Highly efficient iridium-catalyzed asymmetric hydrogenation of unprotected β-enamine esters

Article abstract of DOI:10.1021/ja105674y

A highly efficient and enantioselective hydrogenation of unprotected β-enamine esters catalyzed by Ir-(S,S)-f-Binaphane complex has been developed. This methodology provides straightforward access to free β-amino acids in high yields with excellent enantioselectivities up to 97% ee and high reactivities (TON > 5000).

Full text of DOI:10.1021/ja105674y

Published on Web 08/26/2010
Highly Efficient Iridium-Catalyzed Asymmetric Hydrogenation of Unprotected
ꢀ-Enamine Esters
Guohua Hou, Wei Li, Miaofeng Ma, Xiaowei Zhang, and Xumu Zhang*
Department of Chemistry and Chemical Biology & Pharmaceutical Chemistry, Rutgers, The State UniVersity of New
Jersey, Piscataway, New Jersey 08854
Received July 1, 2010; E-mail: xumu@rci.rutgers.edu
One drawback of this method is really low turnovers (<1000) due
Abstract: A highly efficient and enantioselective hydrogenation
of unprotected ꢀ-enamine esters catalyzed by Ir-(S,S)-f-Bi-
naphane complex has been developed. This methodology pro-
vides straightforward access to free ꢀ-amino acids in high yields
with excellent enantioselectivities up to 97% ee and high reac-
tivities (TON > 5000).
to product inhibition. Later, Ru catalysts were also reported to
catalyze asymmetric hydrogenation of unprotected ꢀ-enamine esters
with high ee’s by the Takasago group.11 More recently, both of
these methodologies have been successfully applied to the synthesis
of Sitagliptin, achieving excellent enantioselectivities.7d,12 Inspired
by these encouraging results and our recent work on the asymmetric
hydrogenation of unprotected N-H imines,13 we decided to tackle
the asymmetric hydrogenation of this class of challenging substrates.
Enantiopure ꢀ-amino acids and their derivatives are ubiquitous
important structural motifs in important natural products and
pharmaceuticals.1 In life sciences, extensive existence and applica-
tions of chiral ꢀ-amino acids have been found in biologically active
peptides. Chiral ꢀ-amino acids are also widely used as key
intermediates or chiral building blocks in the synthesis of small-
molecule pharmaceuticals,2 such as (S)-dapoxetine,3 which is used
for the treatment of a variety of disorders as depression, bulimia
or anxiety, and some antiretroviral agents, (S)-maraviroc,4 com-
pound 1 and 2 (Figure 1).5,6
Herein we report the first example of Ir-catalyzed asymmetric
hydrogenation of unprotected ꢀ-enamine esters affording free
ꢀ-amino esters with excellent enantioselectivities (up to 97% ee)
and high reactivities (TON > 5000) (Scheme 1).14
Scheme 1
Considering the fact that the primary beta amine ester products
in this transformation could have a strong inhibitory effect on the
catalyst,15 and also the fact that the products are unstable with ester
substrates in some solvent,7a we chose ꢀ-enamine hydrochloride
esters as the substrates for our study. Our initial evaluation began
with hydrogenation of ꢀ-enamine hydrochloride ester 3a as the
model substrate with a series of catalysts. Few promising results
were obtained using Rh-phosphine catalysts. A number of Ir-
phosphine complexes were also screened (Table 1, entries 1-11).
We were gratified to find that (S,S)-f-Binaphane ligand was able to
achieve excellent enantioselectivity as well as full conversion (entry
3). Other types of bidentate diphosphine ligands, such as TangPhos,
Figure 1
Due to its significance in chemical synthesis, many approaches
have been developed for the enantioselective synthesis of chiral
ꢀ-amino acids.7 Although catalytic asymmetric hydrogenation could
be a successful methodology for the preparation chiral R-amino
acids in industry,8 its application for large-scale synthesis of
enantiopure ꢀ-amino acids has been largely limited by the indis-
pensable involvement of N-acyl in current/most hydrogenation
approaches. The chelating assistance of the N-protecting group plays
a crucial role in achieving high reactivity and enantioselectivity.9
To avoid the redundancy of introduction and removal of the acyl
group, developing a generally applicable and highly efficient catalyst
system for direct hydrogenation of unprotected enamine esters
would be an ideal solution to access free enantiopure ꢀ-amino acids.
However, only few related works were reported. In 2004, Merck
and Solvias groups reported the first example of catalytic asym-
metric hydrogenation of unprotected ꢀ-enamine esters and amides
by using Rh-Josiphos complexes with excellent enantioselectivity.10
t
Me-DuPhos, BINAP, Bu-Josiphos, and monodentate phosphorus
ligands, such as Monophos, NMe-NBn-Monophos, showed either
significantly lower enantioselectivities or reactivities (entries 1-2
and 4-11). Interestingly, the solvent played a key role in this Ir-
f-Binaphane catalyst system. Low conversions were observed in
CH2Cl2, THF, or toluene (entries 14-16). Only moderate enati-
oselectivities were obtained in MeOH and EtOH, although full
conversions were achieved (entries 12-13). However, consistent
with the asymmetric hydrogenation of N-H imines,13 we discov-
ered that a mixture solvent of MeOH/CH2Cl2 could provide the
best ee’s and high reactivities. By adjusting the solvent ratio to
MeOH/CH2Cl2 ) 2:1, 97% ee was obtained under the optimized
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10.1021/ja105674y  2010 American Chemical Society

