Rh-catalyzed asymmetric hydrogenation of α-aryl imino esters: An efficient enantioselective synthesis of aryl glycine derivatives

Article abstract of DOI:10.1002/anie.200601540

(Chemical Equation Presented) A highly enantioselective synthesis of aryl glycine derivatives from asymmetric hydrogenation was achieved by subjecting N-PMP-protected α-aryl imino esters to hydrogenation under Rh-bisphosphine catalysis (see scheme; PMP = para-methoxyphenyl, cod = cycloocta-1,5-diene). The PMP group could be easily removed for the preparation of enantiomerically pure aryl glycine derivatives.

Full text of DOI:10.1002/anie.200601540

Communications
Asymmetric Catalysis
esters.[6] However, aryl glycines lacking the b-hydrogen
atom cannot be synthesized in an analogous manner by
hydrogenation of alkenes. Nevertheless, asymmetric hydro-
DOI: 10.1002/anie.200601540
=
genation of the C N double bond in the corresponding a-
Rh-Catalyzed Asymmetric Hydrogenation of a-
Aryl Imino Esters: An Efficient Enantioselective
Synthesis of Aryl Glycine Derivatives**
imino acids or esters could be an alternative way to synthesize
chiral aryl glycines. In fact, reduction of a C N bond is the key
=
step of transaminase in some biological transformations.
Despite the great potential of this transformation, there have
been very few reports of both good enantioselectivities and
yields, because the imine substrates are difficult to prepare
and also because the substrates show relatively poor reactivity
toward hydrogenation.[7] Recently, Kadyrov et al. reported
the synthesis of chiral a-N-benzylamino acids resulting from
the reductive amination of keto acids, but the method proved
less successful for aryl glycines.[7c] Amii and co-workers have
also reported the asymmetric hydrogenation of a-fluorinated
imino esters, but this method is successful for only a limited
range of substrates.[7d]
Gao Shang, Qin Yang, and Xumu Zhang*
Enantiomerically pure a-amino acids and their derivatives
are of great importance in pharmaceutical, biological and
synthetic chemistry. An interesting class of these compounds
are the chiral aryl glycines, which are important building
blocks for many bioactive molecules such as amoxicillins,[1]
nocardicins,[2] cephalecins,[3] and glycopeptide antibiotics.[4]
A
number of methods have been applied to synthesize these
intermediates,[5] such as the Sharpless asymmetric amino-
hydroxylation,[5b] the catalytic enantioselective amination of
enolate intermediates,[5c] and the asymmetric Strecker reac-
tion.[5d,e] However, achieving regioselectivity has been a
challenge in the asymmetric aminohydroxylation reaction,
and in the enantioselective amination of enolates, high
catalyst loading has been used with only moderate success.
These problems prompted us to seek for an alternative
approach to synthesize chiral aryl glycines. Herein, we report
a highly enantioselective synthesis of a series of chiral aryl
glycine derivatives by using the asymmetric hydrogenation of
a-aryl imino esters with a Rh–tangphos catalyst (tangphos =
1,1’-di-tert-butyl-(2,2’)-diphospholane, see Scheme 1).
We started our investigation using PMP-protected a-aryl
imino esters 1 (Table 1) as the substrates, since they could be
synthesized in one step and in high yield from the corre-
Table 1: Asymmetric hydrogenation of a-imino ester 1a.
Entry Catalyst[a] H2 pressur-
e [atm]
T [8C] Solvent Conv. [%][b] ee [%][c]
1
2
3
4
5
6
7
8
E
F
30
30
30
30
50
70
50
50
25
25
25
25
25
25
50
80
CH2Cl2 >95
CH2Cl2 >95
CH2Cl2 29
93
83
75
85
93
93
95
91
G
H
E
E
E
E
CH2Cl2 70
CH2Cl2 >95
CH2Cl2 >95
CH2Cl2 >99
CH2Cl2 >99
[a] E: Rh[(S,S,R,R)-tangphos](cod)]BF4; F: [Rh{(S)-binapine}(cod)]BF4;
G: [Rh{(R,R)-Me-duphos}(cod)]BF4; H: [Rh{(R,R)-Et-duphos}(cod)]BF4.
[b] % Conversions were determined by 1H NMR spectroscopy. [c] ee val-
ues were determined by chiral HPLC. PMP=para-methoxyphenyl, cod=
cycloocta-1,5-diene.
Scheme 1. Chiral ligands for asymmetric hydrogenation.
Asymmetric hydrogenation catalyzed by transition metals
has been shown to be highly efficient in many syntheses.[6]
A
sponding a-keto esters,[8] and the resulting products could be
deprotected under mild conditions using cerium ammonium
nitrate (CAN).[9] Moreover, the PMP-protected a-aryl imino
esters are notably more stable than their corresponding
imines. Key to achieving high enantioselectivity and turnover
rates in the reduction of a-aryl imino esters is to find an
effective catalyst. We initially examined the hydrogenation of
1a using the Rh–tangphos catalyst, which was developed
within our research group. Its electron-rich character and
rigid, well-defined geometry offers both high activity and
enantioselectivity in the asymmetric hydrogenation of a wide
range of substrates.[6d,10]
large number of a-alkyl amino acids and their derivatives
have been prepared with high enantioselectivity from the
asymmetric hydrogenation of a-dehydroamino acids or
[*] G. Shang, Q. Yang, Prof. X. Zhang
Department of Chemistry
The Pennsylvania State University
104 Chemistry Building, University Park, PA 16802 (USA)
Fax: (+1)814-863-8403
E-mail: xumu@chem.psu.edu
[**] This work was supported by the National Institutes of Health
(GM58832).
