Total synthesis of (-)-spongidepsin

Article abstract of DOI:10.1021/ol061029w

A convergent and rapid stereoselective synthesis of (-)-spongidepsin has been achieved from the Roche ester in 14 steps with an overall yield of 13%.

Full text of DOI:10.1021/ol061029w

ORGANIC
LETTERS
2006
Vol. 8, No. 16
3441-3443
Total Synthesis of (−)-Spongidepsin
Laurent Ferrie´, Se´bastien Reymond, Patrice Capdevielle, and Janine Cossy*
ESPCI, Laboratoire de Chimie Organique, 10 Rue Vauquelin,
75231 Paris Cedex 05, France
Janine.cossy@espci.fr
Received April 28, 2006
ABSTRACT
A convergent and rapid stereoselective synthesis of (
yield of 13%.
−)-spongidepsin has been achieved from the Roche ester in 14 steps with an overall
(-)-Spongidepsin is a cyclodepsipeptide isolated from the
Vanuatu marine sponge Spongia sp. This compound exhibits
cytotoxic and antiproliferative activities against J774.A1,
WEHI-164, and HEK-293 cancer cell lines.1 (-)-Spongidepsin
is a 13-membered macrolactam with five stereogenic centers.
The structure of spongidepsin was established by spectro-
scopic analysis, and the N-methylphenylalanine residue with
the (L) configuration has been identified at isolation. The
absolute configurations of the other four stereogenic centers
were determined by total synthesis. Up to now, only two
syntheses of spongidepsin have been achieved.2,3
the C6-C13 fragment under Mitsunobu conditions, followed
by the coupling with the C1-C5 fragment (Scheme 1).
Scheme 1
We would like to report here a highly convergent synthesis
of (-)-spongidepsin using a ring-closing metathesis (RCM)
to build up the 13-membered macrocycle, a diastereoselective
crotylstannylation to control the C2 and C4 stereogenic
centers, an enantioselective 1,4-addition of a ketyl radical
to an optically active R,â-unsaturated ester, and a diastereo-
selective alkylation of a five-membered lactone to control
the C7 and C9 stereogenic centers.
As outlined in our retrosynthetic analysis, the 13-
membered macrolactam might be prepared by ruthenium-
catalyzed RCM of diene A and subsequent palladium-
catalyzed alkene hydrogenation. Diene A was planned to be
synthesized by coupling of (S)-N-methylphenylalanine with
The synthesis of the C1-C5 fragment was achieved in
seven steps from the commercially available Roche ester
(S)-1 (Scheme 2). After protection of the primary alcohol
using tert-butyldiphenylsilyl chloride (TBDPSCl, imidazole,
DMF, 0 °C to room temperature), the protected methyl ester
was reduced with DIBAL-H (hexanes, -78 °C) to furnish
(1) Grassia, A.; Bruno, I.; Debitus, C.; Marzocco, S.; Pinto, A.; Gomez-
Paloma, L.; Riccio, R. Tetrahedron 2001, 57, 6257.
(2) Chen, J.; Forsyth, C. Angew. Chem., Int. Ed. 2004, 43, 2148.
(3) Ghosh, A. K.; Xu, X. Org. Lett. 2004, 6, 2055.
10.1021/ol061029w CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/06/2006

