A highly enantioselective Bronsted acid catalyst for the Strecker reaction

Article abstract of DOI:10.1002/anie.200504344

(Chemical Equation Presented) An amenable route to amino acids: An optimized new chiral binol phosphate catalyst (see scheme; Ar = 9-phenanthryl) for the hydrocyanation of imines provides a convenient strategy for the enantioselective synthesis of α-amino

Full text of DOI:10.1002/anie.200504344

Angewandte
Chemie
Organocatalysis
several binol phosphates and tested the corresponding
catalysts 1a–g in the enantioselective Strecker reaction.
Initial explorations, however, concentrated on varying reac-
tion parameters, such as different protected imines, cyanide
sources, catalyst loading, temperature, and concentration.[11]
The best results, with respect to yield and selectivity, were
obtained with benzyl-protected imines and HCN at À408C
using 10 mol% of catalyst.
DOI: 10.1002/anie.200504344
A Highly Enantioselective Brønsted Acid Catalyst
for the Strecker Reaction**
Magnus Rueping,* Erli Sugiono, and Cengiz Azap
The influence of the substituent Ar’ on the catalytic
behavior was studied (Table 1). From this survey sterically
more congested Brønsted acids emerged as catalysts with
good to excellent levels of enantioselectivity. Best selectivities
were obtained with catalyst 1g providing the benzyl-pro-
tected amino nitrile 4 in 93% ee (Table 1, entry 7).
The hydrocyanation of imines, the Strecker reaction, is a
practical and direct method to a-amino acids.[1] Consequently,
various attempts to develop asymmetric Strecker reactions
have been made.[2] In addition to metal-catalyzed cyanations
using chiral Al, Ti, Zr, and lanthanide catalysts,[3] promising
metal-free, enantioselective variants of this reaction have
recently been disclosed. These include processes based on
Table 1: Survey of chiral Brønsted acid catalysts 1a–g for the Strecker
reaction.
chiral guanidines,[4] ureas and thioureas,[5] bis(N-oxides),[6]
ACHTREUNG
and ammonium salts.[7] Given the importance of the Strecker
reaction and the resulting products, we report herein a new
type of Brønsted acid catalyst[8] for this transformation, a
chiral
binol
phosphate
(binol = 2,2’-dihydroxy-1,1’-
binaphthyl).
The starting point for our development of this new
catalyst for the enantioselective Strecker reaction was the
successful application of Brønsted acid catalysts of type 1 in
asymmetric transformations,[9,10] originally reported by
Akiyama and Terada. Recently we reported a Brønsted acid
catalyzed transfer hydrogenation of imines and quinolines[10]
using binol phosphates 1. Based on this reaction, we reasoned
that activation of imine 2 by catalytic protonation would
generate the iminium 3 which would subsequently undergo
addition of HCN to give the desired amino nitrile 4 and the
regenerated Brønsted acid 1 (Scheme 1). Thus we prepared
Entry[a]
Ar’
ee [%][b]
1
2
3
4
5
6
7
phenyl (1a)
26
60
84
32
38
rac
93
4-biphenyl (1b)
1-naphthyl (1c)
2-naphthyl (1d)
3,5-(CF3)2C6H3 (1e)
3,5-(C6H5)2C6H3 (1 f)
9-phenanthryl (1g)
[a] Reactions were performed withimine
(1.5 equiv) at 0.15m concentration in toluene using 10 mol% of catalyst
1. [b] Determined by HPLC analysis using a Chiralcel OD-H column.
2
(Bn=benzyl), HCN
Futher examinations concentrated on the solvent
employed (Table 2). While the hydrocyanations could be
performed in all the solvents tested, the best selectivities were
achieved in nonpolar aromatic solvents (Table 2, entry 1),
followed by chlorinated solvents (entries 2 and 3). This trend
Table 2: Influence of solvent on the enantioselectivity of the Strecker
reaction.
Scheme 1. Assumed catalytic cycle for imine activation by binol
phosphate 1.
[*] Prof. M. Rueping, E. Sugiono, C. Azap
Degussa Endowed Professorship
Entry[a]
Solvent
ee [%][b]
1
2
3
4
5
toluene
93
60
44
rac
rac
Institute for Organic Chemistry und Chemical Biology
Johann Wolfgang Goethe University Frankfurt am Main
Marie-Curie-Strasse 11, 60439 Frankfurt am Main (Germany)
Fax: (+49)69-798-29248
chloroform
dichloromethane
acetonitrile
THF
E-mail: M.rueping@chemie.uni-frankfurt.de
[**] The authors acknowledge Degussa AG for generous funding.
[a] Reactions were performed withimine 2, HCN (1.5 equiv) at 0.15m
