Highly enantioselective strecker reaction of ketoimines catalyzed by an organocatalyst from (S)-BINOL and L-prolinamide

Article abstract of DOI:10.1002/chem.200800454

A study was conducted to propose a new kind of N,N'-dioxide with an axial chirality for the enantioselective cyanation of N-Ts-protected ketoimine. The study assumed that the stereocontrol will be enhanced, by employing a suitable chiral linker. The new k

Full text of DOI:10.1002/chem.200800454

DOI: 10.1002/chem.200800454
Highly Enantioselective Strecker Reaction of Ketoimines Catalyzed by an
Organocatalyst from (S)-BINOL and l-Prolinamide
Zongrui Hou, Jun Wang, Xiaohua Liu, and Xiaoming Feng*[a]
The catalytic asymmetric
Strecker reaction[1] has attract-
ed much attention and
a
number of successful protocols
have been disclosed for its
great importance in the syn-
thesis of chiral a-amino acids
and their derivatives.[2] Howev-
er,in contrast to the relatively
well-developed cyanation of
aldimines,[3] limited reports
were related to the cyanation
of ketoimines[4] to afford phar-
maceutically important disub-
stituted a-amino nitriles. Espe-
Figure 1. Catalysts used in this research.
cially,it is not easy to promote cyanation of ketoimines with
organocatalyst. Since the first successful example reported
by Jacobsen’s group using chiral urea as catalyst,[4a,c] two
types of N,N’-dioxides have been developed by our group
for the Strecker reaction of ketoimines and moderate to
good results were obtained.[4g,i] Herein,we reported a novel
kind of N,N’-dioxide with an axial chirality for the enantio-
selective cyanation of N-Ts-protected ketoimine,providing
excellent results (Figure 1).
Before,the linkers of the previously used N,N’-dioxides
for the Strecker reaction of ketoimines were achiral moiet-
ies. We speculated that the stereocontrol would be enhanced
by employing a suitable chiral linker. On the basis of this
idea,we designed and synthesized the N,N’-dioxide catalyst
derived from BINOL and prolinamide. The general route
was given in Scheme 1. Firstly,( S)-BINOL was formylated
via three steps to afford A1 which was subsequently subject-
ed to the condensation reaction with l-prolinamide. Then
the product B1 was oxidized to achieve the desired novel
N,N’-dioxide 1a. Notably,the absolute configuration of the
newly formed chiral center in catalyst 1a was identified as R
based on the observation of strong NOE signal between H1
and H2 (see Supporting Information). However,the attempt
to synthesize the similar structure from (R)-BINOL and l-
prolinamide was failed,which might be attributed to the in-
stability of the corresponding N,N’-dioxide. Interestingly,
when two hydroxyl groups of B1 were replaced by two me-
thoxy group, N,N’-dioxide 1c could not be prepared as dia-
stereomerically pure form in the oxidation step. Instead,the
mixture of the two epimers with a ratio of 1:1.8 was ob-
tained (see Supporting Information). Other catalysts dis-
played in Figure 1 were prepared in a similar process
(Scheme 1) for the preparation of 1a.
[a] Z. Hou,J. Wang,Dr. X. Liu,Prof. Dr. X. Feng
Key Laboratory of Green Chemistry & Technology
(Sichuan University),Ministry of Education
College of Chemistry,Sichuan University
Chengdu 610064 (PR China)
and
State Key Laboratory of Oral Diseases,Sichuan University
Chengdu 610041 (PR China)
Fax : (+86)28-8541-8249
To examine the initial hypothesis,we evaluated these cat-
alysts in the asymmetric Strecker reaction of N-tosyl keto-
imines with TMSCN. It was found that a promising result
(80% ee) was obtained by employing 5 mol% N,N’-dioxide
1a as catalyst,while inferior asymmetric induction was ob-
E-mail: xmfeng@scu.edu.cn
Supporting information for this article is available on the WWW
under http://www.chemistry.org or from the author.
4484
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Chem. Eur. J. 2008, 14,4484 – 4486

