First total synthesis of bengazole A

Journal of Organic Chemistry

Volumn 64, Issue 13, 1999, Pages 4995-4998

  Mulder, Roger J ^a   Shafer, Cynthia M ^a   Molinski, Tadeusz F ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BENGAZOLE A; PYRROLE DERIVATIVE; UNCLASSIFIED DRUG;

ANALYTIC METHOD; ANTIFUNGAL ACTIVITY; ARTICLE; DRUG SYNTHESIS; ESTERIFICATION; MINIMUM INHIBITORY CONCENTRATION; PROTON NUCLEAR MAGNETIC RESONANCE; STEREOCHEMISTRY; STREPTOMYCES;

EID: 0033603499     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo9906328     Document Type: Article

References (42)

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13. Recent examples include total syntheses of phorboxazole ((a) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am. Chem. Soc. 1998, 120, 5597-5598), calyculin A ((b) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434-9453), calyculin C ((c) Ogawa, A. K.; Armstrong, R. A. J. Am. Chem. Soc. 1998, 120, 12435-12442), hennoxazole ((d) Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 177, 558-559. (e) Wipf, P.; Lim, S. Chimia 1996, 50, 157-167), rhizoxin ((f) Nakada, M.; Kobayashi, S.; Iwasaki, S.; Ohno, M. Tetrahedron Lett. 1993, 34, 1035-1038. (g) Nakada, M.; Kobayashi, S.; Shibasaki, M.; Iwasaki, S.; Ohno, M. Tetrahedron Lett. 1993, 34, 1039-1042. (h) Williams, D. R.; Werner, K M.; Feng, B. N. Tetrahedron Lett. 1997, 38, 6825-6828), and the trisoxazole segment of the halichondramide macrolide family ((j) Knight, D. W.; Pattenden, G.; Rippon, D. E. Synlett 1990, 1, 36).
14. Recent examples include total syntheses of phorboxazole ((a) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am. Chem. Soc. 1998, 120, 5597-5598), calyculin A ((b) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434-9453), calyculin C ((c) Ogawa, A. K.; Armstrong, R. A. J. Am. Chem. Soc. 1998, 120, 12435-12442), hennoxazole ((d) Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 177, 558-559. (e) Wipf, P.; Lim, S. Chimia 1996, 50, 157-167), rhizoxin ((f) Nakada, M.; Kobayashi, S.; Iwasaki, S.; Ohno, M. Tetrahedron Lett. 1993, 34, 1035-1038. (g) Nakada, M.; Kobayashi, S.; Shibasaki, M.; Iwasaki, S.; Ohno, M. Tetrahedron Lett. 1993, 34, 1039-1042. (h) Williams, D. R.; Werner, K M.; Feng, B. N. Tetrahedron Lett. 1997, 38, 6825-6828), and the trisoxazole segment of the halichondramide macrolide family ((j) Knight, D. W.; Pattenden, G.; Rippon, D. E. Synlett 1990, 1, 36).
15. Recent examples include total syntheses of phorboxazole ((a) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am. Chem. Soc. 1998, 120, 5597-5598), calyculin A ((b) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434-9453), calyculin C ((c) Ogawa, A. K.; Armstrong, R. A. J. Am. Chem. Soc. 1998, 120, 12435-12442), hennoxazole ((d) Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 177, 558-559. (e) Wipf, P.; Lim, S. Chimia 1996, 50, 157-167), rhizoxin ((f) Nakada, M.; Kobayashi, S.; Iwasaki, S.; Ohno, M. Tetrahedron Lett. 1993, 34, 1035-1038. (g) Nakada, M.; Kobayashi, S.; Shibasaki, M.; Iwasaki, S.; Ohno, M. Tetrahedron Lett. 1993, 34, 1039-1042. (h) Williams, D. R.; Werner, K M.; Feng, B. N. Tetrahedron Lett. 1997, 38, 6825-6828), and the trisoxazole segment of the halichondramide macrolide family ((j) Knight, D. W.; Pattenden, G.; Rippon, D. E. Synlett 1990, 1, 36).
