+
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J. Am. Chem. Soc. 1996, 118, 7237-7238
7237
Total Synthesis of the Antitumor Depsipeptide
FR-901,228
Khan W. Li, Jerry Wu, Wenning Xing, and
Julian A. Simon*,†
Department of Chemistry and Chemical Biology
HarVard UniVersity
Cambridge, Massachusetts 02138
ReceiVed April 26, 1996
Figure 1.
The identification in 1982 of a mutation in the Ha-ras gene
provided the first indication of a link between specific molecular
changes in regulatory proteins and cancer.1-3 The mutant ras
protein, in which valine replaces glycine-12, was shown capable
of inducing morphological changes in mouse fibroblast (NIH-
3T3) cells. In these cells the transformed phenotype is indicative
of oncogenic activation and correlates with increased tumori-
genicity. Recently, a diverse class of natural products and
synthetic drugs has been identified that reverses this phenotype
and hence “de-transforms” tumorigenic cell lines. Among these
are radicicol4,5 and the tyrphostins,6 leptomycin B,7,8 L-739,749,9
and trapoxin A.10,11 A new member of this class, FR-901,228
(1), was isolated from the culture broth of the terrestrial
bacterium Chromobacterium Violaceum using a phenotypic
reversion assay of Ha-ras transformed NIH-3T3 cells. FR-
901,228 was also shown to be highly active in animal-based
assays.12-14 This finding is not surprising since the ability of
a drug to reverse the morphological effect of oncogenic
transformation is often accompanied by in vivo antitumor
activity. The molecular basis for either activity of FR-901,228
has yet to be identified.15
Scheme 1
D-cysteine suggests the possibility of a redox-controlled con-
formational switch.17 The reducing environment inside the cell
is expected to convert FR-901,228 to a monocyclic dithiol. The
effect of disulfide reduction on the detransforming activity is
unknown. In an effort to address issues raised by the striking
antitumor activity of FR-901,228, we have undertaken its total
synthesis.
There are three principal challenges associated with the
synthesis of FR-901,228: (1) the asymmetric construction of
the hydroxy mercapto heptenoic acid, (2) the formation of a
16-membered cyclic depsipeptide, and (3) an intramolecular
oxidative coupling of the thiols to form a 15-membered
disulfide-containing ring. First, we planned to use an asym-
metric aldol reaction to construct a protected mercapto â-hy-
droxy acid. Secondly, we anticipated that acylation of the allylic
secondary alcohol would render it susceptible to elimination
and therefore designed a route in which the ester bond is formed
late in the synthesis. Finally, molecular modeling of a mono-
cyclic depsipeptide intermediate suggested that the conformation
required for intramolecular disulfide formation would be ac-
cessible, being within 2 kcal/mol of the global minimum. In
this communication we describe the successful application of
this approach.
The Carreira catalytic asymmetric aldol reaction was used
to synthesize the thiol-containing â-hydroxy acid.18 The aldol
substrate 3 was prepared by the three-step sequence shown in
Scheme 1. Conjugate addition of cesium triphenylmethyl
thiolate anion to methyl 2,4-pentadienoate 2 afforded a â,γ-
unsaturated methyl ester which, upon further exposure to Cs2-
CO3, yielded the R,â-unsaturated ester. DIBAL reduction to
the primary alcohol followed by Swern oxidation gave the R,â-
unsaturated aldehyde 3. On the basis of the sense of asymmetric
induction observed by Carreira et al., we anticipated that Ti-
(IV)-catalyzed addition of O-benzyl, O-TMS ketene acetal to
aldehyde 3, in the presence of the ligand derived from (S)-(-)
binaphthyl amino alcohol, would afford an aldol with the
naturally occurring (S) configuration. The aldol product 4a was
formed in 99% yield with >98% enantiomeric excess as judged
by 19F NMR of the corresponding MTPA ester. The correct
absolute stereochemistry was confirmed by the subsequent
FR-901,228 (1) (Figure 1) is a bicyclic depsipeptide structur-
ally unrelated to known classes of cyclic peptides.16 In addition
to a dehydro amino acid, Z-butyrine, the depsipeptide incorpo-
rates an unusual building block, (3S,4E)-3-hydroxy-7-mercapto-
4-heptenoic acid 5a. A disulfide bond between this thiol and
† Present address: Molecular Pharmacology Program, Fred Hutchinson
Cancer Research Center, 1124 Columbia Street, Seattle, WA 98104 (e-
mail, jsimon@fred.fhcrc.org).
(1) Tabin, C. J.; Bradley, S. M.; Bargmann, C. I.; Weinberg, R. A.;
Papageorge, A. G.; Scolnick, E. M.; Dhar, R.; Lowry, D. R.; Chang, E. H.
Nature (London) 1982, 300, 143-149.
(2) Reddy, E. P.; Reynolds, R. K.; Santos, E.; Barbacid, M. Nature
(London) 1982, 300, 149-152.
(3) Taparowsky, E.; Suard, Y.; Fasano, O.; Shimizu, K.; Goldfarb, M.;
Wigler, M. Nature (London) 1982, 300, 762-765.
(4) Evans, G.; White, N. H. Trans. Br. Mycol. Soc. 1966, 49, 563-576.
(5) Zhao, J. F.; Nakano, H.; Sharma, S. Oncogene 1995, 11, 161-173.
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(16) Triostin A is a bicyclic depsipeptide with a disulfide bridge. Olsen,
R. K. Chemistry and Biochemistry of Amino Acids, Peptides and Proteins;
Weinstein, B., Ed.; Marcel Dekker: New York, 1983; Vol. 7, Chapter 1,
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S0002-7863(96)01372-8 CCC: $12 00
© 1996 American Chemical Society