DOI: 10.1002/chem.201000840
Catalytic Asymmetric Synthesis of trans-Configured b-Lactones: Cooperation
of Lewis Acid and Ion Pair Catalysis
Thomas Kull,[b] Josꢀ Cabrera,[a, b] and Renꢀ Peters*[a]
Abstract: The development of the first
trans-selective catalytic asymmetric
[2+2] cyclocondensation of acyl hal-
ides with aliphatic aldehydes furnishing
3,4-disubstituted b-lactones is de-
scribed. This work made use of a new
strategy within the context of asymmet-
ric dual activation catalysis: it com-
bines the concepts of Lewis acid and
organic aprotic ion pair catalysis in a
single catalyst system. The methodolo-
gy could also be applied to aromatic al-
dehydes and offers broad applicability
(29 examples). The utility was further
demonstrated by nucleophilic ring-
opening reactions that provide highly
enantiomerically enriched anti-aldol
products.
Keywords: anti-aldol
· catalysis ·
enolates · ketenes · pyridinium
Introduction
Various bioactive natural and synthetic products possess-
ing a b-lactone structural motif can act as specific enzyme
inhibitors.[11,12] Among the derivatives of natural products,
tetrahydrolipstatin (orlistat, Xenical) has been identified as
an anti-obesity agent and is available as over-the-counter
weight-loss medication in a number of countries. Of late,
trans-configured b-lactones such as tetrahydrolipstatin have
generated renewed interest due to the recent findings that
they can serve as specific inhibitors of fatty acid synthase
(FAS-TE), which is an approved drug target for cancer
treatment.[13] Owing to the significant activity of trans-con-
figured b-lactones, a number of approaches have been re-
ported for their synthesis.[12b,14] Unfortunately, the [2+2] cy-
cloaddition approach using ketenes and aldehydes provides,
in general, cis isomers as the major products. To the best of
our knowledge, there is only one [2+2] cycloaddition avail-
able for the catalytic enantioselective formation of trans-
configured b-lactones,[9b] which appears to be limited to the
use of aromatic aldehydes, whereas many bioactive systems,
such as tetrahydrolipstatin, carry an aliphatic chain at the 4-
position of the 3,4-disubstituted 2-oxetanone.[15–18]
The aim of the present work was to develop a trans-selec-
tive catalytic asymmetric [2+2] cyclocondensation of acyl
halides 1 and aliphatic or aromatic aldehydes 2.[19] A solu-
tion to this problem would provide a protocol for the chal-
lenging catalytic enantioselective anti-aldol addition reac-
tions.[20] The development of such a methodology was based
upon the idea that if an enolate such as 5, and not a ketene
such as 4, represented the reactive intermediate, the trans-
configured product would be expected to be formed in pref-
erence by activation of the aldehyde with a mono-coordinat-
Although b-lactones are fairly reactive four-membered het-
erocyclic ring systems, they were already described in
1883.[1,2] b-Lactones offer rich potential as synthetic inter-
mediates[3] and, most importantly, they can be viewed as
masked and activated aldol products because they readily
undergo nucleophilic ring-opening reactions as a result of
their intrinsic ring strain, which is similar to that of epoxides
(b-lactones: ca. 23 kcalmol1; epoxides: ca. 27 kcalmol).[4]
Various hard nucleophiles, such as metal alkoxides, amines,
ꢀ
or C-nucleophiles can regioselectively cleave the acyl
oxygen bond providing the corresponding aldol adducts in a
divergent manner.[3,5] Accordingly, the development of cata-
lytic, asymmetric [2+2] cycloadditions of ketenes[6] and al-
dehydes[7–9] offers the possibility of replacing catalytic asym-
metric aldol reactions, which often require the preformation
and isolation of enolate equivalents such as silyl ketene ace-
tals.[10]
[a] Dr. J. Cabrera, Prof. Dr. R. Peters
Institut fꢀr Organische Chemie
Universitꢁt Stuttgart, Pfaffenwaldring 55
70569 Stuttgart (Germany)
Fax : (+49)711-685-64321
[b] Dr. T. Kull, Dr. J. Cabrera
ETH Zꢀrich, Laboratory of Organic Chemistry
Wolfgang-Pauli-Str. 10
8093 Zꢀrich (Switzerland)
Supporting information for this article is available on the WWW
9132
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 9132 – 9139