Total Synthesis of the Depsipeptide FR-901375

Article abstract of DOI:10.1021/jo034765b

The first total synthesis of FR-901375, a novel bicyclic depsipeptide isolated from the fermentation broth of Pseudomonas chloroaphis No. 2522, has been achieved. The synthetic approach involves 13 reaction steps and is achieved in 12% overall yield. The key points in the successful synthetic strategy are a concise asymmetric synthesis of the key building block (3R,4E)-3-hydroxy-7-mercapto-4-heptenoic acid, a mild Mitsunobu macrolactonization step, and an I₂-mediated deprotection with concomitant disulfide-bridge formation.

Full text of DOI:10.1021/jo034765b

Tota l Syn th esis of th e Dep sip ep tid e F R-901375
Yanping Chen, Celine Gambs, Yoshito Abe, Paul Wentworth, J r.,* and Kim D. J anda*
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La J olla, California 92037
paulw@scripps.edu; kdjanda@scripps.edu
Received J une 4, 2003
The first total synthesis of FR-901375, a novel bicyclic depsipeptide isolated from the fermentation
broth of Pseudomonas chloroaphis No. 2522, has been achieved. The synthetic approach involves
13 reaction steps and is achieved in 12% overall yield. The key points in the successful synthetic
strategy are a concise asymmetric synthesis of the key building block (3R,4E)-3-hydroxy-7-mercapto-
4-heptenoic acid, a mild Mitsunobu macrolactonization step, and an I2-mediated deprotection with
concomitant disulfide-bridge formation.
In tr od u ction
present within its structure: (1) a tetrapeptide frame-
work consisting of H2N-D-Val-D-Val-D-Cys-L-Thr-OH-, (2)
a 16-membered ring macrocyclic lactone joined by a union
between the carboxy terminus of the tetrapeptide and
the hydroxy moiety from (3S,4E)-hydroxy-7-mercapto-4-
heptenoic acid (5), and (3) a disulfide bond linking the
side chain of the D-cysteine residue and the thiol func-
tionality of 5. Clearly, depsipeptide structures such as
FR-901375 (1) and FR-901228 (2) present exciting syn-
thetic challenges. Herein, we report the total synthesis
of FR-901375.
Simon and co-workers6 recently reported the synthesis
of FR-901228 (2). By analogy to Simon’s synthetic ap-
proach, our retrosynthetic strategy to FR-901375 (1)
involves an initial disconnection wherein we focus our
effort on a simultaneous oxidative deprotection and
disulfide bond formation from a preformed macrolactone
(Scheme 1). Accordingly, the lactone can be constructed
from the acyclic precursor 3 via a mild Mitsunobu
macrolactonization reaction.7 This step was viewed as a
formidable challenge because of the likely possibility for
elimination of the allylic alcohol functionality present in
5. The acyclic precursor 3, itself, was envisaged as being
formed from building blocks, tetrapeptide 4, and 5.
FR-901375 (1) and FR-901228 (2), discovered by Fujisa-
wa Pharmaceutical Co., Ltd., in the fermentation broth
of Pseudomonas chloroaphis (No. 2522) and Chromobac-
terium violaceum (No. 968), respectively, are members
of a rare and structurally elegant family of bicyclic
depsipeptide molecules.1 These natural products possess
potent antitumor activity against a range of murine and
human solid tumors, and their mechanism of action has
been linked to the reversal of prodifferentiation effects
of the ras oncogene pathway via blockade of p21 protein-
mediated signal transduction. FR-901228 (2) is also a
potent Zn-dependent histone deacetylase inhibitor,2,3 and
recent research has provided evidence that bicyclic dep-
sipeptides that contain a disulfide bridge have potent
activity as immunosuppressants.4 Finally, phase II clini-
cal trials are underway for the use of 2 as an anticancer
agent in the United States.5
Resu lts a n d Discu ssion
Tetrapeptide 4 was assembled rapidly and efficiently
using solution-phase Fmoc-based peptide synthesis meth-
odology8 (Scheme 2). Thus, L-threonine methyl ester
79 was reacted with N- Fmoc-D-cysteine-[S-triphenyl-
methyl (Trt)] using 1-[3-(dimethylamino)propyl]-3-eth-
ylcarbodiimide hydrochloride with 1-hydroxybenzotria-
Examination of FR-901375 (1) reveals several unique
structural aspects and challenging molecular motifs
(1) Fujisawa Pharmaceutical Co., Ltd., J apan. J pn. Kokai Tokkyo
Koho J P, 03141296, 1991.
(2) (a) Ueda, H.; Nakajima, H.; Hori, Y.; Fujita, T.; Nishimura, M.;
Goto, T.; Okuhara, M. J . Antibiot. 1994, 47, 301. (b) Shigematsu, N.;
Ueda, H.; Takase, S.; Tanaka, H.; Yamamoto, K.; Tada, T. J . Antibiot.
1994, 47, 311. (c) Ueda, H.; Manda, T.; Matsumoto, S.; Mukumoto, S.;
Nishigaki, F.; Kawamura, I.; Shimomura, K. J . Antibiot. 1994, 47, 315.
(3) (a) Blanchard, F.; Kinzie, E.; Wang, Y.; Duplomb, L.; Godard,
A.; Held, W. A.; Asch, B. B.; Baumann, H. Oncogene 2002, 21, 6264.
(b) Nakajima, H.; Kim, Y. B.; Terano, H.; Yoshida, M.; Horinouchi, S.
Exp. Cell Res. 1998, 241, 126.
(4) Skov, S. PCT Int. Appl., WO 0142282 A1 20010614, 2001.
(5) Vigushi, D. M. Curr. Opin. Invest. Drugs 2002, 1396.
(6) Li, K. W.; Wu, J .; Xing, W.; Simon, J . A. J . Am. Chem. Soc. 1996,
118, 7237.
(7) Mitsunobu, O. Synthesis 1981, 1.
(8) (a) Carpino, L. A.; Han, G. Y. J . Org. Chem. 1972, 37, 3. (b)
Carpino, L. A. Acc. Chem. Res. 1987, 20, 401.
(9) Hakimelahi, G.; J arrahpour, A. A. Helv. Chim. Acta 1989, 72,
1501.
10.1021/jo034765b CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/15/2003
8902
J . Org. Chem. 2003, 68, 8902-8905