concentration using 10 mol% of catalyst. [b] Determined by HPLC
analysis using a Chiralcel OD-H column.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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is in accordance with our observations on Brønsted acid
afford the corresponding diamine 6 (Scheme 2).[13] In addi-
tion, the formylated amino nitrile 7 was subjected to
hydrolysis with subsequent debenzylation to yield amino
acid 8.[5b]
catalyzed hydride transfer reactions.[10]
With the optimized conditions we explored the scope of
the Brønsted acid catalyzed hydrocyanation of various imines
(Table 3). In general, aromatic and heteroaromatic, N-benzyl-
and N-para-methoxybenzyl-protected amines, bearing either
electron-withdrawing or electron-donating groups were
obtained in high enantioselectivities and good yields.[12]
Important products from the Strecker reaction are the
amino nitriles which can be converted into amino acids and
diamines. Hence, to demonstrate the preparation of these
compounds and to determine the absolute configuration of
the products, amino nitrile 5l was reduced and deacetylated to
Table 3: Scope of the Strecker reaction.
Entry[a]
2
R
4
Yield [%][b] ee [%][c]
Scheme 2. Reduction and hydrolysis of amino nitriles 5l and 7.
a) LiAlH4, Et2O; b) 65% (w/v) H2SO4, 458C, 20 h; c) HCl (conc.),
708C, 12 h; d) H2/Pd-C, MeOH.
1
2
2a Ph
2b p-H3COC6H4
75
53
97
96
The observed S-configuration of the products can be
explained by a stereochemical model derived from the X-ray
crystal structure of binol phosphate 1g. In the transition state,
the imine is activated by the Brønsted acid 1g, thereby
forming iminium 3. This process favors the approach of the
cyanide nucleophile from the less hindered Re-face rather
than the Si-face which is efficiently shielded by the large
phenanthryl group of the catalyst (Figure 1).
3
2c Ph
59
98
4
5
2d Ph, R2 =H
85
70
99
94
2e Ph, R2 =OCH3
6
7
2 f Ph
2g Ph
71
88
85
93
8
9
10
2h Ph, X=S, R2 =H
2i Ph, X=O, R2 =H
2j Ph, X=O,
77
84
85
95
89
92
R2 =CH3
11
2k p-H3COC6H4
87
89
Figure 1. Conceivable transition structure derived from an X-ray crystal
structure of chiral Brønsted acid 1g and optimization calculations.
12
13
2l Ph, R2 =OCH3
2m Ph, R2 =CH3
97
55
93
87
In summary, we have developed an organocatalytic
hydrocyanation of imines, which provides direct access to a
diverse range of aromatic amino nitriles and the correspond-
ing amino acids and diamines in high enantioselectivity. The
use of binol phosphates as efficient Brønsted acid catalysts in
the enantioselective Strecker reaction not only increases the
diversity of possible transformations with this catalyst but also
shows the great potential of this type of Brønsted acid in
asymmetric catalysis. Experiments to establish a more
detailed mechanism of activation and the application of this
14
15
2n Ph
2o p-H3COC6H4
69
60
85
86
[a] Reactions were performed withimine 2, HCN (1.5 equiv) at À408C in
toluene at 0.15m concentration for 2–3 days using 10 mol% of catalyst.
[b] Yield of the isolated trifluoroacetamides 5 after acetylation of the
corresponding amino nitriles 4 and chromatography. [c] Determined by
HPLC analysis using Chiralcel OD-H or ADH-columns.
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Chemie
Antonchick, T. Theissmann, Angew. Chem./Angew. Chem. Int.
Ed. 2006, in press.
catalyst to the hydrocyanation of ketimines and to other
reactions of imines with related nucleophiles are currently
under investigation.
[11] N-Boc-, N-tosyl-, N-phenyl-, N-benzhydryl-, and N-phosphinoyl-
protected imines gave inferior results compared to the N-benzyl-
protected ones. As cyanide sources we tested acetone cyanohy-
drine, trimethylsilyl cyanide, and HCN. Reduction of catalyst
loading, temperature, and concentration resulted in loss of
enantioselectivities.
[12] Enantioselectivities decreased in the case of aliphatic imines, for
example, 2-(benzylamino)-3-methylbutane nitrile was obtained
in 55% ee.
Received: December 6, 2005
Published online: March 17, 2006
Keywords: amino acids · binol phosphate · Brønsted acids ·
.
organocatalysis · Strecker reaction
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