Assignment of absolute stereochemistry and total synthesis of (-)-spongidepsin

Article abstract of DOI:10.1021/ol049292p

Equation presented. An enantioselective total synthesis of (-)-spongidepsin (2) and elucidation of the absolute stereochemistry of its four stereocenters are described. Spongidepsin (2), a 13-membered depsipeptide isolated from the Vanuatu marine sponge S

Full text of DOI:10.1021/ol049292p

ORGANIC
LETTERS
2004
Vol. 6, No. 12
2055-2058
Assignment of Absolute
Stereochemistry and Total Synthesis of
(−)-Spongidepsin
Arun K. Ghosh* and Xiaoming Xu
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607
arunghos@uic.edu
Received April 17, 2004
ABSTRACT
An enantioselective total synthesis of (−)-spongidepsin (2) and elucidation of the absolute stereochemistry of its four stereocenters are described.
Spongidepsin (2), a 13-membered depsipeptide isolated from the Vanuatu marine sponge Spongia sp., has shown potent antitumor properties
against a variety of NCI tumor cell lines. Our synthesis is convergent, and the absolute stereochemistry of four of the five chiral centers was
assigned through synthesis.
Recently, the novel cyclodepsipeptide, spongidepsin, was
isolated from the Vanuatu marine sponge Spongia sp. by
Riccio and co-workers.1 Spongidepsin displayed potent
cytotoxicity against a variety of cancer cell lines that included
the HEK-293 cell line.2
novel depsipeptides and now report a total synthesis of
spongidepsin 2 that is amenable to analogue construction.4
Spongidepsin contains a highly functionalized 13-mem-
bered ring with five chiral centers. Only the N-methylphen-
ylalanine residue with L-configuration had previously been
identified at isolation.1 For determination of the relative and
absolute stereochemistry, our approach was to devise a
convergent, efficient synthesis that relied upon chiral starting
materials derived from biocatalysis and asymmetric synthesis.
Our strategy was designed to provide rapid access to all
possible diastereomers for spectroscopic studies.
As outlined in Figure 1, our synthetic strategy involved a
ring-closing olefin metathesis to construct the 13-membered
macrocycle from diene 3. The synthesis of 3 was planned
from the enantiomerically pure C1-C5 segment 5, the C6-
C12 segment 6, and N-methylphenylalanine by Mitsunobu
esterification and amide coupling reactions. Since the relative
stereochemistry of the C2- and C4-centers was initially
assigned as syn, our plan was to synthesize both enantiomers
The gross structure of spongidepsin was initially estab-
lished by extensive spectroscopic analysis. However, the
relative stereochemistry of the C7 and C9 stereocenters and
the absolute configuration of four of its five chiral centers
were not assigned until recently when Forsyth and Chen
reported their synthesis and structural elucidation of
spongidepsin.3
Unfortunately, the extremely low natural abundance of
spongidepsin has made it difficult to evaluate its biological
profile in detail.1 In view of its potent cytotoxic properties
and its interesting structural features, we became interested
in the chemistry and biology of spongidepsin and related
(1) Grassia, A.; Bruno, I.; Debitus, C.; Marzocco, S.; Pino, A.; Gomez-
Paloma, L.; Riccio, R. Tetrahedron 2001, 57, 6257.
(2) Against HEK-293 and WEHI-164 cells, spongidepsin has shown IC50
values of 0.66 and 0.42 µM, respectively.
(3) Forsyth, C. J.; Chen, J. Angew. Chem., Int. Ed. 2004, 43, 2148.
(4) (a) Bai, R.; Covell, D. G.; Ghosh, A. K.; Liu, C.; Hamel, E. J. Biol.
Chem. 2002, 277, 32165. (b) Ghosh, A. K.; Liu, C. Org. Lett. 2001, 3,
635.
10.1021/ol049292p CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/18/2004