16. Recent examples include total syntheses of phorboxazole ((a) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am. Chem. Soc. 1998, 120, 5597-5598), calyculin A ((b) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434-9453), calyculin C ((c) Ogawa, A. K.; Armstrong, R. A. J. Am. Chem. Soc. 1998, 120, 12435-12442), hennoxazole ((d) Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 177, 558-559. (e) Wipf, P.; Lim, S. Chimia 1996, 50, 157-167), rhizoxin ((f) Nakada, M.; Kobayashi, S.; Iwasaki, S.; Ohno, M. Tetrahedron Lett. 1993, 34, 1035-1038. (g) Nakada, M.; Kobayashi, S.; Shibasaki, M.; Iwasaki, S.; Ohno, M. Tetrahedron Lett. 1993, 34, 1039-1042. (h) Williams, D. R.; Werner, K M.; Feng, B. N. Tetrahedron Lett. 1997, 38, 6825-6828), and the trisoxazole segment of the halichondramide macrolide family ((j) Knight, D. W.; Pattenden, G.; Rippon, D. E. Synlett 1990, 1, 36).
17. Recent examples include total syntheses of phorboxazole ((a) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am. Chem. Soc. 1998, 120, 5597-5598), calyculin A ((b) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434-9453), calyculin C ((c) Ogawa, A. K.; Armstrong, R. A. J. Am. Chem. Soc. 1998, 120, 12435-12442), hennoxazole ((d) Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 177, 558-559. (e) Wipf, P.; Lim, S. Chimia 1996, 50, 157-167), rhizoxin ((f) Nakada, M.; Kobayashi, S.; Iwasaki, S.; Ohno, M. Tetrahedron Lett. 1993, 34, 1035-1038. (g) Nakada, M.; Kobayashi, S.; Shibasaki, M.; Iwasaki, S.; Ohno, M. Tetrahedron Lett. 1993, 34, 1039-1042. (h) Williams, D. R.; Werner, K M.; Feng, B. N. Tetrahedron Lett. 1997, 38, 6825-6828), and the trisoxazole segment of the halichondramide macrolide family ((j) Knight, D. W.; Pattenden, G.; Rippon, D. E. Synlett 1990, 1, 36).
18. Recent examples include total syntheses of phorboxazole ((a) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am. Chem. Soc. 1998, 120, 5597-5598), calyculin A ((b) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434-9453), calyculin C ((c) Ogawa, A. K.; Armstrong, R. A. J. Am. Chem. Soc. 1998, 120, 12435-12442), hennoxazole ((d) Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 177, 558-559. (e) Wipf, P.; Lim, S. Chimia 1996, 50, 157-167), rhizoxin ((f) Nakada, M.; Kobayashi, S.; Iwasaki, S.; Ohno, M. Tetrahedron Lett. 1993, 34, 1035-1038. (g) Nakada, M.; Kobayashi, S.; Shibasaki, M.; Iwasaki, S.; Ohno, M. Tetrahedron Lett. 1993, 34, 1039-1042. (h) Williams, D. R.; Werner, K M.; Feng, B. N. Tetrahedron Lett. 1997, 38, 6825-6828), and the trisoxazole segment of the halichondramide macrolide family ((j) Knight, D. W.; Pattenden, G.; Rippon, D. E. Synlett 1990, 1, 36).
19. Recent examples include total syntheses of phorboxazole ((a) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am. Chem. Soc. 1998, 120, 5597-5598), calyculin A ((b) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434-9453), calyculin C ((c) Ogawa, A. K.; Armstrong, R. A. J. Am. Chem. Soc. 1998, 120, 12435-12442), hennoxazole ((d) Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 177, 558-559. (e) Wipf, P.; Lim, S. Chimia 1996, 50, 157-167), rhizoxin ((f) Nakada, M.; Kobayashi, S.; Iwasaki, S.; Ohno, M. Tetrahedron Lett. 1993, 34, 1035-1038. (g) Nakada, M.; Kobayashi, S.; Shibasaki, M.; Iwasaki, S.; Ohno, M. Tetrahedron Lett. 1993, 34, 1039-1042. (h) Williams, D. R.; Werner, K M.; Feng, B. N. Tetrahedron Lett. 1997, 38, 6825-6828), and the trisoxazole segment of the halichondramide macrolide family ((j) Knight, D. W.; Pattenden, G.; Rippon, D. E. Synlett 1990, 1, 36).
20. Recent examples include total syntheses of phorboxazole ((a) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am. Chem. Soc. 1998, 120, 5597-5598), calyculin A ((b) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434-9453), calyculin C ((c) Ogawa, A. K.; Armstrong, R. A. J. Am. Chem. Soc. 1998, 120, 12435-12442), hennoxazole ((d) Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 177, 558-559. (e) Wipf, P.; Lim, S. Chimia 1996, 50, 157-167), rhizoxin ((f) Nakada, M.; Kobayashi, S.; Iwasaki, S.; Ohno, M. Tetrahedron Lett. 1993, 34, 1035-1038. (g) Nakada, M.; Kobayashi, S.; Shibasaki, M.; Iwasaki, S.; Ohno, M. Tetrahedron Lett. 1993, 34, 1039-1042. (h) Williams, D. R.; Werner, K M.; Feng, B. N. Tetrahedron Lett. 1997, 38, 6825-6828), and the trisoxazole segment of the halichondramide macrolide family ((j) Knight, D. W.; Pattenden, G.; Rippon, D. E. Synlett 1990, 1, 36).