Synthesis of FR-901375
SCHEME 1. Retr osyn th etic An a lysis of F R-901375
(1)
effected the removal of the Fmoc protecting group to give
4 in quantitative yield (Scheme 2).
In Simon’s approach to FR-901228, synthon 5 was
generated from an initial three-step synthesis of (2E)-5-
[(triphenylmethyl)thio]-2-pentenal (13). There then fol-
lowed the preparation of a chiral ligand, R-(+)-binaphthyl
amino alcohol, necessary for a transition-metal-catalyzed
chiral aldol approach to â-hydroxy acid 5.6,11 However,
in our hands, we were unable to reproduce the 98% ee in
the Ti(IV)-catalyzed aldolization reaction that Simon
observed in his synthetic approach to 5. Therefore, at this
point in our synthesis of FR-901375, we moved away from
Simon’s synthetic route in an attempt to establish a
practical and scaleable synthetic approach to the key
synthon 5.
The crucial intermediate, 5, is a deceptively simple-
looking molecule that exposes two major limitations of
current asymmetric synthesis methodologies, namely,
lack of effective asymmetric aldol reactions with unsub-
stituted, acetate-derived enolates and the inability to
carry out asymmetric ketone reductions on γ,δ-unsatur-
ated â-keto esters. We rapidly assembled aldehyde 13 in
a two-step, one-pot procedure involving an initial conju-
gate addition of triphenylmethanethiol to acrolein 11 to
afford aldehyde 12.12 Subsequent treatment of 12 with
commercially available (triphenylphosphoranylidene)-
acetaldehyde in refluxing benzene yielded the R,â-
unsaturated aldehyde 13 (overall 60% yield, two steps.
Scheme 3). With the requisite aldehyde 13 in hand, the
asymmetric aldol reaction was investigated. Phillips and
co-workers13 reported a highly diastereoselective acetate
zole, followed by TBS protection to yield protected
dipeptide 8 (83% overall yield).10 The choice of the TBS
protecting group was driven by the anticipated require-
ment for mild deprotection conditions in the later stages
of our synthesis. N-Fmoc deprotection of 8 (Et2NH),
followed by coupling to N-Fmoc-D-valine provided tri-
peptide 9 (97% yield). A further cycle of N-Fmoc depro-
tection and coupling with D-valine furnished the tet-
rapeptide 10 in 71% yield. Treatment of 10 with Et2NH
SCHEME 2. Syn th esis of Tetr a p ep tid e 4
SCHEME 3. Ald ol Rea ction Ba sed on a n Oxa zolid in eth ion e Au xilia r y
J . Org. Chem, Vol. 68, No. 23, 2003 8903

