and trimethylorthoformate, was performed in toluene at 80
°C. The endo adduct 8 was isolated in 61% yield after
chromatography along with less than 5% of the correspond-
ing exo adduct and less than 5% of the adduct resulting from
the cycloaddition with the minor ent-5. The configuration
of the newly created asymmetric centers in 8 was deduced
after NOESY experiments as illustrated in Figure 1. In
Unexpectedly, this compound proved to be unstable and,
for this reason, was subjected without purification7 to
oxidation-hydrolysis3 affording the aldehyde 12. γ,δ-
Unsaturated aldehyde 12 was purified without isomerization
or epimerization and was isolated in 51% overall yield from
9. Ketol 13, a precursor of aminoisoborneol hydrochloride
6,3 was recovered at this stage in 98% yield.
8
Oxidation of aldehyde 12 with buffered NaClO2 was
followed by â-lactone ring formation of the resulting acid
with PhSO2Cl using the previously reported conditions.9 The
â-lactone 14 was thus isolated in 50% yield. Hydrogenation
of the double bond with concomitant hydrogenolysis of the
benzyloxy group gave rise nearly quantitatively to the known
â-lactone 15.4,9 Compound 15 was finally coupled with (S)-
N-formylleucine under Mitsunobu conditions (for this step,
DIAD gave better results than DEAD) and afforded tetrahy-
drolipstatin 110 in 93% yield (Scheme 3): mp 42 °C (mp4,9
4,9
40-42 °C); [R]20 ) -32.0 (c 0.74, CHCl3); [R]20
)
D
D
Figure 1.
-33.0 (c 0.79, CHCl3).
agreement with semiempirical calculations, this cycloaddition
is controlled by HOMO dipole-LUMO dipolarophile
interactions.3b
Scheme 3
Reduction-oxidation of the ester group in 8 gave rise to
the aldehyde derivative 9 in 88% yield.6 In the following
step, the Wittig chain elongation was very sensitive to the
presence of salt. When phophorane 10 was generated by
deprotonation of the corresponding phosphonium bromide
n
salt with BuLi, NaHMDS, or KHMDS, the reaction was
very slow and afforded compound 11 in poor yield. However,
when 10 was generated with NaNH2 in boiling THF followed
by filtration of NaBr, the resulting solution reacted instan-
taneously with aldehyde 9 at -78 °C and gave rise to the
expected compound 11 as the Z isomer (Scheme 2).
Scheme 2
Following this strategy, the synthesis of tetrahydrolipstatin
1 was completed in 11 steps and 14% overall yield from the
known aldehyde 4 and in 14 steps and 5.58% overall yield
(81.4% for each step) from the commercially available
(4) ee was determined by 1H NMR analysis of the corresponding
O-acetylmandelate ester of alcohol 3; see: Hanessian, S.; Tehim, A.; Chen,
P. J. Org. Chem. 1993, 58, 7768.
(5) The same compound has been described under the racemic form:
Oblin, L.; Parrain, J.-L.; Rajzmann, M.; Pons, J.-M. J. Chem. Soc., Chem.
Commun. 1998, 1619.
(6) Direct reduction of the ester 8 with DIBAH gave aldehyde 9 in 76%
yield.
(7) Under these conditions, the Wittig resulting compound 11 was
obtained in 80% yield as a crude product. As degradation occurred during
purification, crude 11 was taken in the next reaction.
(8) Kraus, G. A.; Tashner, M. J. J. Org. Chem. 1980, 45, 1175.
(9) Barbier, P.; Schneider, F. HelV. Chim. Acta 1987, 70, 196.
(10) New compounds are characterized by 1H and 13C NMR spectra,
HRMS, and optical rotation.
754
Org. Lett., Vol. 1, No. 5, 1999