Synthesis of C13-C22 fragment of the marine sponge polyketide callystatin A

Article abstract of DOI:10.1016/S0040-4039(01)02104-9

We wish to report here our initial efforts towards the total synthesis of callystatin A, describing the synthesis of the C13-C22 fragment. This asymmetric approach uses an efficient syn-aldol reaction, and a diastereoselective epoxidation of an allylic al

Full text of DOI:10.1016/S0040-4039(01)02104-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 185–187
Synthesis of C13ꢀC22 fragment of the marine sponge polyketide
callystatin A†
Luiz C. Dias* and Paulo R. R. Meira
Instituto de Qu´ımica, Universidade Estadual de Campinas/UNICAMP CP 6154, 13083-970, Campinas, SP, Brazil
Received 1 November 2001; accepted 6 November 2001
Abstract—We wish to report here our initial efforts towards the total synthesis of callystatin A, describing the synthesis of the
C13ꢀC22 fragment. This asymmetric approach uses an efficient syn-aldol reaction, and a diastereoselective epoxidation of an
allylic alcohol with m-CPBA followed by epoxide opening with Me2CuLi. © 2002 Elsevier Science Ltd. All rights reserved.
In 1997, Kobayashi and co-workers reported the isola-
tion of callystatin A (1), a potent antitumor polyketide
from the marine sponge Callyspongia truncata (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
Callystatin A (1), a polyketide with a terminal a,b-
unsaturated lactone and two diene systems shows
remarkably high activity (IC50=0.01 ng/mL) against
KB tumor 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 analogs.3,4 The approach described here to the
C13ꢀC22 fragment might give access to callystatin A
and additional derivatives with potential relevance to
biological studies.4,5
O
OH
13
10
16
18
Me
Me
12
22
Me
Me Me Me Me
Wittig
coupling
6
Callystatin A (1)
PMB
epoxide
opening
O
1
O
O
OTBS
PBu3
18
O
12
EtO
Me
13
Our disconnection, summarized in Scheme 1, involved
cleavage of the C12ꢀC13 bond to give fragments
C1ꢀC12 (2) and C13ꢀC22 (3).6 Unsaturated ester 3 is
viewed as arising from an allylic alcohol 4 by selective
epoxidation followed by epoxide opening with
Me2CuLi. The allylic alcohol 4 may be further dissected
in a straightforward manner to give Weinreb amide 5.
Of the available options, we speculate that the desired
syn–syn stereocenters in 5 might be established through
a boron enolate mediated aldol reaction.
Br
+
8
Me Me Me Me
Me
C13-C22 (3)
Me
6
C1-C12 (2)
Horner-Emmons
OTBS
O
18
HO 15
Me
OiPr
1
Me Me
OH
4
O
MeO
N
Me
18
Synthesis of fragment C13ꢀC22 began with the known
acyloxazolidinone 6, which was most conveniently pre-
pared by acylation of the corresponding (S)-oxazolidi-
none (Scheme 2).7 Asymmetric aldol addition of the
boron enolate derived from oxazolidinone 6 with 2-(S)-
methylbutanal 7 gave the aldol adduct 8 as a crystalline
solid (mp 88°C) in 89% yield and >95:5 diastereoselec-
tivity (Scheme 2).8 Exchange of the oxazolidinone auxil-
iary in the all syn-aldol 8 with N,O-dimethylhydroxyl-
22
5
Me Me Me
Evans' aldol
Scheme 1.
* Corresponding author. Fax: +55-19-3788-3023; 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(01)02104-9