Chen et al.
SCHEME 4. Asym m etr ic Syn th esis of Ch ir a l Acid 5
SCHEME 5. La tter Sta ge Assem bly of F R-901375 (1)
aldol reaction based on an oxazolidinethione auxiliary.
Unfortunately, the reaction between oxazolidinethione 14
and aldehyde 13 provided the aldol product 15 in poor
yield (35%) and moderate diastereoselectivity (Scheme
3).14
Subsequent hydrolysis of the chiral auxiliary of 18, with
LiOH/H2O2, furnished 5 in 78% yield (Scheme 4).18 Thus,
while our approach to 5 is longer, in terms of synthetic
steps, than Simon’s approach, our methodology allows
us to routinely prepare 5 on a multigram scale and in
essentially enantiomerically pure form.
With chiral acid 5 conveniently accessible, the coupling
of 4 and 5 with BOP reagent ((benzotriazol-1-yloxy)tris-
(dimethylamino)phosphonium hexafluorophosphate) pro-
ceeded smoothly to grant the hydroxy methyl ester 19.
Basic hydrolysis (LiOH/THF) afforded 3 (79% yield over
two steps). The stage was now set for the Mitsunobu
macrolactonization of 3; gratifyingly, this reaction pro-
ceeded quite well to afford lactone 20 in 59% yield. Final
oxidative deprotection of the bis(S-triphenyl)lactone with
iodine in dilute MeOH solution19 and HF/CH3CN20 af-
forded FR-901375 (1) in 63% yield over two steps (Scheme
5). This synthetic material gave 1H and 13C NMR spectral
data, which matched perfectly those for the natural
product.
The use of Evans’ auxiliary-based aldolization reactions
of haloacetyloxazolidinones, as masked chiral acetate
enolate equivalents, has proven reproducibly reliable.15
Thus and to our delight, the asymmetric aldol reaction
between the dibutylboron enolate derivative of chloro-
acetyl-oxazolidinone 16 and aldehyde 13 provided the
desired chlorohydrin 17 (69%) with excellent diastereo-
1
selectivity (>90% de as judged by H NMR, Scheme 4).16
The subsequent dechlorination of 17 was complicated by
the acid sensitivity of the S-trityl protecting group. Thus
Zn/HOAc and Zn/NH4Cl were not applicable methods for
this transformation. However, dechlorination of 17 was
achieved with Al-Hg17 to give 18 in quantitative yield.
(10) Niu, C.; Petterson, T.; Miller, M. J . J . Org. Chem. 1996, 61,
1014.
(11) Smrcina, M.; Lorenc, M.; Hanus, V.; Sedmera, P.; Kocovsky, P.
J . Org. Chem. 1992, 57, 1917.
(12) Gazal, S.; Gellerman, G.; Glukhov, E.; Gilon, C. J . Pept. Res.
2001, 58, 527. In this paper, aldehyde 12 was prepared from 3-bro-
mopropionic acid in three steps.
We have developed an efficient total synthesis of FR-
901375 that involves 13 linear steps, with an overall yield
of 12.4%. Our synthetic effort features a concise asym-
metric synthesis of the quintessential synthon (3R,4E)-
(13) Guz, N. R.; Phillips, A. J . Org. Lett. 2002, 2253.
(14) The absolute configuration of aldol product was tentatively
assigned based on both Phillips’ model and by the optical rotation of
the hydrolyzed product.
(15) (a) Evans, D. A.; Sjogren, E. B.; Weber, A. E.; Conn, R. E.
Tetrahedron Lett. 1987, 28, 39. (b) Evans, D. A.; Carter, P. H.; Carreira,
E. M.; Charette, A. B.; Prunet, J . A.; Lautens, M. J . Am. Chem. Soc.
1999, 121, 7540.
(17) Wang, Y.-C.; Yan, T.-H. Chem. Commun. 2000, 545.
(18) The observed optical rotation of compound 5: [R]25 ) +4.52
D
(2.1, CH2Cl2). Published optical rotation data: [R]20D ) +4.6 (2.0, CH2-
Cl2) in ref 6.
(19) Kamber, B.; Hartmann, A.; Eisler, K.; Riniker, B.; Rink, H.;
Sieber, P.; Rittel, W. Helv. Chem. Acta 1980, 63, 899.
(20) Newton, R. F.; Reynolds, D. P.; Finch, M. A. W.; Kelly, D. R.;
Roberts, S. M. Tetrahedron Lett. 1979, 3981. Care should be taken
when using 48% HF aqueous solution (see SI).
(16) Crude NMR shows only one single diastereomer. The absolute
configuration is based on Evans’ model.
8904 J . Org. Chem., Vol. 68, No. 23, 2003

Synthesis of FR-901375
3-hydroxy-7-mercapto-4-heptenoic acid 5 on the gram
scale, a mild Mitsunobu macrolactonization step, and a
simultaneous I2-mediated deprotection/disulfide bridge
formation. This synthetic approach should provide a
readily accessible route to bicyclic depsipeptide libraries
and thus facilitate SAR profiling of these interesting
structures. Explorations along these lines will be reported
in due course.
Institute of Health (GM53654, K.D.J .). Y.A. thanks
Fujisawa Pharmaceutical Co., Ltd., for financial support
for sabbatical leave at The Scripps Research Institute.
The authors thank Fujisawa Pharmaceutical Co., Ltd.,
for supplying an authentic sample of FR-901375.
Su p p or tin g In for m a tion Ava ila ble: All experimental
details and analytical data. This material is available free of
charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. This work was supported by The
Skaggs Institute for Chemical Biology and The National
J O034765B
J . Org. Chem, Vol. 68, No. 23, 2003 8905