COMMUNICATION
somewhat sluggish,the ee value was gradually enhanced
(Table 1,entries 11–13). Also,reduced concentration was
beneficial to the enantioselectivity (Table 1,entry 14). To
further improve the result,some additives were investigated.
Fortunately,1-admantanol was found to be efficient to en-
hance both reactivity and enantioselectivity,and the best
amount was 1.0 equiv (Table 1,entry 15).
With the optimal conditions (Table 1,entry 15) in hand,
the substrate scope was surveyed. As shown in Table 2,vari-
ous aryl imines bearing no matter electron-withdrawing or
electron-donating group were smoothly converted to their
corresponding adducts in the range of 93–99% ee with high
yields (Table 2,entries 1–11). Heteroaromatic ketoimines
showed high reactivities and enantioselectivities as well
(Table 2,entries 12–13). Aliphatic substrate 4n gave 93% ee
Scheme 1. Synthesis of the catalyst: i) l-prolinamide,ethanol,reflux; ii)
mCPBA,CH Cl2, À788C.
2
served using 1b with two TMS groups on the 6,6’-position of
BINOL (Table 1,entries 1–2). A low ee value was obtained
by replacing the BINOL framework with H8-BINOL
(Table 1,entry 3),which suggested that a proper dihedral
angel in 1a was of great importance. When catalyst 3 de-
rived from axial flexible 2,2’-biphenol was examined,quite
poor enantioselectivity was given,which indicated that the
axial chirality of BINOL in 1a was crucial to achieve the
good ee value (Table 1,entry 4).
(Table 2,entry 14). Besides,
a,b-unsaturated ketoimine
could be transformed to the synthetically important product
5o with 95% ee (Table 2,entry 15). Cyclic ketoimine could
give an excellent result with 98% ee (Table 2,entry 16). Ex-
citingly,current catalyst system could be applied to the aryl
ethyl and aryl propyl ketoimines to give excellent results
(Table 2,entries 17–18). ortho-Chloro diphenylketoimine ex-
hibited good result,too (Table 2,entry 19).
In summary,a novel and efficient organocatalyst was de-
veloped to promote the Strecker reaction of ketoimines
with fairly wide substrate scope and excellent enantioselec-
Table 1. Asymmetric cyanation of ketoimine 4a catalyzed by various cat-
alyst systems.
Table 2. Substrate scope for the Strecker reaction of ketoimines.
Entry[a]
Cat. [mol%]
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
1a (5)
1b (5)
2 (5)
toluene
toluene
toluene
toluene
CH2Cl2
anisole
THF
CH3CN
toluene
toluene
toluene
toluene
toluene
toluene
toluene
71
53
40
43
88
64
84
64
89
99
99
56
42
66
93
80
55
59
27
24
48
18
23
81
60
75
84
86
90
97
Entry[a] R1
R2
Product t [h] Yield [%][b] ee [%][c]
3 (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (5)
1a (10)
1a (2)
1a (1)
1a (2)
1a (2)
1
2
3
4
5
6
7
8
9
Ph
2-FC6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
5a
5b
5c
5d
5e
5 f
5g
5h
5i
72
72
72
72
72
93
95
93
91
94
88
82
81
80
97 (R)
94
94
93 (R)
95
98 (R)
97
3-ClC6H4
4-ClC6H4
4-FC6H4
4-MeC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
9[d]
10[e]
11
12
13
14[f]
15[f,g]
72
120
120
120
96
99 (R)
10
Me
5j
120
74
99 (R)
[a] All the reactions were carried out with 4a (0.1 mmol),TMSCN
(1.5 equiv) in toluene (0.5 mL) at 08C in a dry flask for 48 h unless other-
wise specified. [b] Isolated yield. [c] Determined by chiral HPLC. [d] The
reaction was performed at À208C for 168 h. [e] The reaction was per-
formed at 308C. [f] The reaction was performed in 2.0 mL toluene for
72 h. [g] 1.0 equiv 1-adamantanol was added.
11
12
13
14
2-naphthyl
2-furyl
2-thienyl
tBu
Me
Me
Me
Me
5k
5l
5m
5n
72
72
72
72
82
88
86
96
97 (R)
95
97
93
15
Me
5o
72
86
95
16
–
5p
120
73
98 (R)
Solvent screening showed that toluene was the best sol-
vent (Table 1,entry 1). Other solvents such as CH Cl2,ani-
2
17
18
19
Ph
Ph
2-ClC6H4
Et
nPr
Ph
5q
5r
5s
120
120
120
86
74
76
98
95
90
sole,THF and CH 3CN gave poor enantioselectivities
(Table 1,entries 5–8). When the reaction was performed at
À208C,slight increase in the enantioselectivity was ob-
served,but the reactivity decreased. High temperature was
disadvantageous to asymmetric induction (Table 1,en-
tries 9–10). Although low catalyst loading made the reaction
[a] All the reactions were carried out in a 0.1 mmol scale of 4 using
1.5 equiv TMSCN in 2.0 mL toluene with 2 mol% catalyst and 1.0 equiv
1-admantanol at 08C in a dry tube. [b] Isolated yield. [c] Determined by
chiral HPLC.
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Keywords: asymmetric catalysis · cyanides · ketoimines ·
organocatalysis · Strecker reaction
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Published online: April 9,2008
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