via oxidative cleavage of the PMB protecting group with
DDQ and subsequent DMP oxidation of the resulting primary
hydroxyl group in 74% overall yield.
While RCM was initially performed in CH2Cl2, the use of
1,2-dichloroethane enabled the reaction to be conducted at
higher temperature, thus resulting in shorter reaction times
and allowing for reduced catalyst loads (<0.14 equiv of
catalyst, 1.5 h at reflux versus >0.20 equiv of catalyst, 7 h
at reflux in CH2Cl2). Removal of the TBS groups with
HF·pyridine followed by selective reduction of the disubsti-
tuted endocyclic double bond with in situ generated diimide
(from di-K azodicarboxylate (PADA), ca. 80 equiv)30 and
finally hydrogenolytic removal of the benzyl protecting
groups furnished target structure 4 in very good overall yield
(50-57% for the 3-step sequence from 24). Direct catalytic
hydrogenation (Pd/C; ambient pressure) of the partially
deprotected diene obtained after TBS removal, i.e., without
prior reduction of the endocyclic double bond, led to
complete cleavage of the benzyl groups within 5 h. However,
the reduction of the endocyclic double bond did not reach
completion under these conditions, with the reaction failing
to progress beyond ca. 70% conversion at 6 h. No attempts
were made to conduct the hydrogenation at higher pressure,
given the potential vulnerability of the side chain double bond
under more forcing conditions.
It should be noted here that the double silylation leading
to 22 was best carried out in two separate steps, which
involved reaction of the reduction product of 21 with 6 equiv
of TBSCl and then treatment of the resulting 7:2-mixture of
mono-TBS ethers with 1.6 equiv of TBSOTf. While this
procedure provided 22 in 81% yield from the starting diol,
direct treatment of the latter with 2.1 equiv of TBSOTf
gave incomplete conversion, and reaction with a larger
excess of TBSOTf was associated with the formation of
several unidentified side products, thus furnishing only
57-69% of 22.
To reconfirm the stereochemical outcome of the 1,3-
reduction in 21 (Scheme 5), the resulting diol was converted
to the corresponding acetonide (2,2-dimethoxypropane, cat.
CSA, 75%). The 13C chemical shifts of the two ketal methyl
groups in this derivative were observed at 24.01 and 23.96
ppm, while the quaternary ketal carbon signal appeared at
100.96 ppm. These data are in excellent agreement with the
predicted shifts for acetonides of anti-1,3-diols, which
preferentially adopt a twist-boat conformation with both anti-
substituents in equatorial positions.26
Assessment of the antiproliferative activity of peloruside
A analogue 4 in three human cancer cell lines revealed the
compound to be several-hundred-fold less potent than
peloruside A (1) or B (2). (IC50 values against MCF-7/
HCT116 > 20 µM; IC50 against A549 ) 16.4 µM). In light
of the substantial structural changes relative to 1 or 2, this
result may not seem too surprising, but the observation of
micromolar activity against the A549 cell line is still
encouraging. On the basis of the chemistry developed for
the synthesis of 4, we will now attempt to improve the
activity of this analogue through structural modifications in
the C4-C6 region (analogue numbering, Figure 1). At the
same time, the chemistry developed in the course of this work
for the synthesis of intermediates 8 and 5 could offer a new
entry into the synthesis of the natural products peloruside A
and B. Studies along these lines are currently in progress in
our laboratory.
The elaboration of building blocks 6, 7, and 8 into
peloruside A analogue 4 was initiated with the addition of
the vinyl lithium species derived from 7, by treatment with
t-BuLi, to aldehyde 8 at -78 °C (Scheme 6). The reaction
proceeded with modest selectivity to produce a ca. 2:1
mixture of allylic alcohols 5 and 23 (in favor of the desired
diastereomer 5) in scale-dependent yields. Thus, while 5/23
were obtained in 54% yield on a 0.15 mmol scale for 8,
yields increased to 61% and 84% for reactions with 0.41
and 0.82 mmol of 8, respectively. As the mixture of 5 and
23 could not be separated by FC, it was oxidized with DMP
and the resulting ketone was stereoselectively reduced with
(R)-B-Me-CBS/catecholborane.27 On the basis of this oxida-
tion/reduction sequence, 5 could be obtained in stereochemi-
cally pure form and 46% yield for the two-step sequence
from the 5/23 mixture. The absolute configuration of the
newly established chiral center was again verified by Mosher
ester analysis.24
Acknowledgment. This work was supported by the ETH
Zu¨rich (Grant TH-25 06-3). We are indebted to Dr. Bernhard
Pfeiffer (ETHZ) for NMR support, to Kurt Hauenstein
(ETHZ) for advice, and to Louis Bertschi from the ETHZ-
LOC MS-Service for HRMS spectra.
Yamaguchi esterification28 of acid 6 with allylic alcohol
5 followed by RCM of the resulting ester intermediate with
Grubbs II catalyst29 provided E-configured macrolactone 24
as the only isolable cyclization product in 65-80% yield.
Supporting Information Available: Synthetic procedures,
1
complete spectroscopic data, and H and 13C NMR spectra
(24) Hoye, T. R.; Jeffrey, C. S.; Shao, F. Nat. Protoc. 2007, 2, 2451.
(25) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560.
for all compounds. This material is available free of charge
(26) (a) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990,
31, 945. (b) Tormena, C. F.; Dias, L. C.; Rittner, R. J. Phys. Chem. A
2005, 109, 6077.
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(27) Corey, E. J.; Roberts, B. E. J. Am. Chem. Soc. 1997, 119, 12425.
(28) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
(30) Biswas, K.; Lin, H.; Njardarson, J. T.; Chappell, M. D.; Chou, T.-
C.; Guan, Y.; Tong, W. P.; He, L.; Horwitz, S. B.; Danishefsky, S. J. J. Am.
Chem. Soc. 2002, 124, 9825.
(29) Scholl, M.; Trnka, T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron
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