Scheme 1. Synthesis of C1-C5 Segment 5
furnished olefin 10 in 78% yield. Removal of the silyl group
and PDC-oxidation of the resulting alcohol afforded 5 in 76%
yield.
Figure 1. Retrosynthetic analysis of spongidepsin.
Our enantioselective synthesis of the C6-C12 fragment
6 is shown in Scheme 2. Commercially available 4-pentene-
1-ol was protected as its TBDPS ether to provide 12. Cross-
of the C1-C5 segment 5 using enzymatic desymmetrization
of meso-syn-2,4-dimethylpentane-1,5-diol as the key step.
An enantioselective synthesis of alcohol 6 was envisioned
using an asymmetric alkylation and halolactonization reaction
sequence.
Scheme 2. Synthesis of C6-C12 Segment 6
Our initial strategy for elucidating the structure of
spongidepsin was to construct the 13-membered ring as a
1
diastereomeric mixture and compare the characteristic H
NMR chemical shifts (particularly the C-16 methine proton)
with the reported spectral data for natural spongidepsin.1 Such
a mixture of diastereomers was generated by coupling the
enantiomerically defined C1-C5 segment 5, ent-5, and the
racemic C6-C12 segment 6, using DCC and DMAP.
Mitsunobu esterification with inversion of stereochemistry
at the C9-stereocenter was also investigated. This strategy
ultimately led to successful identification and elucidation of
the absolute stereochemistry of spongidepsin (See Figure 1).5
Forsyth and Chen recently identified the same configuration
of natural spongidepsin.3
Our enantioselective synthesis of C1-C5 segment 5 is
outlined in Scheme 1. Multigram quantitites of meso-diol 7
were prepared as described previously.6 Enzymatic desym-
metrization of 7 with lipase PS-30 provided the monoacetate
8 in 83% yield and 99% ee.7 Protection of 8 as a TBDPS
ether followed by DIBAL reduction afforded alcohol 9 in
94% yield. Oxidation and subsequent Wittig methylation
(5) Full investigation, including biological studies, will be reported in
due course.
(6) Fugita, K.; Mori, K. Eur. J. Org. Chem. 2001, 3, 493.
(7) (a) Wang, Y.-F.; Chen, C.-S.; Girdaukas, G.; Sih, C. J. J. Am. Chem.
Soc. 1984, 106, 3695. (b) Lin, G.-Q.: Xu, W.-C. Tetrahedron 1996, 52,
5907.
2056
Org. Lett., Vol. 6, No. 12, 2004

