ORGANIC
LETTERS
2006
Vol. 8, No. 26
6043-6046
Total Synthesis of Phorboxazole A. 2.
Assembly of Subunits and Completion
of the Synthesis
James D. White,* Tae Hee Lee, and Punlop Kuntiyong
Department of Chemistry, Oregon State UniVersity, CorVallis, Oregon 97331
Received October 13, 2006
ABSTRACT
Subunits of phorboxazole A containing C1
linked C32 with C33 and then C41 with C42. A C3
half of 1. Closure of the macrolide was accomplished by esterification of the C24 alcohol followed by intramolecular Horner
Emmons condensation to set the (E)-C2 C3 alkene.
−
C2, C3
−
C8, C9
−
C19, C20
−
C32, C33
−
C41, and C42
−
C46 were connected in a sequence that first
−
C8 fragment was joined to C9
−C19, and the assembled unit was then joined with the left
−
Wadsworth
−
−
The preceding Letter1 describes the synthesis of four major
subunits of the potent antitumor agent phorboxazole A (1).2
It also reports that attempts to couple two subunits at C32-
C33 through addition of the anion from deprotonation of a
methyl-substituted oxazole representing C20-C32 with a
δ-lactone incorporating C33-C46 encountered difficulties.
Specifically, this reaction resulted in a significant quantity
of a terminal alkyne arising from elimination of HBr from
the bromoalkene. Because we were unsuccessful in attempts
to convert the alkyne byproduct to the desired (E)-bromo-
alkene, we decided to adopt a different strategy for as-
sembling the C20-C46 segment of 1. This Letter reports
an assembly sequence that first combines a C20-C32 unit
2 with C33-C41 (3), adds the remaining segment (C42-
C46) of the phorboxazole side chain, then connects C20 of
2 to a fragment 4 containing C3-C19 before adding the last
two carbons and closing the macrolide (Scheme 1). This
highly convergent strategy takes advantage of certain features
incorporated into other syntheses of phorboxazoles3-8 and
allows us to exploit methodology we developed for the
synthesis of subunits containing tetrahydropyrans A and B.9
To circumvent the problem of HBr elimination encoun-
tered previously in generating the C32-C33 linkage, a
truncated version of the phorboxazole side chain was
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Williams, D. R.; Kiryanov, A. A.; Emde, U.; Clark, M. P.; Berliner, M.
A.; Reeves, J. T. Proc. Natl. Acad. Sci. 2004, 101, 12058.
(6) (a) Gonzalez, M. A.; Pattenden, G. Angew. Chem., Int. Ed. 2003,
42, 1255. (b) Pattenden, G.; Gonza´lez, M. A.; Little, P. B.; Millan, D. S.;
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(9) White, J. D.; Kranemann, C. L.; Kuntiyong, P. Org. Lett. 2001, 3,
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(1) White, J. D.; Kuntiyoung, P.; Lee, T. H. Org. Lett. 2006, 8, 6039.
(2) (a) Searle, P. A.; Molinski, T. F. J. Am. Chem. Soc. 1995, 117, 8126.
(b) Searle, P. A.; Molinski, T. F.; Brzezinski, L. J.; Leahy, J .W. J. Am.
Chem. Soc. 1996, 118, 9422. (c) Molinski, T. F. Tetrahedron Lett. 1996,
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10.1021/ol062531j CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/22/2006