Communications
DOI: 10.1002/anie.201003361
Natural Products Synthesis
Temporary Restraints To Overcome Steric Obstacles: An Efficient
Strategy for the Synthesis of Mycalamide B**
John C. Jewett and Viresh H. Rawal*
In memory of Michael P. Cava
A fundamental concept in synthesis planning is
that of convergence. Rather than the incremen-
tal, step-by-step assembly of a linear synthesis, a
convergent route involves the assembly of two or
more advanced fragments of a molecule in a key
step, thereby reducing the arduousness of the
exercise. While desirable in principle, a conver-
gent path does not guarantee success. The steric
bulk associated with advanced fragments can
frustrate established reactions and thwart the
coupling step. Herein, we describe a convergent
synthesis of mycalamide B, wherein steric hur-
dles are overcome through the use of “chemical
handcuffs” to temporarily restrain portions of a
molecule, thereby enabling a coupling reaction
Scheme 1. Previous coupling approaches to mycalamide B. Bz=benzoyl.
that would otherwise fail.[1] We also demonstrate the success-
ful extension of our route to pederamine, the right-hand part
of pederin, to the more-oxygenated mycalamine system.
Sponges of the genus Mycale have yielded a diverse group
of intricate bioactive natural products.[2] Noteworthy among
these are the mycalamides, highly cytotoxic substances that
are members of the pederin family of compounds.[3] For
example, mycalamide B displays 0.6 nm and 1.3 nm antipro-
liferative activity against A549 and P388 cancer cell lines,
respectively.[4,5] Given their potent anticancer activities,
research groups from around the world have pursued the
chemical synthesis of the mycalamides and their related
natural products, and impressive successes have been
recorded.[6–8] Although creative routes have been developed
for the synthesis of the two halves of these molecules—the
pederic acid and the trioxadecalin parts—no solution has yet
been developed for the stereocontrolled coupling of the two
fully elaborated halves of mycalamides. At the heart of the
problem is that free mycalamine (3) readily epimerizes under
acidic, basic, and neutral conditions, eroding the stereochem-
ical information at the C10 position (Scheme 1), such that
acylation of a free mycalamine component with a pederic acid
derivative proceeds with modest selectivity at best.[9] On the
other hand, acylation of a carbamate-protected mycalamine
unit (e.g., 4) has been accomplished in a stereocontrolled
manner, but only with simpler electrophiles, not with the fully
elaborated pederic acid unit.[10] A solution to this coupling
difficulty would allow a truly convergent synthesis of the
natural product and open up the possibility of concise,
stereocontrolled syntheses of many members of the family,
as well as their analogues.
The route we envisioned for the synthesis of mycal-
amide B hinged on two key transformations: 1) the conver-
sion of dihydropyranone 7 into the highly functionalized
trioxadecalin framework of the mycalamine unit (Scheme 2)
and 2) the stereocontrolled coupling of mycalamine unit 4, or
a derivative thereof, with a pederic acid component (2;
Scheme 1). The successful realization of these two trans-
formations was expected to provide a route to mycalamide B
that would be significantly shorter than those reported
previously. A solution to the first of these processes was
incorporated in the design of our pederin synthesis, but that
for the second process was not evident at the outset.[8c]
Specifically, the Mukaiyama–Michael reaction of an appro-
priately substituted ketene-acetal with dihydropyranone 7
[*] J. C. Jewett, Prof. Dr. V. H. Rawal
Department of Chemistry, The University of Chicago
5735 South Ellis Avenue, Chicago, IL 60637 (USA)
Fax: (+1)773-702-0805
E-mail: vrawal@uchicago.edu
[**] Generous financial support from the National Cancer Institute of
the NIH (R01 CA101438) is gratefully acknowledged.
Supporting information for this article is available on the WWW
Scheme 2. Retrosynthetic analysis of the mycalamine unit. MOM=
methoxymethyl, TBS=tert-butyldimethylsilyl.
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 8682 –8685