Angewandte
Chemie
DOI: 10.1002/anie.201205416
Gold Catalysis
Anion-Induced Enantioselective Cyclization of Diynamides to
Pyrrolidines Catalyzed by Cationic Gold Complexes**
Asmaa Kamal Mourad, Juliane Leutzow, and Constantin Czekelius*
Dedicated to Professor Konstantin-Alexander Hossmann on the occasion of his 75th birthday
In the area of homogeneous catalysis few metals have
received as much attention as gold in recent years, resulting
in the discovery of a plethora of mechanistically diverse
reactions.[1] The ability of gold complexes to activate C C
À
multiple bonds towards the attack of various nucleophiles
under mild conditions makes this catalyst class highly
valuable for the formation of unusual and complex structural
motifs.[2–4] Enantioselective methods employing optically
active gold catalysts are more limited in number.[5] Reliable
methods using chiral phosphine or carbene ligands have been
developed in particular for the transformation of allenes and
Scheme 1. Enantioselective desymmetrization of 1,4-diynamides.
enynes.[6] In contrast, only few examples of the enantioselec-
tive heterofunctionalization of simple alkynes have been
reported.[7,8] Terminal alkynes in particular have proven to be
very difficult substrates. This can be explained by the linear
coordination geometry in gold(I)–alkyne complexes which
results in a large distance between the chiral ligand and the
incoming nucleophile. Based on the development of chiral
Brønsted acids by Akiyama et al., Toste and co-workers
reported the application of chiral counteranions in gold
catalysis, thereby greatly extending the possibilities for
stereocontrol, as exemplified by the functionalization of
allenes.[9,10]
methylene pyrrolidine products incorporate an all-carbon-
substituted quaternary stereocenter. Such scaffolds are found
in many natural products, such as alkaloids, but are very
challenging to prepare in enantiomerically pure form.[12,13]
The diynamide substrates 3a–g were prepared from the
corresponding diynals 1a–g by formation of p-tosyl imines
2a,b and subsequent reduction with NaBH4 or by the SN2
displacement of p-toluene sulfonates 2c–g with p-toluene
sulfonamide (Scheme 2).[11a,14]
Recently, we have developed a new methodology for the
gold-catalyzed cyclization of 1,4-diynes.[7a,11] We have dem-
onstrated that diynols and diynamides can be effectively
cyclized by cationic gold complexes to give the corresponding
unsaturated heterocycles. However, in the screening of
optically active phosphine and carbene ligands, products
with enantioselectivities of only up to 60% ee were obtai-
ned.[7a,11] Herein we disclose the efficient enantioselective
cycloisomerization of diynamides which is the first example of
a highly stereoselective desymmetrization of terminal alkynes
by gold catalysts with chiral counteranions (Scheme 1). The
Scheme 2. Preparation of 1,4-diynamides.
With the substrates in hand we first investigated suitable
conditions for their gold-catalyzed cycloisomerization. It was
found that cationic gold complexes could efficiently catalyze
the formation of the methylene pyrrolidines (Table 1).[15]
When catalysts incorporating various chiral phosphines
were used, the products were isolated in yields up to 93%
but very low enantioselectivities were observed (Table 1,
entry 4).
Given these discouraging results with chiral ligands we
investigated cationic gold complexes with optically active
counteranions derived from binol hydrogen phosphate.[17] We
could show that such catalysts are indeed active for the
intended cycloisomerization (Table 2). Closely related gold
[*] A. K. Mourad, J. Leutzow, Dr. C. Czekelius
Institute for Chemistry and Biochemistry
Freie Universitꢀt Berlin
Takustrasse 3, 14195 Berlin (Germany)
E-mail: cczekeli@chemie.fu-berlin.de
A. K. Mourad
Fayoum University, University Zone
Fayoum, 63514 (Egypt)
[**] This work was generously supported by the DFG in the context of
the Emmy-Noether program (CZ 183/1). A.K.M. is grateful for
a DAAD doctoral fellowship. We thank Dr. Roman Rꢁttinger for
experimental work employing chiral phosphine ligands (Table 1).
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2012, 51, 11149 –11152
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
11149