C O M M U N I C A T I O N S
Table 2. Simultaneous Parallel Synthesis of Saframycin Analogues in a 10-Step Solid-Supported Sequencea
a Yields over 10 steps from 5.
(2) (a) Martinez, E. J.; Owa, T.; Schreiber, S. L.; Corey, E. J. Proc. Natl.
Acad. Sci. U.S.A. 1999, 96, 3496-3501. (b) Danishefsky, S. J.; Zhou, B.
U.S. Pat. Appl. 20020025962, Feb 28, 2002.
dram glass vials (Table 2); a uniform set of reaction conditions
was employed throughout, in all cases providing saframycin
analogues as single compounds following cyclorelease. The cleaved
analogues were isolated by simple filtration through silica gel plugs
(to remove zinc chloride) and concentration. The synthesis provided
0.5-2.0-mg quantities of the bis-hydroquinone products in 9-26%
overall yield (from 5), typically in ∼95% purity,17 representing an
average yield of 79-87% per step over the 10-step solid-phase
sequence.
In summary, we describe the solid-supported synthesis of 23
saframycin analogues, including 16 prepared by simultaneous
parallel synthesis. The route, which bears analogy to solid-phase
peptide synthesis, involved the directed condensation of N-protected
R-amino aldehyde reactants using a novel dual linker both for
attachment to the solid support and in a diastereospecific cyclore-
lease mechanism. By supporting structural variation at multiple sites
in the saframycin core while simultaneously obviating the need for
chromatographic purification of library members, this synthesis
should be suitable for the production of libraries of (conservatively)
hundreds of structurally diverse saframycin analogues.
(3) Myers, A. G.; Plowright, A. T. J. Am. Chem. Soc. 2001, 123, 5114-
5115.
(4) (a) Plowright, A. T.; Schaus, S. E.; Myers, A. G. Chem. Biol. 2002, 9,
607-618. Transcriptional profiles of Et-743 and the more potent synthetic
analogue phthalascidin in two human cancer cell lines were likewise found
to be nearly identical: (b) Martinez, E. J.; Corey, E. J.; Owa, T. Chem.
Biol. 2001, 8, 1151-1160.
(5) Myers, A. G.; Kung, D. W. J. Am. Chem. Soc. 1999, 121, 10828-10829.
(6) Review: Hall, D. G.; Manku, S.; Wang, F. J. Comb. Chem. 2001, 3, 125-
150.
(7) Reviews: (a) Solid-Phase Peptide Synthesis, Fields, G. B., Ed.; Academic
Press: San Diego, 1997. (b) Fmoc Solid-Phase Peptide Synthesis:
A
Practical Approach, Chan, W. C.; White, P. D., Eds.; Oxford University
Press: New York, 2000.
(8) (a) Tam, J. P.; Tjoeng, F. S.; Merrifield, R. B. Tetrahedron Lett. 1979,
20, 4935-4938. (b) Tam, J. P.; Tjoeng, F. S.; Merrifield, R. B. J. Am.
Chem. Soc. 1980, 102, 6117-6127.
(9) Myers, A. G.; Kung, D. W.; Zhong, B.; Movassaghi, M.; Kwon, S. J.
Am. Chem. Soc. 1999, 121, 8401-8402.
(10) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N. Science 1997,
277, 936-938.
(11) Myers, A. G.; Zhong, B.; Kung, D. W.; Movassaghi, M.; Lanman, B. A.;
Kwon, S. Org. Lett. 2000, 2, 3337-3340.
(12) This is presumably a consequence of the introduction of the “remote”
stereocenter at C-2 of the morpholine nucleus, rather than an idiosyncrasy
of solid- versus solution-phase chemistry, but this has not yet been
established experimentally.
(13) Randolph, J. T.; McClure, K. F.; Danishefsky, S. J. J. Am. Chem. Soc.
1995, 117, 5712-5719.
Acknowledgment. Financial support from the NIH and Pfizer,
Inc., is gratefully acknowledged. B.A.L. acknowledges an NSF
predoctoral fellowship.
(14) Unreacted silyl chloride sites on the resin were capped with methanol.
Yields in solid-phase transformations were determined spectrophotometri-
cally from the UV absorption of dibenzofulvene released upon treatment
with 20% piperidine-DMF and were confirmed in several cases by
product isolation following acid-catalyzed cleavage of the silyl ether-linked
intermediates.
Supporting Information Available: Experimental procedures for
the preparation of bis-hydroquinone 11 and tabulated spectroscopic data
for all synthetic analogues (PDF). This material is available free of
(15) Reviews: (a) Van Maarseveen, Jan. H. Comb. Chem. High Throughput
Screening 1998, 1, 185-214. (b) Seitz, O. Nachr. Chem. 2001, 49, 912-
916.
(16) We have previously shown that the pentacyclic intermediate 11 can be
converted into saframycin A in 52% yield (3 steps, see ref 5).
(17) As determined by 1H NMR analysis, with two exceptions: products 20
and 21 were ∼80% pure, containing impurities from self-condensation
of phenylacetaldehyde.
References
(1) Reviews: (a) Arai, T.; Kubo, A. In The Alkaloids; Brossi, A., Ed.;
Academic Press: New York, 1983; Vol. 21, Chapter 3. (b) Remers, W.
A. The Chemistry of Antitumor Antibiotics; Wiley-Interscience: New York,
1988; Vol. 2, Chapter 3.
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