186
L. C. Dias, P. R. R. Meira / Tetrahedron Letters 43 (2002) 185–187
O
O
O
O
O
OH
1. DIBALH, CH2Cl2
1. n-Bu2BOTf
CH2Cl2, Et3N, -78°C
O
OTBS
18
18
Me
0 o
C
15
MeO
OTBS
O
N
O
N
Me
18
22
10
18
MeON
Me
6
Me Me
O
22
Me
2. (EtO)2POCH2CO2Me
THF, 0oC
8
20
Me Me Me
22
Bn
Bn
>95:5
H
7 Me
Me
Me Me
9
diastereoselection > 95:5
22 89%
(90%, 2 steps)
1. Me3Al, THF, 00C
MeONHMe.HCl
O
OTBS
OH
OTBS
O
m-CPBA
15
DIBALH
15
18
MeO
18
19
OTBS
N
Me
22
CH2Cl2 HO
Me
22
CH2Cl2
2. TBSOTf, 2,6-lutidine
CH2Cl2, 25oC
11
18
Me Me Me
Me Me
19
Me
0 oC, 96%
-23 oC, 90%
9
4
22
diastereoselection
>95:5
Me Me
83% (over 2 steps)
PMP
Scheme 2.
Me2CuLi
THF, 0 o
OH OH OTBS
O
15
O
OTBS
PPTS
C
16
18
18
15
17
Me
17
19
Me
MeO OMe
22
22
90%
amine generated the Weinreb amide, whose purification
was facilitated by isolation of the recyclable oxazolidi-
none chiral auxiliary (92%) by efficient crystallization
from the reaction mixture.9 Subsequent protection of
the alcohol functionality as its TBS ether cleanly pro-
vided the Weinreb amide 9, in 83% yield (over two
steps).
Me Me Me
diastereoselection
>95:5
Me Me Me
12
13
96%
Hb
Hc
OMe
16
O
15
JHa-Hb = 10.1 Hz
JHb-Hd = 11.2 Hz
JHb-Hc = 4.8 Hz
Me
O
PMP
R
17
Hd
Ha
13
H
Scheme 3.
This amide was smoothly reduced to the aldehyde on
treatment with diisobutylaluminum hydride at 0°C
(Scheme 3). This unpurified aldehyde was directly sub-
jected to a Horner–Emmons homologation with the
required phosphonate reagent to give a,b-unsaturated
ester 10 in 90% isolated yield over the two-step
sequence.10 Reduction of 10 with 2.2 equiv. of
diisobutylaluminum hydride at −23°C gave allylic alco-
hol 4 (90% yield). Epoxidation of allylic alcohol 4 with
m-CPBA proceeded with complete stereoselectivity
from the opposite side of the C19 tert-butyldimethyl-
silyl group to yield the anti-epoxy alcohol 11 as a single
product in high purity (96% yield, >95:5).6,11 It is
noteworthy that the diastereoselectivity associated with
this epoxidation was exceptional and compared in both
yield and selectivity to related transformations
described earlier by Isobe et al. and later by Miyashita
et al.11 Epoxide opening proceeded smoothly with high
regioselectivity after treatment of the epoxy alcohol 11
with Me2CuLi to give diol 12 in 90% yield and >95:5
selectivity, possessing the anti-anti–syn-syn stereochem-
istry for the five contiguous stereocenters.12 Although
the hydroxyl function at C17 in diol 12 should be
converted to a ketone carbonyl later in the synthesis,
this epoxidation/epoxide opening sequence enabled
control of the C16 stereocenter. Formation of p-
methoxybenzylidene acetal 13 was accomplished by
treatment of the corresponding diol with p-methoxy-
benzaldehyde dimethyl acetal and a catalytic amount of
PPTS (96% yield). The use of CSA instead of PPTS in
this reaction gave the secondary alcohol with loss of the
TBS protecting group. The stereochemical outcome of
the epoxide opening was determined by coupling con-
The stereochemistry of the secondary alcohols at C17
and C19 was determined on the basis of the 13C NMR
analysis of the corresponding 1,3-diol acetonide 15
(Scheme 4). Treatment of diol 12 with TBAF in THF
gave triol 14 in 98% yield. A sequence of selective
protection of the primary alcohol functionality in 14
followed by treatment with 2,2-dimethoxypropane and
catalytic amounts of PPTS gave acetonide 15 in 85%
yield for the two steps. 13C NMR observed resonances
at 23.7, 25.3, and 100.2 are characteristic of an anti
acetonide.13
Selective DIBALH-mediated acetal cleavage in 13 gave
the desired p-methoxybenzyl ether alcohol 16 in 94%
yield with complete regioselectivity (Scheme 5).14 Dess–
Martin periodinane oxidation15 of 16 under standard
conditions followed by Wittig10 type coupling with
carboethoxyethylidene–triphenylphosphorane in reflux-
ing CH2Cl2 gave a,b-unsaturated ester 3 (E:Z>95:5) in
90% overall yield for the two-step sequence, corre-
sponding to the C13ꢀC22 fragment of callystatin A.
OH OH OTBS
OH OH OH
TBAF, THF
98%
15
17
15
19
Me
17
19
Me
22
22
Me Me Me
Me Me Me
12
14
23.7
25.3
1. TBDPSCl
imidazole
DMF, 25 oC
Me Me
100.2
TBDPSO
O
O
1
15
stant analysis in the H NMR spectra of benzylidene
19
17
Me
2. Me2C(OMe)2
PPTS, 0 oC
22
acetal 13. The large vicinal coupling constants between
Ha–Hb (10.1 Hz) and Hb–Hd (11.2 Hz), together with
the small observed value between Hb–Hc (4.8 Hz)
unambiguously established the proposed 1,2-anti rela-
tive stereochemistry between C16 and C17.
Me Me Me
15
85% (2 steps)
Scheme 4.

