scripps Research Institute 10550 North Torrey Pines Road, La Jolla, California 92037 (USA) Fax: (+1) 858-784-8732Search for more papers by this authorJian Sun Dr., Jian Sun Dr. Department of Molecular Biology and the Skaggs Institute for Chemical Biology The Scripps Research Institute 10550 North Torrey Pines Road, La Jolla, California 92037 (USA) Fax: (+1) 858-784-8732Search for more papers by this authorGregory P. Miller, Gregory P. Miller Department of Molecular Biology and the Skaggs Institute for Chemical Biology The Scripps Research Institute 10550 North Torrey Pines Road, La Jolla, California 92037 (USA) Fax: (+1) 858-784-8732Search for more papers by this authorMarkus Wartmann Dr., Markus Wartmann Dr. Oncology Business Unit Novartis Pharma AG, Klybeckstrasse 141 4057 Basel (Switzerland)Search for more papers by this authorRichard A. Lerner Prof., Richard A. Lerner Prof. Department of Molecular Biology and the Skaggs Institute for Chemical Biology The Scripps Research Institute 10550 North Torrey Pines Road, La Jolla, California 92037 (USA) Fax: (+1) 858-784-8732Search for more papers by this author Subhash C. Sinha Prof., Subhash C. Sinha Prof. [email protected] Department of Molecular Biology and the Skaggs Institute for Chemical Biology The Scripps Research Institute 10550 North Torrey Pines Road, La Jolla, California 92037 (USA) Fax: (+1) 858-784-8732Search for more papers by this authorJian Sun Dr., Jian Sun Dr. Department of Molecular Biology and the Skaggs Institute for Chemical Biology The Scripps Research Institute 10550 North Torrey Pines Road, La Jolla, California 92037 (USA) Fax: (+1) 858-784-8732Search for more papers by this authorGregory P. Miller, Gregory P. Miller Department of Molecular Biology and the Skaggs Institute for Chemical Biology The Scripps Research Institute 10550 North Torrey Pines Road, La Jolla, California 92037 (USA) Fax: (+1) 858-784-8732Search for more papers by this authorMarkus Wartmann Dr., Markus Wartmann Dr. Oncology Business Unit Novartis Pharma AG, Klybeckstrasse 141 4057 Basel (Switzerland)Search for more papers by this authorRichard A. Lerner Prof., Richard A. Lerner Prof. Department of Molecular Biology and the Skaggs Institute for Chemical Biology The Scripps Research Institute 10550 North Torrey Pines Road, La Jolla, California 92037 (USA) Fax: (+1) 858-784-8732Search for more papers by this author First published: 23 March 2001 https://doi.org/10.1002/1521-3765(20010417)7:8 3.0.CO;2-9Citations: 44Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Graphical Abstract Naturally occurring epothilones have been synthesized starting from enantiomerically pure β-hydroxy ketones. The latter compounds were obtained in multigram quantities from antibody-catalyzed resolution of their racemic mixtures and then converted to the epothilones by the metathesis processes. Abstract Naturally occurring epothilones have been synthesized starting from enantiomerically pure aldol compounds 9–11, which were obtained by antibody catalysis. Aldolase antibody 38C2 catalyzed the resolution of (±)-9 by enantioselective retro-aldol reaction to afford 9 in 90 % ee at 50 % conversion. Compounds 10 and 11 were obtained in more than 99 % ee at 50 % conversion by resolution of their racemic mixtures using newly developed aldolase antibodies 84G3, 85H6 or 93F3. Compounds 9, 10 and 11 were resolved in multigram quantities and then converted to the epothilones by metathesis processes, which were catalyzed by Grubbs' catalysts. Supporting Information Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2111/2001/f2755_s.pdf or from the author. 1H and 13C NMR spectra for selected compounds, syntheses of compounds (±)-9, (±)-10 and (±)-11, ORTEP diagram of compound 15 (35 pages). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. References 1 1a A. Tramontano, K. D. Janda, R. A. Lerner, Science 1986, 234, 1566; 1b S. J. Pollack, J. W. Jacobs, P. G. Schultz, Science 1986, 234, 1570. 2 2a P. G. Schultz, R. A. Lerner, Science 1995, 269, 1835; 2b E. Keinan, R. A. Lerner, Isr. J. Chem. 1996, 36, 113; 2c J.-L. 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Vite, J. Am. Chem. Soc. 2000, 122, 8890, and references therein. 16 For the preliminary report of this paper, see: 16a Total syntheses of 1 and 3: S. C. Sinha, C. F. Barbas, III, R. A. Lerner, Proc. Natl. Acad. Sci. USA 1998, 95, 14603; 16b formal synthesis of 5: S. C. Sinha, J. Sun, G. Miller, C. F. Barbas, III, R. A. Lerner, Org. Lett. 1999, 1, 1623. 17 Synthesis of desoxyepothilone F and epothilone F were reported after the paper was submitted for publication, see: 17a C. B. Lee, T.-C. Chou, X.