Catalytic asymmetric roskamp reaction of α-Alkyl-α-diazoesters with aromatic aldehydes: Highly enantioselective synthesis of α-Alkyl-β-keto esters

Article abstract of DOI:10.1021/ja102832f

The first catalytic enantioselective Roskamp reaction of α-alkyl-α-diazoesters with aromatic aldehydes was realized using a simple chiral N, N′-dioxide-scandium(III) complex. Remarkably, with 0.05 mol % catalyst, the reaction was performed well over a series of substrates, giving the desired products chemoselectively in excellent yields (up to 99%) and enantioselectivities (up to 98% ee) under mild conditions. This protocol provides a promising method for the synthesis of chiral α-alkyl-β- keto esters and 1,3-diols.

Full text of DOI:10.1021/ja102832f

Published on Web 06/07/2010
Catalytic Asymmetric Roskamp Reaction of r-Alkyl-r-diazoesters with
Aromatic Aldehydes: Highly Enantioselective Synthesis of r-Alkyl-ꢀ-keto
Esters
Wei Li, Jun Wang, Xiaolei Hu, Ke Shen, Wentao Wang, Yangyang Chu, Lili Lin, Xiaohua Liu, and
Xiaoming Feng*
Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan
UniVersity, Chengdu 610064, P. R. China
Received April 5, 2010; E-mail: xmfeng@scu.edu.cn
Scheme 1
The Roskamp reaction, which involves the interaction of alkyl
diazoacetates with aldehydes in the presence of Lewis acids, is one
of the most powerful and efficient methods for the synthesis of
ꢀ-keto esters (R2 ) H, path a in Scheme 1).1 Analogously, it could
be extended to an asymmetric version involving R-alkyl-R-
diazoesters, providing chiral R-alkyl-ꢀ-keto esters (R2 ) alkyl,
Scheme 1). However, this strategy has received much less attention
in the last two decades. There are two major reasons for this: (1)
the reaction process can undergo three rearrangement pathways once
the diazonium intermediate is generated, which makes it difficult
to conduct chemoselectively (Scheme 1), and (2) in comparison
with chiral R-alkyl-ꢀ-keto imides developed by Evans and co-
workers,2 chiral R-alkyl-ꢀ-keto esters may suffer racemization more
easily via enolization. Maruoka and co-workers recently presented
an intriguing chiral-auxiliary-based approach to the Roskamp
reaction with R-alkyl-R-diazocarbonyl compounds.3 As far as we
know, no catalytic asymmetric example has been reported to date.
Herein, we describe the first catalytic asymmetric Roskamp reaction
using chiral N,N′-dioxide-scandium(III) complexes.4
Table 1. Optimization of the Reaction Conditionsa
Using our previously established chiral Lewis acid catalyst
system,4 we initially investigated the catalytic asymmetric Roskamp
reaction of ethyl R-benzyl-R-diazoacetate (1a) with benzaldehyde
(2a) promoted by metal complexes of the chiral N,N′-dioxide ligand
L1 (Table 1, entries 1-4). The reactions catalyzed by the Y(OTf)3
and La(OTf)3 complexes of L1 were sluggish (Table 1, entries 1
and 2). The zinc complex of L1 gave moderate enantioselectivity
with poor reactivity (Table 1, entry 3). Sc(OTf)3 was found to be
a suitable Lewis acid,5 providing the product 3a in 95% yield and
78% ee (Table 1, entry 4 vs entries 1-3). Encouraged by this result,
we next explored complexes of other N,N′-dioxide ligands with
Sc(OTf)3. As for the amino acid backbone, L-ramipril acid-derived
N,N′-dioxide L3 achieved higher enantioselectivity and yield (Table
1, entry 6 vs entries 4 and 5). Steric hindrance of the ligand plays
a key role in promoting both the enantioselectivity and reactivity,
and the highly sterically demanding ligand L3 turned out to be the
best one (Table 1, entries 6-9). To our delight, the reaction time
was reduced to 2 h when 3 Å molecular sieves were used as an
additive (Table 1, entry 10). Remarkably, when the catalyst loading
was decreased to 0.05 mol %, the enantioselectivity was slightly
enhanced to 95% ee without any loss of reactivity (Table 1, entry
11 vs 10). The catalyst loading could even be reduced to 0.01 mol
%, giving the same enantioselectivity with a prolonged reaction
time (Table 1, entry 12).
entry
ligand
metal
x (mol %)
time (h)
ee (%)b
yield (%)c
1
2
3
4
5
6
7
8
L1
L1
L1
L1
L2
L3
L4
L5
L6
L3
L3
L3
Y(OTf)3
La(OTf)3
Zn(OTf)2
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
5
5
5
5
5
5
5
5
5
5
0.05
0.01
29
29
29
7
7
7
29
28
28
2
2
56
-
-
trace
trace
8
95
90
97
10
82
81
55
78
75
94
40
78
80
94
95
95
9
10d
11d,e,f
12d,e,g
97
97
80
a Unless otherwise noted, reactions were carried out with L/Sc(OTf)3
(1/1), 0.1 mmol of 1a, and 0.1 mmol of 2a in 0.5 mL of CH2Cl2 at -20
°C. b Determined by chiral HPLC after flash filtration as the isolation
procedure. c Isolated yield after silica gel column chromatography.
d Using 3 Å molecular sieves (10.0 mg) as an additive. e Reaction was
carried out with L3/Sc(OTf)3 (1/1.2), 1.0 mmol of 1a, and 1.0 mmol of
2a. f Using 0.2 mL of CH2Cl2. g Using 0.1 mL of CH2Cl2.
catalyst could be easily isolated by flash filtration through a thin silica
gel layer without racemization.8
The substrate scope was investigated under the optimized
conditions (Table 1, entry 11), as shown in Table 2. With 0.05
mol % catalyst, a series of R-alkyl-R-diazoesters reacted smoothly
with benzaldehyde, delivering the corresponding products in
It is noteworthy that the possible byproducts that could be produced
via R3 migration (Scheme 1, path b)3c,6 or epoxide formation (Scheme
1, path c)7 were not detected in the current system. The product 3a
suffered racemization to some extent during the purification with silica
gel column chromatography, but fortunately, the product and the
9
8532 J. AM. CHEM. SOC. 2010, 132, 8532–8533
10.1021/ja102832f  2010 American Chemical Society

