ORGANIC
LETTERS
2002
Vol. 4, No. 13
2233-2235
Simultaneous Preparation of Four
Truncated Analogues of Discodermolide
by Fluorous Mixture Synthesis
Dennis P. Curran* and Takashi Furukawa
Department of Chemistry and Center for Combinatorial Chemistry,
UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
Received April 26, 2002
ABSTRACT
Four truncated analogues of the natural product discodermolide were synthesized in a single synthetic sequence. Precursors bearing four
different groups at C22, each with a unique fluorous p-methoxybenzyl substituent on the C17 hydroxy group, were mixed and taken through
an nine-step sequence. Demixing by fluorous chromatography followed by deprotection and purification provided the individual analogues in
3−7% overall yields and with a savings of 24 synthetic steps. Fluorous mixture synthesis is recommended as a new technique to make
multiple natural product analogues in a single multistep synthesis.
The preparation of analogues of small organic molecules for
detailed structure/function analysis is a common goal in
natural products synthesis, medicinal chemistry, and other
areas. Parallel techniques are convenient for syntheses with
only a few steps, but the effort involved increases in direct
proportion to the number of reaction and separation steps.
For syntheses longer than two or three steps, mixing of
intermediates is economical.1 However, the economies in the
collective preparation of several organic compounds by
solution-phase mixture synthesis are generally thought to be
negated by difficulties in analyzing, separating, and identify-
ing mixture components.
pounds are mixed and taken through a series of steps to make
a mixture of tagged products. These are then demixed
(separated by tag structure) and identified by chromatography
over fluorous silica gel3 prior to detagging to give the
individual target products.
Proof-of-principle experiments for fluorous mixture syn-
thesis followed a short, well-worn synthetic path to analogues
of mappicine.2 Is extensive reaction development and
rehearsal a prerequisite, or can fluorous mixture synthesis
be used in an exploratory fashion to make multiple com-
pounds in a new multistep synthesis? We are addressing this
question in the synthesis of analogues of the potent anticancer
agent (+)-discodermolide 14 and now communicate the
We have recently introduced the concept of mixture
synthesis with separation tags and implemented this with
fluorous tags.2 Briefly, members of a series of substrates are
tagged with homologous fluorous tags. The tagged com-
(3) Curran, D. P. Synlett 2001, 1488.
(4) Leading references for prior synthetic work: (a) Nerenberg, J. B.;
Hung, D. T.; Somers, P. K.; Schreiber, S. L. J. Am. Chem. Soc. 1993, 115,
12621. (b) Smith, A. B., III; Qiu, Y.; Jones, D. R.; Kobayashi, K. J. Am.
Chem. Soc. 1995, 117, 12011. (c) Hung, D. T.; Nerenberg, J. B.; Schreiber,
S. L. J. Am. Chem. Soc. 1996, 118, 11054. (d) Marshall, J. A.; Johns, B. A.
J. Org. Chem. 1998, 63, 7885. (e) Smith, A. B.; Beauchamp, T. J.;
LaMarche, M. J.; Kaufman, M. D.; Qiu, Y. P.; Arimoto, H.; Jones, D. R.;
Kobayashi, K. J. Am. Chem. Soc. 2000, 122, 8654. (f) Paterson, I.; Florence,
G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N. J. Am. Chem. Soc. 2001, 123,
9535.
(1) (a) Houghten, R. A.; Pinilla, C.; Appel, J. R.; Blondelle, S. E.; Dollery,
C. T.; Eicheler, J.; Nefzi, A.; Ostresh, J. M. J. Med. Chem. 1999, 42, 3743.
(b) An, H. Y.; Cook, P. D. Chem. ReV. 2000, 100, 3311.
(2) (a) Luo, Z. Y.; Zhang, Q. S.; Oderaotoshi, Y.; Curran, D. P. Science
2001, 291, 1766. (b) Curran, D. P.; Oderaotoshi, Y. Tetrahedron 2001, 57,
5243. (c) Zhang, Q.; Rivkin, A.; Curran, D. P. J. Am. Chem. Soc. 2002,
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10.1021/ol026084t CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/24/2002