Synthesis of C1-C11 fragment of callystatin A

Article abstract of DOI:10.1016/S0040-4039(02)02200-1

We wish to describe here our continuing efforts towards the total synthesis of the marine sponge polyketide callystatin A, describing the synthesis of the C1-C11 fragment.

Full text of DOI:10.1016/S0040-4039(02)02200-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8883–8885
Synthesis of C1ꢀC11 fragment of callystatin A†
Luiz C. Dias* and Paulo R. R. Meira
Instituto de Qu´ımica, Universidade Estadual de Campinas, UNICAMP, C.P. 6154, 13083-970 Campinas, SP, Brazil
Received 25 September 2002; accepted 2 October 2002
Abstract—We wish to describe here our continuing efforts towards the total synthesis of the marine sponge polyketide callystatin
A, describing the synthesis of the C1ꢀC11 fragment. © 2002 Elsevier Science Ltd. All rights reserved.
In 1997, Kobayashi and co-workers reported the isola-
tion of (−)-callystatin A (1), a potent antitumor polyke-
tide from the marine sponge Callyspongia truncata,
collected from Goto Islands, Nagasaki Prefecture,
Japan (Scheme 1).1 The relative as well as the absolute
stereochemistry of (−)-callystatin A was established by
a combination of spectroscopic methods and chemical
synthesis.2–5 (−)-Callystatin A (1), a polyketide with a
terminal a,b-unsaturated lactone and two diene systems
shows remarkably high activity (IC50=10 pg/mL)
against KB tumor cell lines and 20 pg/mL against
L1210 cells.
As the natural supply is extremely restricted, and
attracted by its potent cytotoxicity, we initiated a pro-
ject directed towards its total synthesis. An efficient and
flexible synthesis is essential to provide further material
for more extensive biological studies, along with access
to novel analogues.3–6 We have recently described a
very efficient synthesis of the C13ꢀC22 fragment of
(−)-callystatin A.7 The approach described here to the
C1ꢀC11 fragment might give access to (−)-callystatin A
and additional derivatives with potential relevance to
biological studies.8
Our disconnection, summarized in Scheme 1, involved
cleavage of the C11ꢀC12 bond to give fragments
C1ꢀC11 (2) and C12ꢀC22 (3).9 Fragment C1ꢀC11 is
viewed as arising from coupling between aldehyde 4, a
masked a,b-unsaturated lactone, corresponding to the
C1ꢀC6 fragment and phosphonium salt 5 (C7ꢀC11).
The a,b-unsaturated lactone fragment found in
callystatin A is a common structural motif in polyketide
natural products. Among the strategies available to the
synthesis of this lactone, a ring-closing metathesis using
Grubb’s catalyst is one of the most common.10 Of the
remaining available options, we speculate that the
desired aldehyde 4 might be most conveniently pre-
pared from
D
-malic acid.11
The synthesis of fragment C1ꢀC6 began with full pro-
tection of diol 6 (easily prepared from -malic acid) as
D
its TBS ether to give the corresponding ester in 98%
yield.11 This ester was smoothly reduced to aldehyde 7
(93% yield) on treatment with diisobutylaluminum
hydride in toluene at −78°C (Scheme 2).
Scheme 1.
This unpurified aldehyde was directly subjected to a
Horner–Wadsworth–Emmons homologation with the
required phosphonate reagent under Ando’s conditions
* Corresponding author. Tel.: +55-019-3788-3021; fax: +55-019-3788-
3023; e-mail: ldias@iqm.unicamp.br
† This paper is dedicated to the Brazilian Chemical Society (SBQ).
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02200-1

