Organocatalytic asymmetric biomimetic transamination: From α-keto esters to optically active α-amino acid derivatives

Article abstract of DOI:10.1021/ja203138q

This paper describes an effective chiral base-catalyzed biomimetic transamination of α-keto esters using simple benzyl amines. A wide variety of α-amino esters containing various functional groups can be synthesized in high enantioselectivity and reasonable yield.

Full text of DOI:10.1021/ja203138q

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Organocatalytic Asymmetric Biomimetic Transamination:
From r-Keto Esters to Optically Active r-Amino
Acid Derivatives
Xiao Xiao,† Ying Xie,† Cunxiang Su,† Mao Liu,† and Yian Shi*,†,‡
†Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of
Chemistry, Chinese Academy of Sciences, Beijing 100190, China
‡Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
S Supporting Information
b
catalysts, demethylated quinine derivative C7 was found to be
ABSTRACT: This paper describes an effective chiral base-
catalyzed biomimetic transamination of R-keto esters using
simple benzyl amines. A wide variety of R-amino esters
containing various functional groups can be synthesized in
high enantioselectivity and reasonable yield.
the most effective, giving the amino ester in 69% ee (Table 1,
entry 7).15 The corresponding pseudoenantiomeric catalyst
derived from quinidine (C8) gave the opposite configura-
tion of the amino ester product in 62% ee (Table 1, entry 8).
Further studies showed that the ee increased as the size of
the ester increased (Table 1, entries 9À11), and 92% ee was
obtained with keto ester 17d (Table 1, entry 11). Various
amines donors were also examined. Studies show that the
structure of amine has also a large impact on the enantios-
electivity (Table 1, entries 12À21), with o-ClPhCH2NH2 (8a)
being the most enantioselective (Table 1, entry 11). In all
these cases, high conversions were observed for R-keto esters.
However, there were varying amounts of the corresponding
ketimines (11) and enamines (12) still remaining in the
reaction mixture, consequently affecting the overall yield of
R-amino esters. The relative amounts of the ketimines (11),
enamines (12), and aldimines (14) could be a result of equi-
librium and could be affected by the structure of benzyl amines
(Scheme 2).
As shown in Table 2, the asymmetric transamination can be
extended to a wide variety of R-keto esters to give the corre-
sponding R-amino esters in 88À92% ee and 47À71% yield.
Studies showed that introducing various substituents onto the
phenyl group of 2-oxo-4-phenylbutanoate (15aÀg) did not af-
fect the ee’s (Table 2, entries 1À7). High ee was also obtained
when the phenyl group was replaced with other aromatics such as
thiophene (Table 2, entry 8). A variety of substituted phenyla-
lanine derivatives were formed in 88À91% ee using this transa-
mination process (Table 2, entries 9À15). Keto esters con-
taining no aromatics were equally effective substrates (Table 2,
entries 16À22). Unsaturated R-amino esters can be obtained in
high ee’s (Table 2, entries 18 and 19). Heteroatoms like O and S
are tolerated (Table 2, entries 20À22). However, the current
reaction system is not effective for allylglycine partly due to the
double bond migration during the transamination. No amino
ester product was observed when phenyl keto ester was used
likely due to the fact that tautomerization of the conjugated
ketimine to the corresponding aldimine is thermodynamically
unfavorable.
ptically active R-amino acids and their derivatives are an
O
important class of molecules in biological systems and
organic synthesis.1 Various methods have been developed
for the synthesis of chiral R-amino acids.2À4 Transamination
of R-keto acids (1) from pyridoxamine (2) catalyzed by
transaminase is an important process to generate R-amino
acids in biological systems (Scheme 1).2 Biomimetic transa-
mination with nonenzymatic catalysts provides an attractive
approach to optically active R-amino acids and their deriva-
tives (Scheme 2).5 Such processes with chiral guanidine6 and
Lewis acid catalysts7 have been reported, and up to 46% ee has
been obtained.7b,8À12 It appears that high yields can be
obtained for the reaction with isolated ketimines.6 However,
many ketimines are difficult to isolate, which potentially limits
substrate scope. On the other hand, the in situ process is more
complicated, and the reaction efficiency will be highly dependent
on the delicate balance among all the steps (Scheme 2), which
frequently leads to relatively lower yield. Therefore, the de-
velopment of an effective catalytic biomimetic transamination
with high enantioselectivity and broad substrate scope pre-
sents a formidable challenge. During our studies, we have
found that R-amino esters (16) can be obtained from R-keto
esters (15) with high enantioselectivity in reasonable yield
with quinine derived compound C7 (Figure 1) as catalyst and
o-ClPhCH2NH2 (8a) as amine donor (Scheme 3).13 To the
best of our knowledge, this represents the first catalytic highly
enantioselective synthesis of R-amino esters from R-keto
esters via biomimetic transamination. Herein, we wish to re-
port our preliminary results on this subject.
Our initial studies started with ethyl 2-oxo-4-phenylbutanoate
(17a) as substrate and o-ClPhCH2NH2 (8a) as amine donor
using various chiral bases as catalysts including (À)-sparteine
(C1) and cinchona alkaloid derivatives (C2ÀC8) (Figure 1).14
As shown in Table 1 (entries 1À8), it was found that the
structures of these derivatives have a dramatic effect on
both catalytic activity and enantioselectivity. Among these
Received: April 5, 2011
Published: July 19, 2011
r
2011 American Chemical Society
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|