C O M M U N I C A T I O N S
biological compounds.9 The relative configuration of 7 was
determined to be trans by conversion of the diol to cyclic acetonide
8 and comparison of its analytical data with the reported data.10
The absolute configuration at the secondary alcohol stereocenter
was determined to be S using Horeau’s method by the reaction of
6 with racemic 2-phenylbutyryl chloride.11 Thus, the absolute
configuration of 3a is R.
Table 2. Substrate Scope of the Catalytic Asymmetric Roskamp
Reactiona
In summary, we have achieved the first catalytic enantioselective
Roskamp reaction of R-alkyl-R-diazoesters with aromatic aldehydes.
Remarkably, with 0.05 mol % chiral N,N′-dioxide-scandium(III)
complex, the reaction was performed well over a series of substrates,
giving the desired products chemoselectively in excellent yields
(up to 99%) and enantioselectivities (up to 98% ee) under mild
conditions. This protocol provides a promising method for the
synthesis of chiral R-alkyl-ꢀ-keto esters and 1,3-diols. Further
extension of the approach to ketones is underway.
Acknowledgment. We thank the National Natural Science
Foundation of China (20732003 and 20872096), PCSIRT (IRT0846),
and the National Basic Research Program of China (973 Program)
(2010CB833300) for financial support. We also thank Sichuan
University Analytical & Testing Center for NMR analysis.
Supporting Information Available: Experimental details and
analytical data (NMR, HPLC, and ESI-HRMS). This material is
available free of charge via the Internet at http://pubs.acs.org.
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Scheme 2. Scaled-Up Version of the Roskamp Reaction and
Transformations of the Product
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substituents on the aromatic aldehydes, excellent yields and ee
values were also obtained (Table 2, entries 11-23). Notably,
condensed-ring and heteroaromatic aldehydes were tolerated under
the current system (Table 2, entries 24-26). However, poor results
were obtained for aliphatic and R,ꢀ-unsaturated aldehydes.
As expected, almost the same result was obtained when the model
reaction was scaled up to the gram scale (Scheme 2). More
significantly, 3a was easily converted to the ꢀ-hydroxy ester in good
diastereoselectivity and excellent yield without racemization.
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chromatography was reduced to the chiral 1,3-diol 7, which is a
useful building block in syntheses of both natural products and
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