8884
L. C. Dias, P. R. R. Meira / Tetrahedron Letters 43 (2002) 8883–8885
Scheme 4.
93% isolated yield (Scheme 4).12,15,16 The Z-geometry
for ester 14 was confirmed by the illustrated NOESY
interaction between vinylic hydrogen at C9 and hydro-
gens of the ethyl group. A sequence of DIBALH reduc-
tion followed by treatment of the intermediate allylic
alcohol with PPh3, CBr4 in CH3CN gave bromide 15 in
86% yield over the two-step sequence. Reaction of
bromide 15 with PBu3 gave phosphonium salt 5 in 95%
yield.17
Scheme 2.
to give (Z)-a,b-unsaturated ester 8 (Z:E=92:08) in 92%
isolated yield.12 Treatment of Z-ester 8 with 1N HCl in
MeOH gave lactone 9 in 94% yield. At this point, in
order to avoid partial racemization at C5 at the alde-
hyde stage, the carbonyl group in 9 should be masked
as an acetal, which can be easily hydrolyzed later on in
the synthesis under mild conditions and subsequently
oxidized to regenerate the desired a,b-unsaturated lac-
tone.5,13 Protection of the primary alcohol functionality
in 9 as its TBS ether followed by careful DIBALH
reduction gave an intermediate lactol that was treated
With fragments C1ꢀC6 and C7ꢀC11 in hands, their
coupling was undertaken (Scheme 5). Treatment of a
mixture of aldehyde 4 and phosphonium salt 5 with
LiCH2S(O)CH3 in toluene at −78°C, cleanly provided
diene 2 in 82% yield (E:Z >95:5), corresponding to the
C1ꢀC11 fragment of (−)-callystatin A.5,17
The 10-step sequence from 6 to 2 (longest linear
sequence) proceeded in an overall yield of 42% and is
easily amenable to a gram scale-up. Thus, the synthesis
of C1ꢀC11 fragment of (−)-callystatin A has been
described. Notable features of this approach include an
efficient preparation of the a,b-unsaturated lactone
fragment from diol 6, and Wittig and Horner–
Wadsworth–Emmons reactions to establish the double
bonds at C2ꢀC3, C6ꢀC7 and C8ꢀC9. As a result, the
route to the C1ꢀC11 fragment presented here is, in
principle, readily applicable for the preparation of (−)-
callystatin A and additional analogs. We have now
finished the synthesis of C1ꢀC11 and C13ꢀC22 frag-
ments of (−)-callystatin A. Efforts are being undertaken
to improve the synthesis of both fragments as well as to
complete the total synthesis of (−)-callystatin A and
these studies will be described in a full account of this
work.18
i
with PrOH in the presence of catalytic amounts of
PPTS to provide isopropyl acetal 10 in 70% overall
yield over the three-step sequence. The next step
involved TBS removal in 10 with TBAF in THF (99%
yield) followed by Swern oxidation of the OH-function
under standard conditions to give aldehyde 4 (96%
yield).13,14
An alternative approach to lactone 9 involved reduc-
tion of (Z)-ester 8 with 2.2 equiv. of diisobutylalu-
minum hydride at 0°C to give allylic alcohol 11 in 95%
yield (Scheme 3). Formation of lactone 9 was accom-
plished by treatment of allylic alcohol 11 with
Amberlyst 15® resin in MeOH at room temperature,
followed by subsequent treatment of the resulting triol
with MnO2, in 86% yield over the two-step sequence.
Our approach to fragment C7ꢀC11 began with a
Horner–Wadsworth–Emmons homologation reaction
of aldehyde 12 with b-ketophosphonate 13 under
Ando’s conditions to give (Z)-a,b-unsaturated ester 14
(Z:E>95:05) with a trisubstituted Z-double bond in
Scheme 3.
Scheme 5.

L. C. Dias, P. R. R. Meira / Tetrahedron Letters 43 (2002) 8883–8885
8885
Acknowledgements
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8. For a very interesting review about the chemistry and
biology of the leptomycin family, see: Kalesse, M.;
Christmann, M. Synthesis 2002, 981.
We are grateful to FAPESP and CNPq for financial
support. We also thank Professor Carol H. Collins,
from IQ-UNICAMP, for helpful suggestions about
English grammar and style.
9. The numbering of 1 as well as of each intermediate
follows that suggested in Ref. 1.
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data. Yields refer to chromatographically and spectro-
scopically homogeneous materials.