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Scheme 1. Biological Transamination
Table 1. Studies on Catalysts, r-Keto Esters, and Amine
Donorsa
Scheme 2. Chiral Base-Catalyzed Biomimetic
Transamination
a All reactions were carried out with R-keto ester 17 (0.50 mmol),
benzyl amine 8 (0.50 mmol), catalyst (0.050 mmol), and 4 Å
molecular sieves (0.050 g) in dry benzene for 24 h (for detail, see
Method A in Supporting Information). b The conversion was deter-
1
mined by H NMR of the crude reaction mixture based on R-keto
esters 17. There are varying amounts of the corresponding imines
and enamines present in the reaction mixture besides corresponding
aldimines. c The ee’s were determined by chiral HPLC (Chiralpak
OD-H column) after the amino esters were converted into their
N-benzoyl derivatives.
Figure 1. Selected examples of catalyst examined.
Scheme 3
unfavorable interaction between the butyl group of the catalyst
and the keto ester substrate.
In summary, we have developed an effective biomimetic
asymmetric synthesis of R-amino esters from R-keto esters via
readily available chiral base-catalyzed transamination from
simple benzyl amines. A wide variety of R-amino esters with
various functional groups can be obtained with high enantios-
electivity in reasonable yield. The current process provides a
viable approach to synthesize optically active R-amino acids
and their derivatives, which further illustrates the synthetic
potential of organocatalytic biomimetic transformations.
Further efforts will be devoted to understanding the reaction
mechanism as well as developing more effective catalytic systems
to expand substrate scope and to explore new transamination
processes.
It appears that the enantioselectivity is primarily influenced
by the keto ester moiety, which provides certain degree of
predictability for the stereochemical outcome. While a precise
understanding of the origin of the enantioselectivity awaits
further study, a plausible transition state model is proposed in
Figure 2. The (R)-amino ester is formed predominately since
both transition state B in the deprotonation step and transition
state D in the protonation step are disfavored likely due to the
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Table 2. Catalytic Asymmetric Transamination of r-Keto
Estersa,b
Figure 2. Proposed transition model for transamination.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, char-
b
acterizations, and data for determination of enantiomeric excess
of transamination products and their derivatives along with the
1H and 13C NMR spectra of compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
yian@lamar.colostate.edu
’ ACKNOWLEDGMENT
We gratefully acknowledge the National Basic Research Pro-
gram of China (973 program, 2010CB833300) and the Chinese
Academy of Sciences for the financial support. This paper is
dedicated to Professor Barry M. Trost on the occasion of his 70th
birthday.
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