Direct organocatalytic enantioselective mannich reactions of ketimines: An approach to optically active quaternary α -amino acid derivatives

Article abstract of DOI:10.1002/anie.200460158

You're in control of which diastereomer of a quaternary α-amino acid derivative is formed in a direct organocatalytic diastereoselective and enantioselective Mannich reaction of ketimines with aldehydes (see scheme). The reactions are high yielding and ca

Full text of DOI:10.1002/anie.200460158

Communications
À
Asymmetric Organocatalysis
the C C bond-forming step, as well as electronic effects. A
series of ketimines 1a–f (see Supporting Information) in
which the protecting group on the nitrogen atom is intrinsi-
cally bound to an a-aryl substituent of the imine were
prepared.[5] The anchoring of the protecting group in this way
overcomes the above-mentioned problems by minimizing the
degree of rotational freedom and by blocking the E/Z isome-
rization of the imine double bond. Consequently, and also as a
result of the induced ring strain, ketimines 1a–f showed high
reactivity towards a variety of nucleophiles, in striking
contrast to their non-anchored analogues.[5,10] The reaction
of ketimine 1a with isovaleraldehyde (2a) was investigated as
the model reaction, and a survey of different chiral amines as
catalysts was carried out (Table 1).
Direct Organocatalytic Enantioselective Mannich
Reactions of Ketimines: An Approach to
Optically Active Quaternary a-Amino Acid
Derivatives**
Wei Zhuang, Steen Saaby, and Karl Anker Jørgensen*
À
The Mannich reaction is an effective C C bond-forming
process for the construction of nitrogen-containing com-
pounds, such as a- and b-amino acid derivatives, as well as a
variety of natural products.[1] The catalytic enantioselective
addition of preformed nucleophiles, such as silyl ketene
acetals and silyl enol ethers, to imines is well established,[2] but
only recently were the first examples of direct enantioselec-
tive Mannich reactions reported. By the use of either
bifunctional chiral Lewis acid complexes[3] or secondary
chiral amines[4] as the catalyst for the reaction of imines
with unmodified carbonyl donors, the formation of the
corresponding optically active Mannich bases has been
reported.
Table 1: Direct organocatalytic asymmetric Mannich reaction of ketimine
1a with 2a.
Solvent Yield[a] 3a/4a[b] ee[c]
However, despite the tremendous amount of work and
effort devoted to the development of efficient and versatile
Mannich reactions, the structure of the electrophile has been
restricted to imines derived from aldehydes. The organo-
catalytic enantioselective Mannich reaction of imines derived
from ketones (ketimines) is to date unprecedented,[5]
although substrates such as a-substituted a-ketimino esters
would constitute an interesting template for the synthesis of
quaternary a- and b-amino acids.[6,7]
As a result of the tetrasubstituted asymmetric carbon
atom, quaternary a-amino acids are considerably more stable
than tertiary a-amino acid derivatives, and therefore prob-
lems of metabolic degradation, for example, of peptidomi-
metics, may be avoided. Moreover, a,a-disubstituted a-amino
acids exert a remarkable influence on the conformation of
peptides into which they are incorporated.[8] Finally, non-
natural a-aryl a-alkyl a-amino acid derivatives have shown
strong inhibitory effects on aldose reductases, that is, as
potential drugs for the treatment of various diabetes-related
diseases.[9] Herein the development of the first direct organo-
catalyzed enantioselective Mannich reaction of ketimines and
unmodified aldehydes is presented.
Entry Catalyst
T
2a
(mol%) [8C]
[equiv]
[%]
[%]
1
2
3
4
5
6
7
8
9
5a (30)
5b (30)
5c (30)
5d (30)
5e (30)
5e (5)
5e (5)
5e (5)
5e (5)
5e (2)
0
0
0
0
0
0
0
5
5
5
5
5
5
5
2
2
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
Et2O
Et2O
Et2O
84
11
trace
39
56
73
74
99
51
1:8
>20:1
>20:1
>20:1
15:1
2:1
19:1
>20:1
17:1
18:1
82
7
–
80
86
88
90
91
92
91
0
À24
10
0
93
[a] Combined yield of the two isolated diastereomeric products. [b] The
diastereomeric ratio was determined by 1H NMR spectroscopic analysis
of the crude product mixture. [c] The ee of the major product was
determined by HPLC on a Daicel Chiralpak AS column.
Ketimines are in general less reactive towards nucleo-
philic additions than aldimines owing to steric hindrance in
Initial experiments were performed with l-proline (5a;
30 mol%) as the catalyst and with 5 equivalents of the
aldehyde donor. The reaction proceeded smoothly to afford
the desired Mannich products in a combined yield of 84%
with a diastereomeric ratio of 1:8 in favor of 4a (82% ee;
Table 1, entry 1). The more soluble methyl ester of l-proline
also promoted the reaction of ketimine 1a with 2a, but the
yield dropped to 11%, the diastereoselectivity was inversed
(> 20:1), and the enantioselectivity was almost completely
eroded (7% ee) (Table 1, entry 2). The l-proline-derived
catalyst 5c was a poor catalyst for this reaction (Table 1,
entry 3). However, the removal of the hydroxy group and
introduction of sterically demanding aryl substituents pro-
vided the catalyst 5d, which showed good stereoselectivity
[*] Dr. W. Zhuang, Dr. S. Saaby, Prof. K. A. Jørgensen
The Danish National Research Foundation:
Center for Catalysis
Department of Chemistry, Aarhus University
DK-8000 Aarhus C (Denmark)
Fax: (45)8619-6199
E-mail: kaj@chem.au.dk
[**] This work was made possible by a grant from The Danish National
Research Foundation. We are grateful to Dr. R. G. Hazell for X-ray
crystallographic analysis.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
4476
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DOI: 10.1002/anie.200460158
Angew. Chem. Int. Ed. 2004, 43, 4476 –4478

