Communications
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adduct, the corresponding substrate for the lipase reaction,
was among the lowest in the DCL in the absence of the
enzyme. Nevertheless, 3–6 was the main compound selected
as a substrate for the transesterification. A minor amount of
the 1–6 ester, derived from 4-trifluoromethylbenzaldehyde
(1) and 2-nitropropane (6), was also formed in the reaction.
The two final products were obtained in a combined overall
yield of 24% after 24 h, although the resolution of the two
products could be identified earlier in the reaction. Better
yields were observed after longer reaction times; the products
were obtained in over 80% yield (3–6 ester: 52%, 1–6 ester:
33%) after 14 days (Figure 2d). The reaction proceeded
almost to completion (95% yield) in 20 days. The amplifica-
tion was slightly improved when the reactions were per-
formed at ambient temperature and when less enzyme was
used; however, the time required also increased (65% yield
after 14 days).
The nitroaldol–lipase DCR process does not only amplify
specific b-nitroalcohol derivatives, but also leads to their
asymmetric discrimination. HPLC analysis showed that the
enantioselectivity of the process is very high: The R enan-
tiomer of the 3–6 ester was resolved to 99% ee, and the
R enantiomer of the 1–6 ester to 98% ee. The Mosher method
was used to determine the absolute configuration of the
products.[17,18]
In conclusion, we have identified the nitroaldol (Henry)
À
reaction as a new and efficient C C bond-forming route to
DCL formation. Furthermore, we have demonstrated that
primary DCLs under thermodynamic control can be coupled
successfully to a secondary synthetic process mediated by a
lipase under kinetic control. This dynamic combinatorial
resolution process was used to generate a collection of
potential enzyme substrates and to identify the best substrates
for the lipase PS-C I from Pseudomonas cepacia. When the
formation of a nitroaldol DCL was combined with lipase-
mediated transesterification in a one-pot process, complete
asymmetric resolution of the library occurred to produce
enantiomerically pure b-nitroacetates in high yield.
Received: September 12, 2006
Published online: December 15, 2006
Keywords: aldol reaction · combinatorial chemistry ·
.
dynamic chemistry · enzyme catalysis · reversible reactions
950
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Angew. Chem. Int. Ed. 2007, 46, 948 –950