Scheme 2
Scheme 3
the protected hydroxy aldehyde 2 in 88% yield (overall yield
for the two steps).4
By treatment of 2 with but-2-enyl-(tri-n-butyl)-stannane I
in the presence of BF3‚OEt2 (CH2Cl2, -78 °C), the diaste-
reoselective crotylstannylation produced the syn-syn ste-
reotriad 3 with a good level of diastereoselectivity (dr )
87:13) in 76% isolated yield.5,6
presence of the easily available R,â-unsaturated aminoester
(1S,2R)-II produced lactone (S)-9 in 35% isolated yield (er
) 85:15).8,9 This lactone was then transformed to the desired
C6-C13 fragment in a three-step sequence. The first step
involved a diastereoselective alkylation of 9 by using MeI
(LDA, THF, -78 °C), providing the methylated lactone 10
in 65% yield as an inseparable mixture of diastereomers (dr
) 85:15).10 After reduction of 10 to the corresponding lactol
(DIBAL-H, CH2Cl2, -78 °C), followed by a Wittig meth-
ylenation (Ph3PdCH2, THF, 0 °C), the C6-C13 fragment
11 was isolated in 55% yield (Scheme 3).
The assembly of (S)-N-methylphenylalanine with com-
pounds 11 and 6, to produce the key dienic substrate 13
required for the ring-closing metathesis, is shown in Scheme
4. At first, a Mitsunobu esterification (PPh3, DIAD, Et2O,
room temperature)11 of the N-Boc protected (S)-N-meth-
ylphenylalanine III with the secondary alcohol 11 led to the
ester 12 accompanied by minor isomers. After separation
by flash chromatography on silica gel, ester 12 was obtained
To transform 3 into the unsaturated primary alcohol 5,
compound 3 was mesylated (MsCl, pyridine, CH2Cl2, room
temperature) to produce 4 quantitatively, which was reduced
with LiAlH4 (Et2O, room temperature) and then transformed
into the unsaturated alcohol 5 in 65% yield after treatment
with TBAF (THF, room temperature) (overall yield for the
two steps). After oxidation of 5 using Jones’ reagent (CrO3,
H2O, H2SO4, acetone, 0 °C to room temperature), the desired
unsaturated carboxylic acid 6 was obtained in 72% yield.
Compound 6 was thus obtained from the commercially
available Roche ester (S)-1, with an overall yield of 31%
(Scheme 2).
The stereoselective synthesis of the C6-C13 fragment 11
started with 5-hexen-1-ol 7. After protection of 7 as a TBDPS
ether (TBDPSCl, imidazole, DMF, room temperature), an
ozonolysis of the terminal double bond was achieved (O3,
-78 °C, CH2Cl2 then Et3N)7 to produce the protected
hydroxyaldehyde 8 in 92% yield. The crucial step was the
transformation of 8 to 9 by using an intermolecular stereo-
selective condensation of a ketyl radical to an optically active
R,â-unsaturated ester mediated by SmI2, which should
undergo direct cyclization to produce lactone 9. Thus, the
treatment of 8 with SmI2 (THF, tert-BuOH, 0 °C) in the
(8) Fukuzawa, S.; Seki, K.; Tatsuzawa, M.; Mutoh, K. J. Am. Chem.
Soc. 1997, 119, 1482.
(9) After reduction of aldehyde 8 by SmI2, a ketyl radical is formed. An
intermolecular complexation of the SmIII attached to the ketyl intermediate
can take place with the ester carbonyl group of (1S,2R)-II to produce B to
minimize the steric interactions.
(4) Johns, A. B.; Grant, C. M.; Marshall, J. A. Org. Synth. 2002, 79, 59.
(5) Keck, G. E.; Savin, K. A.; Cressman, E. N. K.; Abbott, D. E. J.
Org. Chem. 1994, 59, 7889.
(6) The dr was determined on the crude reaction mixture by H NMR
spectroscopy.
The (S) configuration of lactone 9 was obtained using (1S,2R)-II, derived
from (+)-(1S,2R)-N-methylephedrine (ref 8). The er of this lactone was
determined by HPLC analysis using a Daicel Chiralpak AS-H column:
hexane/EtOH 97:3, 1 mL/min, 215 nm, tR(S) 13.3 min, tR(R) 14.7 min.
1
1
(7) Hon, Y. S.; Lin, S. W.; Lu, L.; Chen, Y. J. Tetrahedron 1995, 51,
(10) Based on the H NMR spectra.
5019.
(11) Mitsunobu, O. Synthesis 1991, 1.
Org. Lett., Vol. 8, No. 16, 2006
3442

reduced using a hydrogenation (Pd/C 5%, AcOEt, room
temperature).12 The terminal alcohol was then oxidized to
an aldehyde using Dess-Martin periodinane13 and then
transformed to a terminal acetylenic group using Bestmann’s
reagent (K2CO3, MeOH, 35 °C).14 (-)-Spongidepsin was
obtained in 60% yield for the last four steps. All the spectral
Scheme 4
20
data (1H, 13C NMR),15 HMRS, and the optical rotation ([R]D
-210.5, c 0.49, MeOH)16 matched with those of the synthetic
(-)-spongidepsin reported by Ghosh.17
In summary, by using a convergent synthesis and diaste-
reoselective reactions such as a crotylstannylation, 1,4-
addition of a ketyl radical to an optically active R,â-
unsaturated ester, and a diastereoselective alkylation, we
synthesized (-)-spongidepsin in 14 steps from the com-
mercially available Roche ester (S)-1 with an overall yield
of 13%.
Acknowledgment. L.F. thanks the MRES for a grant.
We thank Dr. Fisher and Dr. Trimmer from Materia for a
generous gift of Grubbs catalyst second generation.
Supporting Information Available: Experimental pro-
cedures for all compounds and 1H and 13C NMR spectra for
compounds 1-14 and (-)-spongidepsin. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL061029W
(12) In our efforts to shorten the synthesis, when Pd/C hydrogenation
and TBAF deprotection were carried out in one pot, epimerization of the
macrocycle was observed.
in 67% isolated yield. Removal of the N-Boc protecting
group with TFA (CH2Cl2, room temperature) produced the
free amine which was coupled with the unsaturated acid 6
to afford diene 13 in 76% yield (overall yield for the two
steps). Ring-closing metathesis of this diene 13 using Grubbs
catalyst second generation (20 mol %, CH2Cl2, 40 °C)
furnished the (Z)-macrolactam 14 in 93% yield. As described
previously,3 the TBDPS ether was cleaved by TBAF (THF,
room temperature) and the (Z)-macrocyclic double bond was
(13) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(14) Mu¨ller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996,
521.
(15) See Supporting Information for 1H and 13C NMR spectra of our
synthetic (-)-spongidepsin.
(16) At higher dilution, our (-)-spongidepsin has shown a similar optical
20
rotation: [R]D -209.4 (c 0.18, MeOH).
(17) Spongidepsin synthesized by Ghosh shows optical rotation similar
to ours ([R]D23 -198 (c 0.29, MeOH)) (see ref 3). However, spongidepsin
synthesized by Forsyth (ref 2) and the natural spongidepsin isolated by
Riccio (ref 1) show different optical rotations: [R]D23 -67.3 (c 1, MeOH)
23
and [R]D -61.8 (c 0.14, MeOH), respectively.
Org. Lett., Vol. 8, No. 16, 2006
3443