Angewandte
Chemie
(d.r. > 20:1, 80% ee), although it had only a moderate
turnover number (39% yield). The chiral diamine (S)-1-(2-
pyrrolidinylmethyl)pyrrolidine (5e) finally proved to be the
catalyst of choice, and under the same conditions afforded the
Mannich product in 56% yield, with a d.r. of 15:1 and with
86% ee for the major diastereomer (Table 1, entry 5). By
lowering the amount of catalyst and aldehyde to 5 mol% and
2.0 equivalents, respectively, and changing the solvent to
Et2O, it was possible to prepare 3a in almost quantitative
yield (99%), with excellent diastereoselectivity (> 20:1), and
with 91% ee (Table 1, entries 6–8). Lowering of the temper-
ature only had a minimal effect on the enantioselectivity
(Table 1, entry 9), but the Mannich reaction could be carried
out in the presence of only 2mol% of the catalyst without
compromising the yield or enantioselectivity (Table 1,
entry 10).
bases 3e,f with 87 and 84% ee, respectively (Table 2, entries 5
and 6).
The best results with propionaldehyde (2b) as the
substrate in the reaction with ketimine 1a were obtained in
CH2Cl2. The major diastereomer 3g (d.r. 5:1) was formed in
good yield and with high enantioselectivity (95% ee; Table 2,
entry 7). Finally, when unsaturated 4-pentenal (2c) was used
as the aldehyde donor, the Mannich base 3h was isolated in
82% yield with an excellent optical purity of 98% ee (Table 2,
entry 8).
It was demonstrated previously that these cyclic carba-
mates are readily cleaved under basic solvolytic reaction
conditions to liberate the phenolic hydroxy group.[5] By this
protocol, triflate-substituted aryl compounds are potentially
accessible for further elaboration, such as palladium-cata-
lyzed cross-coupling reactions and deoxygenation.
The absolute and relative configuration of the Mannich
products 3 and 4 was determined by X-ray crystallography
and by comparison of HPLC traces and signs of optical
rotation (see Supporting Informa-
Having optimized the reaction conditions, we investigated
the scope of the reaction by treating a series of ketimines 1a–f
with aldehyde donors 2a–c, as summarized in Table 2. Imines
tion). The condensation of 3 f
Table 2: Reaction of ketimines 1a–f with aldehydes 2a–c under the optimized reaction conditions.
(84% ee) with 2,4,6-trichlorophe-
nylhydrazine and subsequent crys-
tallization from acetone provided
optically pure crystals of the corre-
sponding chiral hydrazone which
were suitable for X-ray crystallo-
graphic analysis.
Based on the absolute config-
uration of the product, attack at
the Si face of the ketimine was
observed for all catalysts 5a–e
tested. However, a very interesting
reversal of diastereoselectivity was
found when the carboxylic acid
functionality of l-proline (5a) was
Entry Imine Solvent R1 R2
R3
R4
Product Yield [%][a] 3/4[b]
ee [%][c]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1a
1a
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
CH2Cl2
CH2Cl2
H
H
H
H
H
H
H
H
H
H
Me
OMe iPr
F
H
H
H
H
iPr
iPr
3a
3b
3c
3d
3e
3 f
3g
99
98
95
97
90
93
72
82
>20:1 91
6:1 89
9:1 86
19:1 83
>20:1 87
>20:1 84
5:1 95
iPr
iPr
iPr
Me
OMe
À
À
C4H4
substituted for
a non-acidic or
H
H
H
H
basic substituent (Table 1, entry 1
versus entries 2–5). The observed
stereoselectivity with l-proline as
the catalyst is in good agreement
with the transition-state models
proposed by Córdova and Bar-
bas,[4f] List et al.,[4d] and Bahma-
nyar and Houk[11] for the catalytic
allyl 3h
4:1 98
[a] Combined yield of the two isolated diastereomeric products. [b] The diastereomeric ratio was
determined by 1H NMR spectroscopic analysis of the crude product. [c] The ee value for the major
product (with R configuration at the quaternary stereocenter) was determined by HPLC on a chiral
stationary phase (see Supporting Information for details).
with an electron-donating substituent (a methyl or a methoxy
group) in the 4-position underwent a clean reaction with
isovaleraldehyde (2a) in the presence of the catalyst 5e
(5 mol%). Upon filtration of the reaction mixture through a
column of silica gel, the corresponding products 3b,c were
isolated in very high yields, with good diastereomeric ratios of
6:1 and 9:1, and with 89 and 86% ee, respectively (Table 2,
entries 2and 3). The reaction of the 4-fluoro-substituted
ketimine 1d afforded the Mannich product 3d in nearly
quantitative yield (97%) with excellent diastereoselectivity
(19:1) and 83% ee (Table 2, entry 4). The 3-methoxy-substi-
tuted and 1-naphthol-derived ketimines 1e,f were also
successfully employed as substrates in the reaction with
