Angewandte
Chemie
DOI: 10.1002/anie.201402332
Asymmetric Catalysis
Direct Catalytic Asymmetric Vinylogous Conjugate Addition of
Unsaturated Butyrolactones to a,b-Unsaturated Thioamides**
Liang Yin, Hisashi Takada, Shaoquan Lin, Naoya Kumagai,* and Masakatsu Shibasaki*
Abstract: Soft Lewis acid/Brønsted base cooperative catalysts
have enabled direct catalytic asymmetric vinylogous conjugate
addition of a,b- and b,g-unsaturated butyrolactones to a,b-
unsaturated thioamides with perfect atom economy. When
using a-angelica lactone and its derivatives as pronucleophiles,
as little as 0.5 mol% catalyst loading was sufficient to complete
the reaction necessary to construct consecutive tri- and
tetrasubstituted stereogenic centers in a highly diastereo- and
enantioselective fashion.
pounds.[5,6] The direct use of butenolides as pronucleophiles
instead of 2-siloxyfurans[7–11] obviates undesired co-genera-
tion of silicon-derived by-products and the preactivation of
butenolides, thus enabling an atom-economical entry into
chiral building blocks bearing butenolide units.[12] The direct
use of g-butenolide in catalytic asymmetric conjugate addi-
tion was pioneered by Trost et al.,[13] and several reports from
other groups demonstrated the synthetic utility of the direct
conjugate addition.[14] However, the use of inherently less
reactive a,b-unsaturated carboxylic acid derivatives as an
electrophile has not been reported yet. In this context, we
directed our efforts toward merging the specific activation of
a,b-unsaturated thioamides and the utility of unsaturated
butyrolactones as pronucleophiles in soft Lewis acid/Brønsted
base cooperative catalysis (Scheme 1).[2]
Catalytic asymmetric conjugate additions are one of the
most widely used methodologies in asymmetric carbon–
carbon bond-forming reactions.[1] Compared with highly
reactive enones, enals, and a,b-unsaturated nitroolefins, a,b-
unsaturated carboxylic acid derivatives have been much less
explored as Michael acceptors because of their inherently low
electrophilicity. In the context of our continuing program of
research in soft Lewis acid/hard Brønsted base cooperative
catalysis,[2] specific activation of soft Lewis-basic a,b-unsatu-
rated thioamides by a soft Lewis acid is key to compensating
for the intrinsic low electrophilicity. Herein, we document the
catalytic asymmetric vinylogous conjugate addition of a,b-
and b,g-unsaturated butyrolactones to a,b-unsaturated thio-
amides, a reaction allowing the generation of consecutive tri-
and tetrasubstituted stereogenic centers.[3]
Butenolide units that feature a five-membered g-lactone
with unsaturation at a,b-carbon atoms occur in a wide range
of natural products and biologically active compounds.[4] This
ubiquitous nature of butenolides has attracted considerable
attention regarding the development of a synthetic method-
ology for optically active butenolide-containing com-
Scheme 1. Direct catalytic asymmetric vinylogous conjugate addition
of unsaturated butyrolactones to an a,b-unsaturated thioamide by
a soft Lewis acid/Brønsted base cooperative catalysis.
We set out to identify the optimal combination of a soft
Lewis acid and Brønsted base in the reaction of g-crotono-
lactone (1a) with the a,b-unsaturated thioamide 2a (Table 1).
[Cu(CH3CN)4]PF6/(R)-Segphos/Li(OC6H4-p-OMe)
[*] Dr. L. Yin, Dr. H. Takada, S. Lin, Dr. N. Kumagai,
Prof. Dr. M. Shibasaki
Institute of Microbial Chemistry (BIKAKEN)
3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021 (Japan)
E-mail: nkumagai@bikaken.or.jp
shibasaki-lab/index_e.html
(5 mol%) produced the best reaction outcome, as it afforded
3a with a yield of 84% and 98% ee, and the designated
syn diastereomer was obtained exclusively.[15] The use of
other soft Lewis acidic metal salts in combination with (R)-
Segphos proved the superior catalytic efficiency of the
copper(I) catalyst (entry 2 versus entries 7–9). Because
Li(OC6H4-p-OMe) had to be prepared from nBuLi and
HOC6H4-p-OMe just before use under anhydrous conditions,
the alternative use of amine bases was advantageous for
operational simplicity. DBU did not facilitate the reaction,
but 50 mol% of either Et3N or Cy2NMe was effective in
producing 3a with comparable stereoselectivity (entries 10–
12). Cy2NMe afforded a slightly better yield and the catalyst
loading could be further reduced to 2.5 mol% with Cy2NMe
(entry 13).
Prof. Dr. M. Shibasaki
JST, ACT-C
3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021 (Japan)
[**] This work was financially supported by JSPS KAKENHI (Grant
Number 25713002) and JST, ACT-C. L.Y. thanks JSPS for a postdoc-
toral fellowship. Akinobu Matsuzawa is gratefully acknowledged for
technical assistance in X-ray crystallographic analysis of 7m. We
thank Dr. Ryuichi Sawa and Yumiko Kubota for technical support in
NMR analysis.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2014, 53, 5327 –5331
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5327