21. Recent examples include total syntheses of phorboxazole ((a) Forsyth, C. J.; Ahmed, F.; Cink, R. D.; Lee, C. S. J. Am. Chem. Soc. 1998, 120, 5597-5598), calyculin A ((b) Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434-9453), calyculin C ((c) Ogawa, A. K.; Armstrong, R. A. J. Am. Chem. Soc. 1998, 120, 12435-12442), hennoxazole ((d) Wipf, P.; Lim, S. J. Am. Chem. Soc. 1995, 177, 558-559. (e) Wipf, P.; Lim, S. Chimia 1996, 50, 157-167), rhizoxin ((f) Nakada, M.; Kobayashi, S.; Iwasaki, S.; Ohno, M. Tetrahedron Lett. 1993, 34, 1035-1038. (g) Nakada, M.; Kobayashi, S.; Shibasaki, M.; Iwasaki, S.; Ohno, M. Tetrahedron Lett. 1993, 34, 1039-1042. (h) Williams, D. R.; Werner, K M.; Feng, B. N. Tetrahedron Lett. 1997, 38, 6825-6828), and the trisoxazole segment of the halichondramide macrolide family ((j) Knight, D. W.; Pattenden, G.; Rippon, D. E. Synlett 1990, 1, 36).
22. 13C NMR spectral data and elemental analysis or HRMS.
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29. Oxazole (2) is no longer commercially available, In our hands, the most expedient preparation of 2 was saponification of ethyl oxazole-4-carboxylate, prepared from ethyl isocyanoacetate according to Schöllkopf (Henneke, K.-W.; Schöllkopf, U.; Neudecker, T. Liebigs Ann. Chem. 1979, 1370-1387 ), followed by decarboxylation-distillation from hot quinoline-CuO (Cornforth, J. W.; Cornforth, R. H. J. Chem. Soc. 1947, 96-102). Our overall yield of 2 from the isocyanide was 54%.
30. Oxazole (2) is no longer commercially available, In our hands, the most expedient preparation of 2 was saponification of ethyl oxazole- 4-carboxylate, prepared from ethyl isocyanoacetate according to Schöllkopf (Henneke, K.-W.; Schöllkopf, U.; Neudecker, T. Liebigs Ann. Chem. 1979, 1370-1387 ), followed by decarboxylation-distillation from hot quinoline-CuO (Cornforth, J. W.; Cornforth, R. H. J. Chem. Soc. 1947, 96-102). Our overall yield of 2 from the isocyanide was 54%.
31. 15b (equation presented)
32. N1 participation in the Mitsunobu nucleophilic displacement of benzylic alcohol 5b,which gives ∼8% retention of configuration.
33. Routine separation of 5a,b was achieved by preparative HPLC (21.4 × 250 mm, Rainin Dynamax, silica, 2:3 EtOAc, hexane, 13 mL/ min). The unwanted epimer 5b could be recycled by either of the two methods for inversion (see text).
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36. It was essential to use a freshly opened bottle of borane (Aldrich). The use of aged borane resulted in return of starting material or reduction of the aldehyde.
37. As expected, the stereocenter at C10 (bengazole numbering) is too remote to afford any stereocontrol in the addition of 7 to 8. Shioiri has reported an enantioselective reduction of a (5′-oxazolyl)(4″-oxazolyl)ketone i to afford alcohol ii in 78% yield with modest enantioselectivity [(R)-(+)-BINAL-H, -100 °C, 3 h, -75 °C, 7 days, 66% ee]. Chittari, P.; Hamada, Y.; Shioiri, T. Synlett 1998 (9), 1022-1024. We are pursuing diastereoselective addition of 7 to 8 by employing a chiral auxiliary that may preorganize reaction components during metalation-addition, but it will not solve the lack of separation of the C10 epimers 9a,b. (equation presented)
38. 1H NMR spectrum of 1/1a was identical to natural 1, in particular, H10 and the three oxazole singlets (δ 7.30, s; 7.85, s; 8.25, s).
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