Angewandte
Chemie
DOI: 10.1002/anie.200902385
Multicomponent Reactions
Brønsted Acid Catalyzed Enantioselective Three-Component Reaction
Involving the a Addition of Isocyanides to Imines**
Tao Yue, Mei-Xiang Wang,* De-Xian Wang, Gꢀraldine Masson, and Jieping Zhu*
The Passerini three-component reaction (P-3CR)[1] and the
Ugi four-component reaction (U-4CR)[2] are two of the most
important multicomponent reactions (MCRs) known to date.
Because of the mildness of reaction conditions, the wide
application scope, and the high variability (four diversity
points for U-4CR) they are ideally suited for generating
molecular diversity and complexity; they are widely used in
the syntheses of natural products and medicinally relevant
compounds.[3] In these reactions, one chiral center is created,
which results from the a addition of divalent isonitrile carbon
atom to polarized double bonds (carbonyl or imine groups),
therefore the ability to control the stereochemical outcome
would significantly expand their synthetic utility. Although
diastereoselective P-3CR[4] and U-4CR[5] using chiral sub-
strates or chiral auxiliaries have been reported,[6] the develop-
ment of an enantioselective version of these reactions remains
a significant challenge. In spite of the great efforts dedicated
to this field, only limited success has been made, thereby
highlighting the difficulties associated with the development
of such a catalyst.[7] In this context, Denmark and Fan
developed an elegant Lewis base catalyzed enantioselective
two-component Passerini reaction.[8] Dꢀmling and co-workers
discovered that a stoichiometric amount of a titanium–taddol
(taddol = 1,1,4,4-tetraphenyl-2,3-O-isopropylidene-d-threi-
tol) complex was capable of promoting the P-3CR reaction to
afford the a-acyloxyamides in moderate enantioselectivi-
ties.[9] Schreiber and co-workers demonstrated that an indan
copper(II)–pybox (pybox = pyridine-2,6-bisoxazoline) com-
plex was able to catalyze the P-3CR; however, the enan-
tioenriched Passerini adducts were obtained only when
chelating aldehydes were used as reaction partners.[10] We
have recently reported that the chiral aluminum–salen
(salen = N,Nꢁ-bis(salicylidene)ethylenediamine) complex[11]
was an efficient catalyst for the enantioselective Passerini
three-component reaction.[12] All these enantioselective cata-
lytic processes involve an a addition of isocyanides to
aldehydes as a key step. To the best of our knowledge, there
is no single report on Ugi-type reactions which involve the
a addition of isocyanides to imines for generating the chiral
centers. As a continuation of our interests in developing
enantioselective isocyanide-based transformations, we report
herein that the chiral phosphoric acid 5g is able to catalyze
the three-component reaction of the aldehydes 2, anilines 3,
and a-isocyanoacetamides 4, leading to 2-(1-aminoalkyl)-5-
aminoxazoles (1) in excellent yields and moderate to good
enantioselectivities (Scheme 1).[13]
Scheme 1. Chiral phosphoric acid catalyzed enantioselective a addition
of a-isocyanoacetamides to imines: Three-component synthesis of
2-(1-aminoalkyl)-5-aminooxazoles.
[*] T. Yue, Dr. M.-X. Wang, Dr. D.-X. Wang
National Natural Laboratory for Molecular Sciences
Laboratory of Chemical Biology, Institute of Chemistry
Chinese Academy of Sciences, Beijing 100190 (China)
and
Chiral phosphoric acids are now well-established as
bifunctional organocatalysts, particularly in catalyzing the
addition of nucleophiles to imines/acylimines.[14,15] As a
prelude of our work, we examined the reaction of the
preformed imine 6a (R1 = tBu) and the a-isocyanoacetamide
4a (R2 = Bn)[16] in the presence of chiral phosphoric acids.[17]
As it can be seen from Table 1, all the phosphoric acids
investigated were able to catalyze the oxazole formation,
however the enantioselectivity varied significantly with 5g
and 5l being the most efficient. The N-triflyl phosphoramide
5o,[18] a stronger Brønsted acid than 5l, efficiently catalyzed
the reaction but with reduced asymmetric induction (Table 1,
entry 18). Among the solvents screened, toluene was found to
be the most appropriate (Table 1, entries 19–21). Overall, the
optimum conditions consisted of performing the reaction in
toluene (c = 0.05m) at À208C in the presence of 5g or 5l
(0.2 equiv) as a catalyst. Oxazoles synthesized under these
The Key Laboratory of Bioorganic Phosphrous Chemistry and
Chemical Biology (Ministry of Education), Department of Chemistry
Tsinghua University, Beijing 100084 (China)
E-mail: mxwang@iccas.ac.cn
Dr. G. Masson, Dr. J. Zhu
Institut de Chimie des Substances Naturelles, CNRS
91198 Gif-sur-Yvette Cedex (France)
E-mail: zhu@icsn.cnrs-gif.fr
[**] We gratefully acknowledge the National Science Foundation of
China (NSFC), the Chinese Academy of Science, and CNRS, ANR
(France) for financial support.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2009, 48, 6717 –6721
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6717