Organic Process Research & Development 2004, 8, 92−100
Large-Scale Synthesis of the Anti-Cancer Marine Natural Product
(
+)-Discodermolide. Part 1: Synthetic Strategy and Preparation of a Common
Precursor
Stuart J. Mickel,* Gottfried H. Sedelmeier, Daniel Niederer, Robert Daeffler, Adnan Osmani, Klaus Schreiner,
Manuela Seeger-Weibel, Brigitte B e´ rod, Karl Schaer, and Remo Gamboni
Chemical and Analytical DeVelopment, NoVartis Pharma AG, CH 4002 Basel, Switzerland
Stephen Chen, Weichun Chen, Christopher T. Jagoe, Frederick R. Kinder, Jr., Mauricio Loo, Kapa Prasad, Oljan Repi cˇ ,
Wen-Chung Shieh, Run-Ming Wang, Liladhar Waykole, David D. Xu, and Song Xue
NoVartis Institutes for Biomedical Research, One Health Plaza, East HanoVer, New Jersey 07936, U.S.A.
3
Abstract:
mouse models (including PTX-resistant tumors). Discoder-
molide is currently undergoing phase I clinical trials.
The synthetic strategy for producing multigram quantities of
(+)-discodermolide (1) using a hybridized Novartis-Smith-
Paterson synthetic route via common precursor 3 is described.
In the first part of this five-part series, we present a multiki-
logram preparation of r-methyl aldehyde 10 from Roche ester,
its syn-aldol reaction with Evans boron enolate, removal of the
chiral auxiliary, and the preparation of Weinreb amide 3 (Smith
common precursor). The common precursor was produced
without any chromatography.
Structurally, discodermolide consists of a linear polypro-
pionate chain containing 13 stereocentres, six of which are
hydroxyl-bearing, with one of these esterified as a δ-lactone
(C5) with another as a carbamate (C19). It also features seven
methyl-bearing stereocentres and three Z-configured alkenes,
one of these being part of the terminal diene unit. Also
present in the structure is a common stereo triad (methyl,
hydroxyl, and methyl) that is repeated three times. The
Schreiber group has synthesized both antipodes, thus estab-
Introduction
A small, but structurally diverse collection of naturally
occurring non-taxane microtubule-stabilizing agents (MTS)
has been discovered over the past decade. These include the
epothilones (EPO), eleutherobin, laulimalide, and discoder-
molide. (+)-Discodermolide (1) is a novel polyketide natural
product first isolated from extracts of the marine sponge
Discodermia dissoluta by researchers at Harbor Branch
4
lishing the absolute configuration of 1. Since the publications
1
5-8
Oceanographic Institution (HBOI). Discodermolide stabi-
of Schreiber’s synthesis, several total syntheses
and
lizes microtubules faster and more potently than any of the
other known MTS agents and is a potent inhibitor of tumor
cell growth in vitro, including paclitaxel (PTX)- and EPO-
resistant cells. Discodermolide also demonstrates significant
human tumor growth inhibition in hollow fiber and xenograft
(
3) Kinder, F. R., Jr.; Bair, K. W.; Chen, W.; Florence, G.; Francavilla, C.;
Geng, P.; Gunasekera, S.; Guo, Q.; Lassota, P. T.; Longley, R. E.; Palermo,
M. G.; Paterson, I.; Pomponi, S.; Ramsey, T. M.; Rogers, L.; Sabio, M.;
Sereinig, N.; Sorensen, E.; Wang, R. M.; Wright, A. Synthesis and Antitumor
Activity of Analogues of the Novel Microtubule Stabilizing Agent Disco-
dermolide. In Abstracts of Papers; 224th American Chemical Society
National Meeting, Boston, MA, August 18-22, 2002; American Chemical
Society: Washington, DC, 2002; MEDI-236.
2
*
Author for correspondence. E-mail: stuart_john.mickel@pharma.novartis.
com.
(4) (a) Nerenberg, J. B.; Hung, D. T.; Sommers, P. K.; Schreiber, S. L. J. Am.
Chem. Soc. 1993, 115, 12621. (b) Hung, D. T.; Nerenber, J. B.; Schreiber,
S. L. J. Am. Chem. Soc. 1996, 118, 11054.
(5) (a) Smith, A. B.; Qui, Y.; Jones, D. R.; Kobayashi, K. J. Am. Chem. Soc.
1995, 117, 12011. (b) Smith, A. B.; Kaufmann, M. D.; Beauchamp, T. J.;
LaMarche, M. J.; Arimoto, H. Org. Lett. 1999, 1, 1823; Additions and
corrections Org. Lett. 2000, 2, 1983. (c) Smith, A. B.; Beauchamp, T. J.;
LaMarche, M. J.; Kaufmann, M. D.; Qui, Y.; Arimoto, H.; Jones, D. R.;
Kobayashi, K. J. Am. Chem. Soc. 2000, 112, 8654.
(
1) (a) Gunasekera, S. P.; Gunasekera, M.; Longley, R. E.; Schulte, G. K. J.
Org. Chem. 1990, 55, 4912, Correction J. Org. Chem. 1991, 56, 1346. (b)
Gunasekera, S. P.; Pomponi, S. A.; Longley, R. E.; U. S. Patent 5,840,750,
November 24, 1998. (c) Gunasekera, S. P.; Paul, G. K.; Longley, R. E.;
Isbrucker, R. A.; Pomponi, S. A. J. Nat. Prod. 2002, 65, 1643.
(
2) (a) Jordan, M. A. Curr. Med. Chem.: Anti-Cancer Agents 2002, 2, 1. (b)
Altmann, K. H. Curr. Opin. Chem. Biol. 2001, 5, 424. (c) He, L. F.; Orr,
G. A.; Horwitz, S. B. Drug DiscoVery Today 2001, 6, 1153. (d) He, L.;
Chia-Ping, H. Y.; Horwitz, S. B. Mol. Cancer Ther. 2001, 1, 3. (e)
Kowalsky, R. J.; Giannakakou, P.; Gunasekera, S. P.; Longley, R. E.; Day,
B. W.; Hamel, E. Mol. Pharmacol. 1997, 52, 613. (f) Kalesse, M.
ChemBiochem. 2000, 1, 171. (g) Longley, R. E.; Caddigan, D.; Harmody,
D.; Gunasekra, M.; Gunasekra, S. P. Transplantation 1991, 52, 650. (h)
Longley, R. E.; Caddigan, D.; Harmody, D.; Gunasekra, M.; Gunasekra, S.
P. Transplantation 1991, 52, 656. (i) Martello, L. A.; LaMarche, M. J.; He,
L.; Beauchamp, T. J.; Smith, A. B.; Horwitz, S. B. Chem. Biol. 2001, 8,
(6) Harried, S. S.; Yang, G.; Strawn, M. A.; Myles, D. C. J. Org. Chem. 1997,
62, 6098.
(7) Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885.
(8) (a) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P. Angew. Chem.,
Int. Ed. 2000, 39, 377. (b) Paterson, I.; Florence, G. J. Tetrahedron Lett.
2000, 41, 6935. (c) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.;
Sereinig, N. J. Am. Chem. Soc. 2001, 123, 9535. (d) Paterson, I.; Delgado,
O.; Florence, G. L.; Lyothier, I.; Scott, J. P.; Sereinig, N. Org. Lett. 2003,
5, 35.
8
43.
9
2
•
Vol. 8, No. 1, 2004 / Organic Process Research & Development
10.1021/op034130e CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/04/2003