L. C. Dias, P. R. R. Meira / Tetrahedron Letters 43 (2002) 185–187
187
PMP
O
Higuchi, K.; Aoki, S.; Kobayashi, M. Tetrahedron Lett.
1997, 38, 5533.
3. (a) Hamamoto, T.; Seto, H.; Beppu, T. J. Antibiot. 1983,
36, 646; (b) Absolute stereochemistry and synthesis of
leptomycin B: Kobayashi, M.; Wang, W.; Tsutsui, Y.;
Sugimoto, M.; Murakami, N. Tetrahedron Lett. 1998, 39,
8291.
PMB
O OTBS
DIBALH
CH2Cl2
1.Dess-Martin
CH2Cl2, rt
OH
O
15
OTBS
18
18
15
O
Me
EtO
0 oC, 94%
Me
2.
PPh3
Me
22
22
Me Me Me
Me Me Me
NOESY
16
13
CH2Cl2, ∆
(90%, 2 steps)
PMB
O OTBS
4. For total syntheses of callystatin A, see: (a) Murakami,
N.; Wang, W.; Aoki, M.; Tsutsui, Y.; Sugimoto, M.;
Kobayashi, M. Tetrahedron Lett. 1998, 39, 2349; (b)
Crimmins, M. T.; King, B. W. J. Am. Chem. Soc. 1998,
120, 9084; (c) Smith, A. B., III; Brandt, B. M. Org. Lett.
2001, 3, 1685; (d) Kalesse, M.; Quitschalle, M.; Khan-
davalli, C. P.; Saeed, A. Org. Lett. 2001, 3, 3107.
5. For previous synthesis of C13ꢀC22 fragment of
callystatin A, see: (a) Marshall, J. A.; Fitzgerald, R. N. J.
Org. Chem. 1999, 64, 4477; (b) Marshall, J. A.; Schaaf,
G. M. J. Org. Chem. 2001, 66, 7825.
OEt
H
18
O
13
Me
15
22
Me Me Me Me
E:Z > 95:5
C13-C22 fragment (3)
Scheme 5.
The E-geometry for ester 3 was confirmed by the
illustrated NOESY interaction between vinylic hydro-
gen at C15 and hydrogens of the ethyl group. Ester 3 is
a very useful intermediate to be used in the synthesis of
callystatin A, by the same strategies already used by
others4.
6. The numbering of 1 as well as of each intermediate
follows that suggested in Ref. 1.
7. Gage, J. R.; Evans, D. A. Org. Synth. 1990, 68, 83.
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Tetrahedron Lett. 1980, 21, 4675.
9. Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun.
The 12-step sequence from 6 to 3 proceeded in an
overall yield of 42% and is amenable to a multigram
scale-up. Thus, the synthesis of C13ꢀC22 fragment of
callystatin A has been described. Notable features of
this approach include an efficient syn aldol reaction, a
diastereoselective epoxidation of an allylic alcohol fol-
lowed by epoxide opening with Me2CuLi, and a
diastereoselective Wittig coupling. As a result, the route
to the C13ꢀC22 fragment presented here is, in principle,
readily applicable for the preparation of callystatin A
and additional analogs. Efforts are being undertaken to
complete the total synthesis of callystatin A and these
studies will be described in a full account of this work.16
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Acknowledgements
We are grateful to FAPESP and CNPq for financial
support. We thank also Professor Carol H. Collins,
from IQ-UNICAMP, for helpful suggestions about
English grammar and style.
14. Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem.
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