aldehyde 2a to give the diastereomerically pure Mannich
enantioselective Mannich reaction of imines derived from
glyoxylic aldehydes. We propose that l-proline directs
reaction at the Re face of the enamine, and the transition-
state model in Scheme 1a may account for the stereochem-
istry of the Mannich product 4a observed.
In contrast, when 5e was used as the catalyst, interactions
such as hydrogen bonding between the enamine intermediate
and the lone pair of electrons on the nitrogen atom of the
ketimine can not occur, as the reaction is conducted under
neutral conditions.[12] The concept of intrinsic protecting-
group anchoring inherently rules out the possibility of E/Z
isomerization of the ketimine, and a linear transition state in
which the Si face of the enamine approaches the Si face of the
imino electrophile may explain the observed stereochemistry
Angew. Chem. Int. Ed. 2004, 43, 4476 –4478
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Communications
Martin, J. Am. Chem. Soc. 2002, 124, 827 – 833; e) A. Córdova,
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Scheme 1. A schematic representation of the approach of the ketimine
to two enamine intermediates that accounts for the observed diaster-
eoselectivities: a) reaction occurs at the Si face of the imine and the
Re face of the enamine; b) reaction occurs at the Si face of the imine
and the Si face of the enamine.
(Scheme 1b).[13] An E geometry of the enamine double bond
is anticipated on the basis of energy calculations, and an
antiperiplanar approach of the reaction partners would
[5] For the Lewis acid catalyzed enantioselective Mannich reaction
of ketimines, see: S. Saaby, K. Nakama, M. A. Lie, R. G. Hazell,
K. A. Jørgensen, Chem. Eur. J. 2003, 9, 6145 – 6154.
[6] For recent reviews on the asymmetric construction of quaternary
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402– 415; Angew. Chem. Int. Ed. 1998, 37, 388 – 401.
[7] For a review on the asymmetric synthesis of quaternary a-amino
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b) M. Altorfer, C. Lehmann, P. Schꢀnholzer, K. Mꢁller, J. Org.
Chem. 1996, 61, 4080 – 4086, and references therein.
À
minimize steric repulsions in the C C bond-forming step.
In conclusion, we have reported the first organocatalytic
enantioselective Mannich reaction of ketimines and unmodi-
fied aldehydes based on the concept of intrinsic protecting-
group anchoring. Under the catalysis of chiral secondary
amines (2–5 mol%), optically active quaternary a-amino acid
derivatives were formed in high yields (72–99%) with optical
purities ranging from 83 to 98% ee. Depending on the choice
of catalyst, either diastereomer of the Mannich base can be
prepared.
Received: March 30, 2004 [Z460158]
[9] See, for example: a) R. Sarges, J. Bordner, B. W. Donimy, M. J.
Peterson, E. B. Whipple, J. Med. Chem. 1985, 28, 1716 – 1720;
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Kikkiwa, T. Kaneko, A. Takahashi, K. Sugimura, Y. Koike, J.
Ishii, N. Sakamoto, Diabetes Care 2001, 24, 1776 – 1782.
Keywords: amino acids · chiral amines · Mannich bases ·
.
organocatalysis · quaternary stereocenters
[1] For a review, see: a) E. F. Kleinmann in Comprehensive Organic
Synthesis, Vol. 2 (Eds.: B. M. Trost, I. Fleming), Pergamon,
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[10] The ketimine 6, without intrinsic protecting-group anchoring,
did not react with isovaleraldehyde (2a) in the presence of
5 mol% of l-proline (5a).
[2] For leading references, see: a) A. E. Taggi, A. M. Hafez, T.
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Matsubara, Y. Nakamura, H. Kitigawa, M. Sugiura, J. Am.
Chem. Soc. 2003, 125, 2507 – 2515, and references therein.
[3] For Lewis acid catalyzed direct asymmetric Mannich reactions,
see, for example: a) S. Yamasaki, T. Iida, M. Shibasaki,
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M. Shibasaki, Tetrahedron 1999, 55, 8857 – 8867; c) S. Matsu-
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[4] For direct organocatalyzed enantioselective Mannich reactions
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122, 9336 – 9337; b) K. Sakthivel, W. Notz, T. Bui, C. F. Barba-
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[12] For an example of the combination of protic acids and chiral
diamines as the catalyst, see: S. Saito, M. Nakadai, H.
Yamamoto, Synlett 2001, 1245 – 1248.
[13] See also references [4f,n] for another approach of imines to a
related enamine intermediate.
4478
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 4476 –4478