Asymmetric activation of tropos 2,2′-biphenol with cinchonine generates an effective catalyst for the asymmetric strecker reaction of n-tosyl-protected aldimines and ketoimines

Article abstract of DOI:10.1002/anie.200703188

(Chemical Equation Presented) Tropo' bello! Asymmetric activation of tropos biphenol 1 and Ti(OiPr)₄ with cinchonine 2 generates a remarkably effective catalyst in situ for the asymmetric Strecker reaction of N-tosyl (Ts) imines under mild cond

Full text of DOI:10.1002/anie.200703188

Communications
DOI: 10.1002/anie.200703188
Asymmetric Catalysis
Asymmetric Activation of tropos 2,2’-Biphenol with Cinchonine
Generates an Effective Catalyst for the Asymmetric Strecker Reaction
of N-Tosyl-Protected Aldimines and Ketoimines**
Jun Wang, Xiaolei Hu, Jun Jiang, Shaohua Gou, Xiao Huang, Xiaohua Liu, and Xiaoming Feng*
The catalytic asymmetric Strecker reaction is one of the most
powerful strategies for the synthesis of chiral a-amino acids.
In the last decade, great endeavors have been devoted to this
area and a number of successful protocols have been
disclosed.[1–3] However, more efforts are still needed in this
area, first, because highly efficient cyanation of ketoimines to
afford the precursors of pharmaceutically important a-
quaternary amino acids[4] is difficult and little reported, and
second, as searching for a catalyst system which could work
well not only on aldimines but also on ketoimines is
challenging and interesting. Herein, we present a highly
enantioselective cyanation of N-Ts-protected (Ts = p-tolue-
nesulfonyl) aldimines and ketoimines promoted by a novel
Scheme 1. Ligands used in this study.
catalyst generated from the asymmetric activation[5] of axially
flexible 2,2’-biphenol (bipol) with a chiral activator 1 through
coordinative interaction with a metal (Scheme 1).
Table 1: Identification of the most efficient catalyst system, and
optimization of the reaction conditions.[a]
Our initial studies showed that bipol/Ti(OiPr)4 activated
by cinchonine 1 was a promising catalyst for the cyanation of
N-Ts benzaldimine 4a using trimethylsilyl cyanide (TMSCN)
as the cyanide reagent at À208C in toluene in the presence of
20 mol% catalyst (Table 1, entry 1). Further improvement of
ee values was achieved by screening several modified bipol
derivatives (Table 1, entries 2–10). Especially, the bipol ligand
bearing a sterically demanding aromatic substituent at the
3,3’-position greatly enhanced the enantioselectivity to 94–
95% ee (Table 1, entries 7–10). Considering the excellent
performance and relatively facile preparation of 3h, we used
this to optimize the other parameters. After adjusting the
ratio of 3h/Ti(OiPr)4/1 to 1.2:1.2:1, 5a was obtained in up to
97% ee and greater than 99% yield (Table 1, entry 11).
Entry
2,2’-biphenol
3/Ti(OiPr)4/1 [mol%]
ee [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13[c]
14[c]
3a
3b
3c
3d
3e
3 f
3g
3h
3i
20:20:20
20:20:20
20:20:20
20:20:20
20:20:20
20:20:20
20:20:20
20:20:20
20:20:20
20:20:20
24:24:20
12:12:10
12:12:10
6:6:5
71
64
74
34
71
70
94
95
94
95
97
90
97
97
3j
3h
3h
3h
3h
[*] J. Wang, X. Hu, J. Jiang, S. Gou, X. Huang, X. Liu, Prof. X. Feng
Key Laboratory of Green Chemistry & Technology
Ministry of Education, College of Chemistry
Sichuan University
[a] Unless noted otherwise, the reaction was carried out with 4a
(0.1 mmol) and TMSCN (0.12 mmol) in toluene (0.5 mL) at À208C for
2.5–18 h, and complete conversion of the imine was observed by TLC
detection. [b] Determined by chiral HPLC. [c] iPrOH (1.2 equiv) was used
as additive.
Chengdu 610064 (P.R. China)
Fax: (+86)28-8541-8249
E-mail: xmfeng@scu.edu.cn
Prof. X. Feng
State Key Laboratory of Biotherapy
Sichuan University
Chengdu 610041 (P.R. China)
However, when the catalyst loading was lowered, the
presence of 1.2 equivalents of iPrOH[6] was essential to
maintain the excellent results (Table 1, entries 12–14). Other
conditions such as the central metal, solvent, and temperature
were also investigated, but no superior results were obtained.
Under optimal conditions (Table 1, entry 14), a series of
imines (4a–4o) derived from aromatic, heterocyclic, a,b-
unsaturated, and aliphatic aldehydes were tested and excel-
lent results (up to 97% ee) were achieved (Table 2, entries 1–
[**] We are grateful to the National Natural Science Foundation of China
(20602025) for financial support. We also thank the Sichuan
University Analytical and Testing Center for NMR spectroscopic
analysis and the State Key Laboratory of Biotherapy for HRMS
analysis.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
8468
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Angew. Chem. Int. Ed. 2007, 46, 8468 –8470

