ORGANIC
LETTERS
2008
Vol. 10, No. 14
3149-3152
Formal Total Synthesis of RK-397 via an
Asymmetric Hydration and Iterative
Allylation Strategy
Haibing Guo, Matthew S. Mortensen, and George A. O’Doherty
Department of Chemistry, West Virginia UniVersity, Morgantown, West Virginia 26506
george.odoherty@mail.wVu.edu
Received May 7, 2008
ABSTRACT
A formal total synthesis of the oxopentaene macrolide antibiotic RK-397 has been achieved. Nine stereocenters were established by a combination
of allylation and our asymmetric hydration reactions and a 1,5-anti-selective aldol reaction. The synthesis proceeded in 19 steps from simple
achiral conjugated dienoates.
RK-397 (1) is a 32-membered oxopentaene macrolide
antibiotic which was first isolated from a Japanese soil
bacterium and characterized in 1993 by Osada and co-
workers.1 Like all members of this class of compounds, RK-
397 possesses antifungal properties; however, unlike the other
oxopolyene macrolides, RK-397 exhibits potent oncotoxicity
(GI50 of 50 µg/mL and 50 µg/mL against HL-60 and K-562,
respectively). Due to this unique activity and challenging
architecture, RK-397 has garnered much interest from the
synthetic community. The first total synthesis of RK-397 (1,
Figure 1) was reported by McDonald in 2003,2 which was
subsequently followed by two more total syntheses in 20053
and 2007.4 In addition, several approaches to polyol portion
also have been reported.5
Figure 1. RK-397, a 32-membered oxopentaene antibiotic.
for the synthesis of 1,3-syn-polyol-containing natural prod-
ucts.7 As an outgrowth from these efforts, we became
interested in the application of these approaches for the
synthesis of the polyene macrolide antibiotic.8 Herein, we
describe our successful efforts to implement these methods
for the formal total synthesis of RK-397, which contains a
cautionary tale regarding the intricacies of the boron aldol
reaction for 1,5-anti-control of stereochemistry.9
We have been interested in developing new methods for
the synthesis of 1,3-syn-polyols6 and applying these methods
(1) (a) Kobinata, K.; Koshino, H.; Kudo, T.; Isono, K.; Osada, H. J.
Antibiot. 1993, 46, 1616–1618. (b) Koshino, H.; Kobinata, K.; Isono, K.;
Osada, H. J. Antibiot. 1993, 46, 1619–1621.
(2) Burova, S. A.; McDonald, F. E. J. Am. Chem. Soc. 2004, 126, 2495–
2500.
(3) Denmark, S. E.; Fujimori, S. J. Am. Chem. Soc. 2005, 127, 8971–
8973.
(6) Hunter, T. J.; O’Doherty, G. A. Org. Lett. 2001, 3, 1049–1052.
(7) (a) Hunter, T. J.; O’Doherty, G. A. Org. Lett. 2001, 3, 2777–2780.
(b) Garaas, S. D.; Hunter, T. J.; O’Doherty, G. A. J. Org. Chem. 2002, 67,
2682–2685. (c) Smith, C. M.; O’Doherty, G. A. Org. Lett. 2003, 5, 1959–
1962. (d) Hunter, T. J.; O’Doherty, G. A. Org. Lett. 2002, 4, 4447–4450.
(8) For excellent background on oxopolyene macrolide antibiotics, see:
(a) Rychnovsky, S. D. Chem. ReV. 1995, 95, 2021–2040. (b) Macrolide
Antibiotics: Chemistry, Biology and Practice, 2nd ed.; Omura, S., Ed;
Academic Press: New York, 2002.
(4) Mitton-Fry, M. J.; Cullen, A. J.; Sammakia, T. Angew. Chem., Int.
Ed. 2007, 46, 1066–1070.
(5) (a) Schneider, C.; Tolksdorf, F.; Rehfeuter, M. Synlett 2002, 2098–
2100. (b) Vogel, P.; Gerber-Lemaire, S.; Carmona, A. T.; Meilert, K. T.;
Schwenter, M. E. Pure Appl. Chem. 2005, 77, 131–137. (c) Gerber-Lemaire,
S.; Carmona Asenjo, A. T.; Meilert, K.; Vogel, P. Eur. J. Org. Chem. 2006,
89, 1–900.
10.1021/ol801055b CCC: $40.75
Published on Web 06/13/2008
2008 American Chemical Society