one of which allows access to bacillariolides I and III, while
the other provides access to bacillariolide II.
Scheme 2
The unique feature of our strategy lies in the stereodiver-
gency that allows access to both the diastereomeric series
from a common precursor. Retrosynthetically, bacillariolide
I/III may be obtained through hydroxylation of the cyclo-
pentene 1, which in turn would be available from the
unsaturated ester 2 (Scheme 1). The unsaturated ester 2 is
Scheme 1
appropriately functionalized to deliver the lactone ring at one
side and the cyclopentene ring on the other side, with the
desired anti stereochemistry between the hydrogens at C-6
and C-7. A similar consideration depicts that the unsaturated
ester 4 will be required for the construction of the diaster-
eomeric bicyclic lactone 3 for entry into bacillariolide II.
An ortho ester Claisen rearrangement of the allyl alcohol 6
derived from the R-(+)-glyceraldehyde derivative 56 will give
rise to the stereodivergency, providing the required diaster-
eomeric unsaturated esters 2 and 4.
Initially we focused our attention on the construction of
the bicyclic lactones 1 and 3 from the unsaturated esters 2
and 4, respectively. The unsaturated esters 2 and 4 were
prepared according to our previously published procedure.6d
We needed to construct the cyclopentene derivative, for
example, 10 (Scheme 2), in which the ketal unit is cis to the
ester group so as to facilitate lactone formation. However,
earlier we have observed6d that alkylation of the enolate of
the ester 4a with allyl bromide, followed by ring-closing
metathesis (RCM)7 of the resulting mixture of the diene 7a
and its syn isomer with Grubbs’ catalyst (PCy3)2Cl2Rud
CHPh 8, led to a mixture of the cyclopentene 9a and its
cis-isomer in 3:1 ratio. Thus, it is necessary to convert the
trans-cyclopentene derivative 9 to the cis-cyclopentene 10a.
On the basis of Houk’s model8 for addition of electrophiles
to CdC double bonds having a R-chiral center, we antici-
pated that alkylation of the enolate derived from the
cyclopentene ester 9 with an electrophile would take place
from the side of the smallest group (H atom in the present
case) of the chiral center to produce the cis-analogue 10 (R4
* H). Subsequent lactone formation and removal of the group
(R4) would provide the desired bicyclic framework of bacill-
ariolides. To this end, alkylation of the enolate of the ester
9a with PhSeBr led to reversal of the cis/trans ratio from
1:3 to 2.5:1 with the cis-isomer 11a being the major product.
(5) (a) Seo, S. Y.; Jung, J. K.; Paek, S. M.; Lee, Y. S.; Kim, S. H.; Lee,
K. O.; Suh, Y. G. Org. Lett. 2004, 6, 429. (b) Miyaoka, H.; Tamura, M.;
Yamada, Y. Tetrahedron Lett. 1998, 39, 621. (c) Miyaoka, H.; Tamura,
M.; Yamada, Y. Tetrahedron 2000, 56, 8083.
(6) (a) For a review on the application of R-(+)-glyceraldehyde derivative
in synthesis, see: Jurczak, J.; Pikul, S.; Bauer, T. Tetrahedron 1986, 42,
447. For our own work in this area, see: (b) Nayek, A.; Banerjee, S.; Sinha,
S.; Ghosh, S. Tetrahedron Lett. 2004, 45, 6457. (c) Sarkar, N.; Nayek, A.;
Ghosh, S. Org. Lett. 2004, 6, 1903. (d) Banerjee, S.; Ghosh, S.; Sinha, S.;
Ghosh, S. J. Org. Chem. 2005, 70, 4199.
(7) For a recent review on the RCM reaction, see: Nicolaou, K. C.;
Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490.
(8) Mengel, A.; Reiser, O. Chem. ReV. 1999, 99, 1191.
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