Communications
DOI: 10.1002/anie.201102405
Asymmetric Catalysis
Highly Enantioselective Catalytic Synthesis of Functionalized Chiral
Diazoacetoacetates**
Xinfang Xu, Wen-Hao Hu, and Michael P. Doyle*
The Michael reaction is one of the most general and versatile
methods for carbon–carbon bond formation,[1] and its
Mukaiyama–Michael variant provides an efficient strategy
for the addition of silyl enol ethers to a,b-unsaturated
carbonyl compounds.[2] Catalytic asymmetric reactions with
broad variations in the a,b-unsaturated carbonyl compounds
and chiral catalysts (Lewis acid and Brønsted acid) are well
documented,[3,4] and the enantioenriched 1,5-dicarbonyl com-
pounds formed from these reactions have proven to be useful
building blocks. However, there has been limited variation in
the silyl enol ethers used in these reactions, and none of them
have incorporated multiple functional groups.
We have recently reported condensation reactions of
Scheme 1. Synthesis of diazoacetoacetates by condensation reactions
of 1a. TBS=tert-butyldimethylsilyl, Tf=trifluoromethanesulfonyl.
methyl 3-(trialkylsilanoxy)-2-diazo-3-butenoates (e.g. 1a) in
Mukaiyama–aldol,[5] Mukaiyama–Michael,[6] and Mannich[5]
processes (Scheme 1) in our efforts to construct functional-
ized diazo compounds. These reactions are especially facile
because of the stabilization afforded by the diazo functional
group to the intermediate formed by electrophilic addition
(E+ + 1a!5). The resulting multifunctional diazoacetoace-
tates have proven to be valuable building blocks for the
efficient synthesis of functionally complex organic com-
pounds.[5,7] However, attempts to construct chiral multifunc-
tional diazoacetoacetates have only been moderately suc-
cessful, with the only example being the asymmetric catalytic
Mukaiyama–aldol reactions of a limited array of aromatic
aldehydes with 1a in the presence of a AgF/(R)-binap
(binap = 2,2ꢀ-bis(diphenylphosphanyl)-1,1ꢀ-binaphthyl) cata-
lyst.[8] We now report the first examples of a broadly
applicable, highly enantioselective synthesis of chiral g-
functionalized diazoacetoacetates by catalytic Mukaiyama–
Michael addition reactions of 3-(tert-butyldimethylsilyloxy)-
2-diazo-3-butenoate (1).
A survey of chiral Lewis acids for the direct Mukaiyama–
aldol or Mukaiyama–Michael reactions of 1 with a,b-unsatu-
rated carbonyl compounds showed limited reactivity and low
enantioselectivity. The success of the N-oxazolidinone-deriv-
atized a,b-unsaturated carbonyl compounds prepared by
Evans and co-workers in chiral Lewis acid catalyzed asym-
metric reactions[9] prompted us to use 6, but no reaction with
1a was observed, even using copper(II) triflate ligated with
chiral bis(oxazoline) (box) or bis(oxazolinyl)pyridine
(pybox). Since the oxazolidinone basicity of 6 was too
strong to effect activation of the a,b-unsaturated carbonyl
unit for electrophilic addition, we turned to the less basic a,b-
unsaturated 2-acylimidazole 7a.[10] In a reaction of 7a with 1a
catalyzed by copper(II) triflate ligated with the (S,S)-tBu-box
L1 (Table 1, entry 5), the Mukaiyama–Michael condensation
product 8 was formed in 66% yield but with only 10% ee. In a
screening of potential Lewis acids (Table 1), scandium(III)
triflate, a preferred catalyst for Mukaiyama–aldol reac-
tions,[2c,11] was ineffective for addition to 1a (Table 1,
entry 1). In contrast, the mild Lewis acids, Ni(OTf)2, Zn-
(OTf)2, and Mg(OTf)2, combined with L1, offered moderate
[*] Dr. X. Xu, Prof. M. P. Doyle
Department of Chemistry and Biochemistry, University of Maryland
College Park, MD 20742 (USA)
Fax: (+11)301-314-2779
E-mail: mdoyle3@umd.edu
enantioselectivity with moderate to low product yields
[12]
(Table 1, entries 2–4), but Cu(SbF6)2
proved to be the
Prof. W. Hu
Institute of Drug Discovery and Development
East China Normal University
most active and effective, giving the desired product in 77%
yield with 46% ee (Table 1, entry 7). The enantioselectvity
was improved to 54% ee with this copper(II) catalyst by
reducing the temperature to ꢀ788C (Table 1, entry 8). Since
Cu(SbF6)2 in combination with L1 exhibited the highest
reactivity in these reactions, this catalytic system was selected
for further elaboration.
Optimization of this Mukaiyama–Michael transformation
was effected on 7a by initially changing the ester alkyl and
silyl ether groups of 1 (1a–1d). Compared to the TBS group
3663 Zhongshan Bei Road, Shanghai 200062 (China)
[**] Support for this research to M.P.D. from the National Institutes of
Health (GM 46503) and National Science Foundation (CHE-
0748121) is gratefully acknowledged. W.H. thanks the National
Science Foundation of China (20932003) and the MOST of China
(2011CB808600).
Supporting information for this article is available on the WWW
6392
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 6392 –6395