ORGANIC
LETTERS
2011
Vol. 13, No. 6
1482–1485
Synthesis of the Cytotrienin A Core via
Metal Catalyzed C-C Coupling
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Michael Rossle, David J. Del Valle, and Michael J. Krische*
University of Texas at Austin, Department of Chemistry and Biochemistry, Austin,
Texas 78712, United States
Received January 18, 2011
ABSTRACT
A synthetic approach to the C17-benzene ansamycins via metal catalyzed C-C coupling is described. Key bond formations include direct iridium
catalyzed carbonyl crotylation from the alcohol oxidation level followed by chelation-controlled Sakurai-Seyferth dienylation to form the
stereotriad, which is attached to the arene via Suzuki cross-coupling. The diene-containing carboxylic acid is prepared using rhodium catalyzed
acetylene-aldehyde reductive C-C coupling mediated by gaseous hydrogen. Finally, ring-closing metathesis delivers the cytotrienin core.
Beginning with the discovery of the antibacterial rifa-
mycin B, ansamycin antibiotics continue to evoke interest
as antibiotic and antineoplastic agents.1 An important
ansamycin subclass is represented by the ansatrienins,
which are classified as triene-containing C17-benzene an-
samycins. Members of this subclass, which are produced
from various Streptomyces and Bacillus species, include
the mycotrienins and mycotrienols,2 the trienomycins,3
and the cytotrienins (Figure 1).4 Whereas the mycotrienins
exhibit potent antifungal activity,2d,e the trienomycins and
cytotrienins display antineoplastic properties.3a,5 For
(4) For isolation of cytotrienin A-D, see: (a) Zhang, H.-P.; Kakeya,
H.; Osada, H. Tetrahedron Lett. 1997, 38, 1789. (b) Kakeya, H; Zhang,
H.-P.; Kobinata, K.; Onose, R.; Onozawa, C.; Kudo, T.; Osada, H.
J. Antibiot. 1997, 50, 370. (c) Osada, H.; Kakeya, H.; Zhang, H.-P.;
Kobinata, K. PCT Int. Appl. WO 9823594, 1998.
(5) (a) Komiyama, K.; Hirokawa, Y.; Yamaguchi, H.; Funayama, S.;
Masuda, K.; Anraku, Y.; Umezawa, I.; Omura, S. J. Antibiot. 1987, 40,
1768. (b) Funayama, S.; Anraku, Y.; Mita, A.; Yang, Z. B.; Shibata, K.;
Komiyama, K.; Umezawa, I.; Omura, S. J. Antibiot. 1988, 41, 1223. (c)
Kakeya, H.; Zhang, H.-p.; Kobinata, K.; Onose, R.; Onozawa, C.;
Kudo, T.; Osada, H. J. Antibiot. 1997, 50, 370.
(6) For stereochemical assignment of the trienomycins and myco-
trienins, see: (a) Smith, A. B., III; Wood, J. L.; Wong, W.; Gould, A. E.;
Rizzo, C. J. J. Am. Chem. Soc. 1990, 112, 7425. (b) Smith, A. B., III;
Wood, J. L.; Omura, S. Tetrahedron Lett. 1991, 32, 841. (c) Smith, A. B.,
III; Barbosa, J.; Hosokawa, N.; Naganawa, H.; Takeuchi, T. Tetrahe-
dron Lett. 1998, 39, 2891. (d) Smith, A. B., III; Wood, J. L.; Wong, W.;
Gould, A. E.; Rizzo, C. J.; Barbosa, J.; Funayama, S.; Komiyama, K.;
Omura, S. J. Am. Chem. Soc. 1996, 118, 8308.
(7) For the total and formal syntheses of triene-ansamycins, see: (a)
Trienomycins A and F and thiazinotrienomycin E: Smith, A. B., III;
Barbosa, J.; Wong, W.; Wood, J. L. J. Am. Chem. Soc. 1995, 117, 10777.
(b) Smith, A. B., III; Barbosa, J.; Wong, W.; Wood, J. L. J. Am. Chem.
Soc. 1996, 118, 8316. (c) Smith, A. B., III; Wan, Z. J. Org. Chem. 2000,
65, 3738. (d) Mycotrienol I and mycotrienin I: Panek, J. S.; Masse, C. E.
J. Org. Chem. 1997, 62, 8290. (e) Masse, C. E.; Yang, M.; Solomon, J.;
Panek, J. S. J. Am. Chem. Soc. 1998, 120, 4123. (f) Cytotrienin A:
Hayashi, Y.; Shoji, M.; Ishikawa, H.; Yamaguchi, J.; Tamaru, T.; Imai,
H.; Nishigaya, Y.; Takabe, K.; Kakeya, H.; Osada, H. Angew. Chem.,
Int. Ed. 2008, 47, 6657.
(1) For selected reviews on ansamycin natural products, see: (a)
Wrona, I. E.; Agouridas, V.; Panek, J. S. C. R. Acad. Sci., Paris 2008,
11, 1483. (b) Funayama, S.; Cordell, G. A. In Studies in Natural Products
Chemistry; Atta-ur-Rahman, Ed.; Elsevier: New York, 2000; Vol. 23, pp
51-106.
(2) For isolation of mycotrienols I and II and mycotrienins I and II
(ansatrienins A and B), see: (a) Weber, W.; Zuehner, H.; Damberg, M.;
Russ, P.; Zeeck, A. Zbl. Bakt. Hyg., Abt. Orig. C2 1981, 122. (b) Zeeck,
A.; Damberg, M.; Russ, P. Tetrahedron Lett. 1982, 23, 59. (c) Sugita, M.;
Furihata, K.; Seto, H.; Otake, N.; Sasaki, T. Agric. Biol. Chem. 1982, 46,
1111. (d) Sugita, M.; Natori, Y.; Sasaki, T.; Furihata, K.; Shimazu, A.;
Seto, H.; Otake, N. J. Antibiot. 1982, 35, 1460. (e) Sugita, M.; Sasaki, T.;
Furihata, K.; Seto, H.; Otake, N. J. Antibiot. 1982, 35, 1467. (f) Sugita,
M.; Natori, Y.; Sueda, N.; Furihata, K.; Seto, H.; Otake, N. J. Antibiot.
1982, 35, 1474. (g) Sugita, M.; Hiramoto, S.; Ando, C.; Sasaki, T.;
Furihata, K.; Seto, H.; Otake, N. J. Antibiot. 1985, 38, 799.
(3) For isolation of trienomycins A-F, see: (a) Umezawa, I.;
Funayama, S.; Okada, K.; Iwasaki, K.; Satoh, J.; Masuda, K.; Komiyama,
K. J. Antibiot. 1985, 38, 699. (b) Hiramoto, S.; Sugita, M.; Ando, C.;
Sasaki, T.; Furihata, K.; Seto, H.; Otake, N. J. Antibiot. 1985, 38, 1103.
(c) Funayama, S.; Okada, K.; Komiyama, K.; Umezawa, I. J. Antibiot.
1985, 38, 1107. (d) Funayama, S.; Okada, K.; Iwasaki, K.; Komiyama,
K.; Umezawa, I. J. Antibiot. 1985, 38, 1677. (e) Nomoto, H.; Katsumata,
S.; Takahashi, K.; Funayama, S.; Komiyama, K.; Umezawa, I.; Omura,
S. J. Antibiot. 1989, 42, 1677. (f) Smith, A. B., III; Wood, J. L.; Gould,
A. E.; Omura, S.; Komiyama, K. Tetrahedron Lett. 1991, 32, 1627.
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10.1021/ol200160p
Published on Web 02/16/2011
2011 American Chemical Society