ORGANIC
LETTERS
2001
Vol. 3, No. 6
929-932
Asymmetric Synthesis of the Northern
Half C1−C16 of the Bryostatins
A. Vakalopoulos, T. F. J. Lampe, and H. M. R. Hoffmann*
Department of Organic Chemistry, UniVersity of HannoVer, Schneiderberg 1 B,
D-30167 HannoVer, Germany
hoffmann@mbox.oci.uni-hannoVer.de
Received January 12, 2001
ABSTRACT
Starting from 8-oxabicyclo[3.2.1]oct-6-en-3-one and racemic 2,2-dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one, the C1−C16 segment of the bryostatins
has been synthesized in 30 steps and 9% overall yield (17 steps longest linear sequence). Fragment coupling by dithiane strategy and protecting
group manipulations provided an advanced chemodifferentiated northern half segment.
The bryostatins,1 first described by Pettit in 1982, are a family
of 18 promising cancer chemotherapeutic candidates. They
exhibit a highly oxygenated pattern with a polyacetate-
derived backbone. The bryostatins bind to protein kinase C
(PKC) and activate it in a fashion different from the phorbol
esters: Exogenous agonists of PKC, such as the phorbol
esters, usually are tumor promoters, but the bryostatins act
as anticancer drugs.2 Although the molecular mode of
biological activity is unknown, the bryostatins are currently
in phase II human clinical trials for treatment of non-
Hodgkin’s lymphoma, melanoma, and renal cancer.3
groups,5 including our own,6 set up a program directed
toward a convergent and efficient synthesis of these chal-
lenging macrolides and especially of bryostatin 1 and some
simplified bryostatin analogues,7 which exhibit biological
activity similar to that of bryostatin 1. In this study, we
describe the completion of the C1-C16 segment, the
northern half of the bryostatins.
(5) Other segment syntheses: (a) Almendros, P.; Rae, A.; Thomas, E. J.
Tetrahedron Lett. 2000, 41, 9565. (b) Hale, K. J.; Hummersone, M. G.;
Bhatia, G. S. Org. Lett. 2000, 2, 2189. (c) Baxter, J.; Mata, E. G.; Thomas,
E. J. Tetrahedron 1998, 54, 14359. (d) Gracia, J.; Thomas, E. J. J. Chem.
Soc., Perkin Trans I 1998, 2865. (e) Maguire, R. J.; Munt, S. P.; Thomas,
E. J. J. Chem. Soc., Perkin Trans. I 1998, 2853. (f) Kiyooka, S.; Maeda,
H. Tetrahedron: Asymmetry 1997, 8, 3371. (g) De Brabander, J.; Kulkarni,
A.; Garcia-Lopez, R.; Vandewalle, M. Tetrahedron: Asymmetry 1997, 8,
1721. (h) Kalesse, M.; Eh, M. Tetrahedron Lett. 1996, 37, 1767. (i) De
Brabander, J.; Vandewalle, M. Pure Appl. Chem. 1996, 68, 715. (j)
Hoffmann, R. W.; Stiasny, H. C. Tetrahedron Lett. 1995, 36, 4595. Detailed
review of the literature prior to early 1995. (k) Norcross, R. D.; Paterson,
I. Chem. ReV. 1995, 95, 2041-2114.
(6) (a) Lampe, T. F. J.; Hoffmann, H. M. R. Tetrahedron Lett. 1996,
37, 7695. (b) Lampe, T. F. J.; Hoffmann, H. M. R. J. Chem. Soc., Chem.
Commun. 1996, 1931. (c) Weiss, J. M.; Hoffmann, H. M. R. Tetrahedron:
Asymmetry 1997, 8, 3913.
(7) (a) Wender, P. A.; De Brabander, J.; Harran, P. G.; Jimenez, J.-M.;
Koehler, M. F. T.; Lippa, B.; Park, C.-M.; Shiozaki, M. J. Am. Chem. Soc.
1998, 120, 4534. (b) Wender, P. A.; De Brabander, J.; Harran, P. G.; Hinkle,
K. W.; Lippa, B.; Pettit, G. R. Tetrahedron Lett. 1998, 39, 8625. (c) Wender,
P. A.; Lippa, B. Tetrahedron Lett. 2000, 41, 1007. (d) Wender, P. A.; Hinkle,
K. W. Tetrahedron Lett. 2000, 41, 6725.
Since their discovery, three total syntheses of a bryostatin
have been completed up to date.4 Furthermore, several
(1) (a) Pettit, G. R. J. Nat. Prod. 1996, 59, 812. (b) Pettit, G. R. The
Bryostatins. In Progress in the Chemisty of Organic Natural Products; Herz,
W., Ed.; Springer-Verlag: New York, 1991; Vol. 57, p 153.
(2) (a) Kraft, A. S. Natl. Cancer Inst. 1993, 85, 1790. (b) Stone, R. M.
Leukemia Res. 1997, 21, 399. (c) Schuchter, L. M.; Esa, A. H.; May, W.;
Laulis, M. K.; Pettit, G. R.; Hess, A. D. Cancer Res. 1991, 51, 682.
(3) Information on the status of bryostatin clinical trials can be found
(4) (a) Kageyama, M.; Tamura, T.; Nantz, M. H.; Roberts, J. C.; Somfai,
P.; Whritenour, D. C.; Masamune, S. J. J. Am. Chem. Soc. 1990, 112, 7407
and references therein. (b) Evans, D. A.; Carter, P. H.; Carreira, E. M.;
Charette, A. B.; Prunet, J. A.; Lautens, M. J. Am. Chem. Soc. 1999, 121,
7540 and references therein. (c) Ohmori, K.; Ogawa, Y.; Obitsu, T.;
Ishikawa, Y.; Nishiyama, S.; Yamamura, S. Angew. Chem. 2000, 112, 2376;
Angew. Chem., Int. Ed. 2000, 39, 2290 and references therein.
10.1021/ol015551o CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/27/2001