-G. Zhang, Z. G. Wang, S. D. Kuduk, M. D. Chappell, S. J. Stachel, S. J. Danishefsky, J. Org. Chem. 2000, 65, 6525; 17b K. C. Nicolaou, D. Hepworth, N. P. King, M. R. V. Finlay, R. Scarpelli, M. Pereira, A. Manuela, B. Bollbuck, A. Bigot, B. Werschkun, N. Winssinger, Chem. Eur. J. 2000, 6, 2783. 18 B. List, D. Shabat, C. F. Barbas, III, R. A. Lerner, Chem. Eur. J. 1998, 4, 881. 19 S. C. Sinha, E. Keinan, J. Am. Chem. Soc. 1995, 117, 3653. 20 J. Hasserodt, Synlett 1999, 12, 2007. 21 The absolute structure of the resolved product by reaction with antibody 38C2 was determined by a comparison with the synthetic sample of 9. A synthetic sample of 9 for comparison was obtained by the reaction of pent-2-en-3-ol diisocampheyl-borinate (prepared from (+)-(Ipc)2BOTf and 3-pentanone) with aldehyde 12 by the method of Paterson (I. Paterson, J. M. Goodman, M. A. Lister, R. C. Schumann, C. K. McClure, R. D. Norcross, Tetrahedron 1990, 46, 4663). 22 Antibody 38C2 catalyzed resolution of (±)-10 was not optimized. Our studies suggested that the amount of antibody used here can be decreased to 0.01 molar percent ratio instead of 0.06. 23 The unreacted aldol compound was identified as 10 by comparison (For HPLC conditions, see: Supporting Information) with the synthetic sample of 10 as well as one derived from the resolution of (±)-10 with the antibody 38C2. Synthetic 10 was synthesized by the reaction of prop-1-en-2-ol diisocampheylborinate (prepared from (+)-(Ipc)2BOTf and acetone) with the aldehyde 13 using the methodology of Paterson, see ref. [21]. 24 A solution (100 μL) of compound (±)-10 (0.01 M in CH3CN, 10 μL) and antibody 84G3 (6 μM, 90 μL in PBS buffer, pH 7.4) was kept at room temperature under argon atmosphere for 12 h. The reaction mixture was then shown to contain only one enantiomer of (±)-10 by HPLC analysis equipped with a chiral reverse phase column (Daicel Chemical Industries; for HPLC conditions see: Supporting Information). 25 Compound (±)-11 (0.01 M solution in CH3CN, 10 μL) was incubated with the antibody 84G3, 85H6 or 93G3 (6 μM antibody solution in PBS buffer, pH 7.4, 90 μL) and the progress of the reaction was followed by HPLC equipped with a chiral reverse phase ODR column. The absolute stereochemistry was determined by comparison of the specific rotation and HPLC trace of 11 with those of 10. 26 Crystallographic data (excluding structure factors) for structure 15 reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-146207. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: (+44) 1223-336-033; e-mail: [email protected]); see also Supporting Information. 27 P. H. J. Carsen, T. Hatsuki, V. S. Martin, K. B. Sharpless, J. Org. Chem. 1981, 46, 3936. 28 m-CPBA or dioxirane could also be used to epoxidize the silylenol ethers, but the results were not reproducibile. 29 Aldehyde 29 a was used in Danishefsky's and Nicolaou's syntheses of epothilones by macrolactonization approach and prepared in three steps from 29 (see refs. [10d] and [11d]). The same compound was prepared from 10 a, although in five steps, but the overall processes were carried out with minimum number (2) of column chromatography. 30 J. S. Kingsbury, J. P. A. Harrity, P. J. Bonitatebus, Jr., A. H. Hoveyda, J. Am. Chem. Soc. 1999, 121, 791. 31 31a R. R. Schrock, J. S. Murdzek, G. C. Bazan, J. Robbins, M. Dimare, M. O'Regan, J. Am. Chem. Soc. 1990, 112, 3875; 31b G. C. Bazan, E. Khosravi, R. R. Schrock, W. J. Feast, V. C. Gibson, M. B. O'Regan, J. K. Thomas, W. M. Davis, J. Am. Chem. Soc. 1990, 112, 8378; 31c G. C. Bazan, J. H. Oskam, H. N. Cho, L. Y. Park, R. R. Schrock, J. Am. Chem. Soc. 1991, 113, 6899. 32 32a M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999, 1, 953; 32b A. K. Chatterjee, R. H. Grubbs, Org. Lett. 1999, 1, 1751. 33 S. C. Sinha, J. Sun, M. Wartmann, R. A. Lerner, ChemBioChem 2001, 2, in press. 34 For the previously described method, see ref. [16a]. 35 For the deprotection of the compound 29 b to 29, and for the physical and spectral data of 29, see ref. [12c]. 36 Esterification of acids 25 and 26 with alcohols 29 and 30, respectively, to produce 31 and 32 were achieved as reported (see refs. [11c], [12c], and [12d]). Physical and spectral data of the products matched the reported data (see refs. [10d], [11c], [12c], and [12d]). 37 Epothilones A (1) and C (3): Following a known method, compound 31 was metathesized to produce a mixture of 35 and (E)-35, which was deprotected using HF/pyridine and the crude product was separated to afford 3 and (E)-3. Compound 3 was then converted to epothilone A (1) and its α-epoxide. Physical and spectral data of 1, 3 and all the intermediates were identical to the reported data (see refs. [10d], [11c]). Citing Literature Volume7, Issue8April 17, 2001Pages 1691-1702 ReferencesRelatedInformation