Angewandte
Chemie
Table 3: Substrate scope for the catalytic asymmetric Strecker reaction of
15). Different N-sulfonyl-protected imines were also exam-
ined, and good results were obtained (Table 2, entries 16–18)
which facilitated the preparation of various chiral N-sulfonyl-
protected amino acids.
N-Ts ketoimines.[a]
Entry R1
R2
Product
x
t [h] Yield [%][b] ee [%][c]
Table 2: Substrate scope for the catalytic asymmetric Strecker reaction of
N-sulfonyl aldimines.[a]
1
2
3
4
5
Ph
Me 7a
Me 7b
Me 7c
Me 7d
Me 7e
5
5
5
5
8
4
>99
90
>99 (S)
98
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeC6H4
4
8
4
4
4
4
22
22
22
4
>99
>99
>99
99
>99
>99
90
97
97
>99
93
>99 (S)
>99 (S)
>99 (S)
>99 (S)
>99
90
>99 (S)
99
10
10
5
10
5
Entry
R
Product
t [h]
Yield [%][b]
ee [%][c]
6
4-MeOC6H4 Me 7 f
7
8
9
10
11
12
13
3-ClC6H4
2-FC6H4
2-naphthyl
2-furyl
2-thienyl
Ph
Me 7g
Me 7h
Me 7i
Me 7j
Me 7k
1
2
3
4
5
6
Ph
5a
5b
5c
5d
5e
5 f
2.5
3
3
22
8
8
>99
>99
97
>99
>99
>99
97(S)
96
93
97
94
4-FC6H4
4-ClC6H4
4-MeC6H4
3-MeC6H4
4-MeOC6H4
5
5
>99
>99
>99
Et
7l
10
10
97
Ph
nPr 7m
4
7
5g
3
>99
97
14
Me 7n
5
17
97
98
8
9
10
11
1-naphthyl
2-naphthyl
2-furyl
5h
5i
5j
4
22
3
92
97
93
94
91
96
90
94
15
16
17
c-hexyl
tBu
2-FC6H4
2-ClC6H4
2-MeC6H4
Me 7o
Me 7p
Ph 7q
Ph 7r
Ph 7s
10
10
10
10 45
10 45
4
4
5
>99
98
96
95
90
94
69
98
97
97
2-thienyl
5k
5
18
19[d]
12
5l
4
96
91
13[d]
14[d]
15[d]
16[e]
17[f]
18[g]
c-hexyl
iPr
tBu
Ph
Ph
Ph
5m
5n
5o
5p
5q
5r
6
6
6
4
4
4
>99
96
98
>99
94
75
92
84
84
94
94
90
[a] Unless noted otherwise, reactions were carried out with imine
(0.1 mmol), TMSCN (0.12 mmol), iPrOH (0.12 mmol) and toluene
(0.5 mL) at À208C. [b] Isolated yield. [c] Determined by HPLC and the
absolute configurations were determined by comparison with literature
data.[3g] [d] 1.5 equiv TMSCN and 1.5 equiv iPrOH were used.
[a] Unless noted otherwise, ArSO2 =Ts and reactions were carried out
with imine (0.1 mmol), TMSCN (0.12 mmol), catalyst (5 mol%), iPrOH
(0.12 mmol), and toluene (0.5 mL) at À208C. [b] Isolated yield.
[c] Determined by HPLC; see Supporting Information for the assignment
of the absolute configuration of 5a. [d] 15 mol% catalyst was used.
[e] Ar=4-ClC6H4. [f] Ar=Ph. [g] Ar=2,4,6-trimethylphenyl.
Table 4: Identification of the configuration of bipol 3h in the most active
species by taking cyanation of 6a as the benchmark reaction.[a]
Given the remarkable performance of the present catalyst
system in the cyanation of aldimines, its general applicability
in the cyanation of ketoimines 6a–6p was also examined
under the same reaction conditions. The results listed in
Table 3show that a wide spectrum of ketoimines could
achieve excellent enantioselectivities (up to 99% ee) and high
yields employing 5–10 mol% catalyst (Table 3, entries 1–16).
Significantly, the current system could be extended to the
cyanation of ortho-substituted diarylketoimines 6q–6s
(Table 3, entries 17–19)[7] to generate chiral a-diaryl a-
amino nitriles, which made it possible to synthesize chiral
5,5-diarylhydantoins[8] and their derivatives. As far as we
know, the catalytic asymmetric Strecker reaction of such kind
of substrates has not been reported before.
