this letter, we disclose our fourth-generation synthesis, which
evolved from the successful one-gram approach; the synthesis
now proceeds with a longest linear sequence of 17 steps and
9.0% overall yield.
Scheme 1
The first major improvement to the gram-scale approach
was to eliminate the ultra-high-pressure reaction that was
required to minimize cyclopentane byproduct formation that
occurred during generation of Wittig salt 8a from the
corresponding iodide (Scheme 2, entry A).5h As previously
reported,5l replacement of the sterically encumbering C(11)
TBS moeity with a less bulky MOM group significantly
reduced cyclopentane ring formation, thereby permitting
formation of 8 at ambient pressure (entries B and C).
Scheme 2
possess the degree of efficiency and scalability necessary
for the required large-scale production to permit clinical
development.
Our initial approach to (+)-discodermolide (Scheme 1),
later improved to encompass a practical (i.e., scalable) total
synthesis, called for construction of three advanced subtargets
[(+)-3, (+)-4, and (-)-5] from a common precursor [(-)-
6] possessing the triad of stereogenicity that appears in each
subtarget. Ultimately, this process led to the generation of
over 1 g of the natural product.5e,h Subsequently, Novartis
Pharmaceuticals licensed the University of Pennsylvania
synthesis and, employing a hybrid of this approach and the
effective endgame of Paterson,5g produced over 60 g of (+)-
discodermolide, a feat that afforded the natural product in
an overall yield of 1%, with a longest linear sequence of 26
steps.5m More recently, Paterson disclosed a significantly
improved (third-generation-Paterson) synthesis, exploiting a
Still-Gennari Horner-Wadsworth-Emmons olefination as
the key improvement, to furnish (+)-discodermolide in an
overall yield of 11.1% over a 21 step linear sequence.5n In
To increase the convergence of the overall synthetic route,
the fully elaborated C(15)-C(24) dienyl alkyl iodide (+)-
14 (Scheme 3) was designed as a replacement for acetal
(+)-3 and employed in a Pd(0)-catalyzed cross-coupling
reaction, a tactic exploited to great advantage by the Novartis
(4) (a) Martello, L. A.; McDaid, H. M.; Regl, D. L.; Yang, C.-P. H.;
Meng, D.; Pettus, T. R. R.; Kaufman, M. D.; Arimoto, H.; Danishefsky, S.
J.; Smith, A. B., III; Horwitz, S. B. Clin. Cancer Res. 2000, 6, 1978-
1987. (b) Honore, S.; Kamath, K.; Braguer, D.; Horwitz, S. B.; Wilson, L.;
Briand, C.; Jordan, M. A. Cancer Res. 2004, 64, 4957-4964.
(5) (a) Nerenberg, J. B.; Hung, D. T.; Somers, P. K.; Schreiber, S. L. J.
Am. Chem. Soc. 1993, 115, 12621-12622. (b) Smith, A. B., III; Qiu, Y.;
Jones, D. R.; Kobayashi, K. J. Am. Chem. Soc. 1995, 117, 12011-12012.
(c) Harried, S. S.; Yang, G.; Strawn, M. A.; Myles, D. C. J. Org. Chem.
1997, 62, 6098-6099. (d) Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998,
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LaMarche, M. J.; Arimoto, H. Org. Lett. 1999, 1, 1823-1826. (f) Halstead,
D. P., Ph.D. Thesis, Harvard University, 1999. (g) Paterson, J.; Florence,
G. J.; Gerlach, K.; Scott, J. Angew. Chem., Int. Ed. 2000, 39, 377-380. (h)
Smith, A. B., III; Beauchamp, T. J.; LaMarche, M. J.; Kaufman, M. D.;
Qiu, Y.; Arimoto, H.; Jones, D. R.; Kobayashi, K. J. Am. Chem. Soc. 2000,
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Sereinig, N. J. Am. Chem. Soc. 2001, 123, 9535-9544. (j) Harried, S. S.;
Lee, C. P.; Yang, G.; Lee, T. I. H.; Myles, D. C. J. Org. Chem. 2003, 68,
6646-6660. (k) Paterson, I.; Delgado, O.; Florence, G. J.; Lyothier, I.; Scott,
J. P.; Sereinig, N. Org. Lett. 2003, 5, 35-38. (l) Smith, A. B., III; Freeze,
B. S.; Brouard, I.; Hirose, T. Org. Lett. 2003, 5, 4405-4408. (m) Mickel,
S. J.; Sedelmeier, G. H.; Niederer, D.; Daeffler, R.; Osmani, A.; Schreiner,
K.; Seeger-Weibel, M.; Be´rod, B.; Schaer, K.; Gamboni, R.; Chen, S.; Chen,
W.; Jagoe, C. T.; Kinder, F. R., Jr.; Loo, M.; Prasad, K.; Repic, O.; Shieh,
W.-C.; Wang, R.-M.; Waykole, L.; Xu, D. D.; Xue, S. Org. Process Res.
DeV. 2004, 8, 101-130 and references therein. (n) Paterson, I.; Lyothier, I.
Org. Lett. 2004, 6, 4933-4936.
Scheme 3
1826
Org. Lett., Vol. 7, No. 9, 2005