metathesis8 of 12 with allyl chloride in CH2Cl2 at 42 °C in
the presence of 5 mol % second-generation Grubbs’s catalyst9
afforded a 15:1 mixture (E:Z) of cross-metathesis products
in 68% yield. Displacement of the chloride with sodium
iodide furnished allylic iodide 13 in 92% yield. Evans’
asymmetric alkylation10 of acyloxazolidinone 14 with iodide
13 in THF afforded alkylation product 15 diastereoselectively
in 90% yield and 96% de (by 1H NMR analysis). Exposure
of 15 to NBS using Bradbury’s protocol,11 furnished bro-
molactone 16 diastereoselectively. Removal of the bromide
using a catalytic tributyltin hydride in a mixture (1:1) of
benzene and t-BuOH at 84 °C provided 17 in 96% yield.12
Dibal reduction of 17 in CH2Cl2 at -78 °C provided the
lactol, which underwent Wittig olefination to afford 6 in 76%
yield in two steps.
CH2Cl2 at 42 °C using 10 mol % second-generation Grubbs’s
catalyst14 gave excellent results, affording the macrocycle
19 as a single isomer in 93% yield. The coupling constants
of the olefinic protons (Jab ) 10.1 Hz) indicated that the
cis-lactone had been formed.15 Deprotection of the silyl group
followed by hydrogenation in methanol afforded the saturated
lactone 20. Oxidation of 20, followed by exposure of the
resulting aldehyde to the Ohira-Bestmann reagent,16 pro-
vided synthetic spongidepsin (2) with defined absolute
stereochemistry of all five chiral centers. The spectral data
(1H and 13C NMR) of synthetic spongidepsin ([R]D23 -198,
c 0.29, MeOH) was identical to that of natural spongidepsin
23
(lit.1 [R] -61.8, c 0.014, MeOH).17,18
D
During the course of our synthesis and structural elucida-
tion of spondidepsin, four other possible diastereomers were
synthesized with the stereochemistry depicted in Figure 2.
Our assembly of the key olefin-metathesis substrate 3 is
shown in Scheme 3. Alkylation of N-Boc-phenylalanine with
Scheme 3. Synthesis of (-)-Spongidepsin (2)
Figure 2. Diastereomers of spongidepsin.
The C1-C5 segment of diastereomers 21-23 was derived
from ent-5, which was prepared from optically active alcohol
(8) Liu, B.; Das, S. K.; Roy, R. Org. Lett. 2002, 4, 2723.
(9) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am.
Chem. Soc. 2000, 122, 3783 and references therein.
(10) Evans, D. A.; Takacs, J. M.; McGee, L. R.; Ennis, M. D.; Mathre,
D. J.; Bartroli, J. Pure Appl. Chem. 1981, 53, 1109.
(11) Bradbury, R. H.; Revill, J. M.; Rivett, J. E.; Waterson, D.
Tetrahedron Lett. 1989, 30, 3845.
(12) Crich, D.; Sun, S. J. Org. Chem. 1996, 61, 7200.
(13) Mitsunobu, O. Synthesis 1981, 1.
(14) Scholl, M.; Ding, S.; Lee, C.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(15) Extensive NOESY experiment also suggested the formation of (Z)-
olefin. A strong NOE was observed between the C4 and C7 methine protons.
Interestingly, Forsyth and Chen have observed the formation of the (E)-
isomer as the major product under different reaction conditions; please see
ref 3.
(16) Ohira, W. Synth. Commun. 1989, 19, 561.
methyl iodide provided the acid. Mitsunobu esterification13
of acid 4 with alcohol 6 furnished ester 18 in 73% yield.
Trifluoroacetic acid-promoted removal of the BOC group
followed by coupling of the resulting amine with acid 5
afforded 3 in 92% yield. Ring-closing metathesis of 3 in
(17) Synthetic (-)-spongidepsin (2) has shown similar optical rotation
in chloroform as well ([R]23 -209, c 0.75, CHCl3).
D
(18) Our synthetic (-)-spongidepsin has shown different optical rotations
than those reported previously. Reported optical rotation of natural
spongidepsin is significantly lower, possibly due to measurement of rotation
under very dilute conditions. Our observed rotation is also higher than the
value recently reported by Forsyth and Chen3 ([R]23D -67.3, c 1.0, MeOH).
Org. Lett., Vol. 6, No. 12, 2004
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7 using procedures similar to those in Scheme 1. The C9
stereochemistry of diastereomers 22 and 24 was derived from
esterification of C6-C12 segment 6 and phenylalanine
derivative 4 in the presence of DCC and DMAP. Subsequent
reaction steps as described in Scheme 3 provided 22 and
24.5 The spectroscopic data and optical rotation of these
diastereomers are quite different from that of 2.
Acknowledgment. The authors thank Professor Riccio
for providing a copy of the H NMR spectrum of natural
1
spongidepsin. Partial financial support by the National
Institutes of Health is gratefully acknowledged. We also
thank Dr. Park for preliminary experimental assistance and
Mr. Gongli Gong and Mr. Gary Schiltz for helpful discus-
sions.
Thus, we have determined the absolute configuration and
achieved the total synthesis of (-)-spongidepsin. The
synthesis features enzymatic desymmetrization of meso-diol
in excellent enantiomeric purity, diastereoselective alkylation
and halolactonization to set the C7 and C9 stereochemistry,
and efficient cross-metathesis of functionalized substrates.
The synthesis now paves the way for important structure-
activity studies.
Supporting Information Available: Experimental pro-
1
cedures and H and 13C NMR spectra for compounds 2, 3,
6, and 15-24. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL049292P
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Org. Lett., Vol. 6, No. 12, 2004