C O M M U N I C A T I O N S
conditions (entry 20). Examination of the hydrogen pressure effect
revealed that insufficient H2 pressure could result in incomplete
conversion albeit without any enantiselectivity loss (entry 21).
To explore the potential application of the Ir-(S,S)-f-Binaphane
catalyst system in the practical synthesis of chiral ꢀ-amino acids,
we further studied the reactivity and the turnover number (TON)
limit of the hydrogenation of 3b (Scheme 2). The transformation
was completed with 0.1 mol % catalyst (TON ) 1000) at rt and
even with as low as 0.02 mol % catalyst (TON ) 5000) at 40 °C.
Only very slight erosions of ee were observed. Furthermore, when
the substrate to catalyst ratio (S/C) was furthered increased to 10 000
(0.01 mol % catalyst), the excellent enantioselectivity still remained
unchanged. To our best knowledge, this is the highest turnover for
asymmetric hydrogenation of unprotected ꢀ-enamine esters to date.
The high reactivity suggested that the hydrogenation possibly
proceeded via a “nonchelate” mechanism, without Ir/nitrogen
interaction. Aminium salt loss of the coordination ability compared
to the amine counterpart could also minimize or avoid the product
inhibition.15
Table 1. Asymmetric Hydrogenation of 3a (Ar ) Phenyl, R ) Et)a
entry
ligand
solvent
conv (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
(S,S,R,R)-TangPhos MeOH/CH2Cl2 (2:1)
>99
>99
>99
60
>99
>99
23
46
37
97
6
14
29
35
19
20
(S,R)-DuanPhos
(S,S)-f-Binaphane
(R)-Me-DuPhos
(R)-BINAP
MeOH/CH2Cl2 (2:1)
MeOH/CH2Cl2 (2:1)
MeOH/CH2Cl2 (2:1)
MeOH/CH2Cl2 (2:1)
MeOH/CH2Cl2 (2:1)
MeOH/CH2Cl2 (2:1)
MeOH/CH2Cl2 (2:1)
MeOH/CH2Cl2 (2:1)
(R)-SEGPHOS
(S)-PhanePhos
(R,S)-tBu-JosiPhos
(S)-NMe-NBn-
MonoPhos
78
98
10
11
(R)-MonoPhos
(S,RR)-MonoPhos-
PE
MeOH/CH2Cl2 (2:1)
MeOH/CH2Cl2 (2:1)
74
96
3
12
12
13
14
15
16
17
18
19
(S,S)-f-Binaphane
(S,S)-f-Binaphane
(S,S)-f-Binaphane
(S,S)-f-Binaphane
(S,S)-f-Binaphane
(S,S)-f-Binaphane
(S,S)-f-Binaphane
(S,S)-f-Binaphane
MeOH
EtOH
CH2Cl2
Toluene
>99
>99
10
5
14
>99
>99
>99
>99
69
75
4
Scheme 2
41
33
89
87
94
94
97
97
THF
MeOH/CH2Cl2 (1:1)
MeOH/CH2Cl2 (3:1)
MeOH/THF (2:1)
MeOH/CH2Cl2 (2:1)
MeOH/CH2Cl2 (2:1)
20d (S,S)-f-Binaphane
21e
(S,S)-f-Binaphane
a Reaction conditions: [Ir(COD)Cl]2/phosphine/substrate
) 0.5:1.0:100,
In conclusion, we have developed a highly efficient and highly
enantioselective hydrogenation of unprotected ꢀ-enamine esters
catalyzed by the Ir-(S,S)-f-Binaphane complex, which provides
efficient access to enantiomerically enriched ꢀ-amino acids without
use of a protecting group. This method could be potentially useful
for the practical preparation of chiral drug intermediates. Further
studies are underway and will be reported in due course.
ligand/metal ) 1:1, rt, 100 atm of H2, 12 h. b Determined by GC analysis.
c Determined by chiral GC analysis of the corresponding acetamides (see
Supporting Information). d 50 atm of H2. e 20 atm of H2.
Encouraged by the promising result in the hydrogenation of
substrate 3a, a variety of ꢀ-enamine hydrochloride esters were
examined using the Ir-f-Binaphane catalyst system (Table 2). The
R group in the ester moiety had no obvious influence on the
reactivity and enantioselectivity of this reaction (entries 1-2).
The electronic property of substituents on the aryl ring of the
substrate had very little effect on the enantiomeric excess of the
product. Substrates bearing electron-donating or electron-withdraw-
ing substituents on the aromatic ring were all smoothly hydroge-
nated to the corresponding products with high enatioselectivities,
92-97% ee (entries 3-9). The substrate with a substituent at the
ortho position (3j) and with a 1-naphthyl group (3l) resulted in
diminished ee values possibly due to the steric hindrance (entries
10-11). Both the 2-naphthyl substrate 3m and 2-thienyl 3k afforded
products in 94 and 95% ee, respectively (entries 12-13).
Acknowledgment. We thank the National Institutes of Health
(GM58832) and Merck & Co., Inc. for the financial support.
Supporting Information Available: Complete ref 5, experimental
procedures, the characterizations of substrates and products, and the
analysis of enantioselectivities of hydrogenation products. This material
is available free of charge via the Internet at http://pubs.acs.org.
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