To gain preliminary insight into the catalyst structure,
atropos[9] (chirally rigid) ligands (R)-8 and (S)-8 were
prepared and evaluated in the cyanation of 6a (Table 4).
When (S)-8/Ti(OiPr)4 was employed, no product was detected
(Table 4, entry 2). However, 1/(S)-8/Ti(OiPr)4 displayed the
same result as that when 1/3h/Ti(OiPr)4 was used (Table 4,
entries 1 and 3). When (R)-8 replaced (S)-8, the reaction
proceeded very slowly and led to low ee values (Table 4,
Entry
Activator
Diol
3h
(S)-8
(S)-8
(R)-8
(R)-8
(S)-8
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
1
3.5
8
3.5
3.5
8
>99
–
>99
25
95
49
>99 (S)
–
none
1
1
2
2
2
>99 (S)
71 (S)
98 (R)
68 (R)
94 (R)
8
8
3h
87
[a] Unless noted otherwise, reactions were carried out with imine
(0.1 mmol), TMSCN (0.12 mmol), iPrOH (0.12 mmol), and toluene
(0.5 mL) at À208C. [b] Isolated yield. [c] Determined by HPLC.
entry 4). As expected, with cinchonidine 2 as the activator,
(R)-8 rather than (S)-8 was demonstrated as the matched
ligand (Table 4, entries 5–6). Additionally, asymmetric acti-
vation of tropos (chirally flexible) 3h with 2 was also
investigated, and a high yield with slightly decreased ee
value was observed (Table 4, entry 7). With these data in
hand, at least three conclusions could be drawn: 1) the
absolute configuration of the product was controlled by
activator 1 or 2; 2) on the basis of the large differences
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Communications
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In view of the biological importance[10] of the N-sulfonyl
amino acids, a representative conversion of 5a to the
corresponding N-Ts amino acid was attempted and eventually
realized easily without racemization (see Supporting
Information).
In summary, a highly efficient catalytic asymmetric
Strecker reaction with an extremely broad substrate scope
was accomplished by a strategy of asymmetric activation of
tropos bipol derivative 3h with cinchonine under mild
conditions. In the presence of 5–10 mol% catalyst, excellent
enantioselectivities up to 99% ee and high yields were
achieved for most of the substrates. Preliminary studies of
the catalyst structure were performed, and application of this
catalyst to other reactions is underway.
Experimental Section
General procedure for the Strecker reaction of N-Ts imine: The
freshly prepared catalyst (5–10 mol%) (see Supporting Information)
was introduced to a dry reaction tube charged with N-Ts imine
(0.1 mmol) and toluene under Ar atmosphere at À208C. The cyanide
reagent (0.12 mmol) and iPrOH (0.12 mmol) were sequentially added
with stirring. After the imine was consumed, the residue was purified
by silica gel column chromatography to afford the desired product.
Received: July 17, 2007
Published online: September 4, 2007
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g,l,3f–h] and X. H. Liu, B. Qin, X. Zhou, B. He, X. M. Feng, J.
Am. Chem. Soc. 2005, 127, 12224.
Keywords: amino acids · asymmetric catalysis · cyanides ·
.
imines · Strecker reaction
[7] However, meta- and para-substituted benzophenone imines gave
poor ee values (see Supporting Information).
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