Several commercially available chiral ligands were also
screened for the hydrogenation of 1a (Scheme 1). We
achieved up to 93% ee with the Rh–tangphos catalyst,
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
6360
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Angewandte
Chemie
Table 2: Asymmetric hydrogenation of a-imino esters.
(Table 1, entry 1), while 83% ee was obtained with the Rh–
binapine catalyst (Table 1, entry 2). Hydrogenation with Me-
duphos and Et-duphos offered moderate conversions and
ee values (29% and 75% ee for F; 70% and 85% ee for G;
Table 1, entries 3 and 4).
The effects of hydrogen pressure and reaction temper-
ature on the hydrogenation were also studied. An increase in
pressure from 30 to 70 atm had no apparent effect on the
conversion or enantioselectivity of this transformation
(Table 1, entries 1, 5, and 6). However, increasing the reaction
temperature from 258C to 508C resulted in a slightly higher
enantioselectivity (Table 1, entry 7), but the ee value dropped
to 91% at 808C (Table 1, entry 8). An investigation into the
effects of the solvent was also carried out. Common solvents
such as THF, methanol, toluene, and acetone gave either poor
conversion or low ee values. Only dichloromethane and
trifluoroethanol resulted in both high conversion and enan-
tioselectivity.
We examined the scope of the reaction using different a-
imino esters under the optimized reaction conditions
(Table 1, entry 7). Thus, we synthesized a number of a-
imino esters 1a–1o with various substituents on the aromatic
ring or the ester group.[8] Asymmetric hydrogenation was
performed using the [Rh{(S,S,R,R)-tangphos}(cod)]BF4 com-
plex as the catalyst precursor. Good conversions were
observed for all substrates, with ee values ranging from 90%
to 95%. Notably, 99% ee was achieved after one recrystal-
lization when using 2a. The electronic properties of the
substituents had no apparent effect on the yields or the
enantioselectivities. The presence of the sterically hindered
naphthyl group resulted in slightly lower enantioselectivity
(90% and 91% ee; Table 2, entries 11 and 12). A lower
ee value was also observed with 1n bearing an ethyl group at
the R’ position (84% ee; Table 2, entry 14). To explore the
efficiency of the catalyst for a-alkyl imino esters, 1o was
synthesized and hydrogenated under the optimized condi-
tions. We were pleased to find that a high ee value was
observed (94% ee; Table 2, entry 15).
To determine the potential of the asymmetric hydro-
genation of a-aryl imino esters catalyzed by Rh–tangphos as a
practical means to synthesize chiral a-aryl amino acid
derivatives the hydrogenation of 1a was carried out using a
low catalyst loading (substrate/catalyst 1000:1) and a gram of
the substrate (1.08 g, 4 mmol). Using catalyst made in situ and
CH2Cl2 as the solvent, a-aryl amino ester 2a was obtained in
82% yield (turnover number (TON) > 820) and with
91% ee.[11] Moreover, the PMP group of 2a could be easily
removed by CAN in 86% yield, without affecting the
ee value.[9]
In conclusion, a series of chiral aryl glycines were
synthesized in high enantioselectivity in the first Rh-catalyzed
asymmetric hydrogenation of the corresponding a-aryl imino
esters using the tangphos ligand. This method is potentially
useful for the preparation of a variety of chiral aryl glycines
with high ee values and yields. However, the synthesis of the
imine substrates and the relatively high catalytic loadings are
limitations of this work. Further studies to improve the results
and to expand the range of substrates that can be used will be
reported in due course.
Entry
R
R’
Product Conv. [%][a] ee [%][b] Config.[c]
1
2
3
4
5
6
7
C6H5 (1a)
2-FC6H4 (1b)
3-FC6H4 (1c)
4-FC6H4 (1d)
4-ClC6H5 (1e)
4-BrC6H5 (1 f)
2-CH3OC6H4
(1g)
3-CH3OC6H4
(1h)
4-CH3OC6H5
(1i)
4-CH3C6H5 (1j) CH3 2j
2-naphthyl (1k) CH3 2k
1-naphthyl (1l) CH3 2l
3-nitro (1m)
C6H5 (1n)
CH3 2a
CH3 2b
CH3 2c
CH3 2d
CH3 2e
CH3 2 f
CH3 2g
>99(99)
>99
>95
>95
>99
95(99) S(À)
91
94
93
92
92
95
(À)
(À)
(À)
(À)
(À)
(À)
>95
>95
8
9
CH3 2h
CH3 2i
>99
>95
93
93
(À)
(À)
10
11
12
13
14
15
>99
>99
>95
>99
>95
84
93
90
91
93
84
94
(À)
(À)
(À)
(À)
(À)
(+)
CH3 2m
C2H5 2n
cyclohexyl (1o) CH3 2o
1
[a] % Conversions were determined by H NMR spectroscopy and the
values in parentheses correspond to the yield of the isolated product.
[b] ee values were determined by chiral HPLC and the value in
parentheses corresponds to the ee value after one recrystallization.
[c] Absolute configuration was determined by comparison of the sign of
the optical rotation of the deprotected product (phenylglycine methyl
ester) with (S)-phenylglycine methyl ester.
Experimental Section
General procedure for asymmetric hydrogenation of a-imino esters:
[Rh(cod)2]BF4 (40.6 mg, 0.1 mmol) and (S,S,R,R)-tangphos (28.6 mg,
0.1 mmol) were dissolved in degassed dichloromethane (2mL) in a
Schlenk tube under N2. After stirring the solution at room temper-
ature for 1 h, degassed hexanes (10 mL) was added to precipitate the
catalyst, which was filtered under nitrogen to give [Rh{(S,S,R,R)-
tangphos}(cod)]BF4 as an orange solid. The complex (52.0 mg, 88.9%
yield) was stored in a nitrogen-filled glovebox until required. The
complex (11.7 mg, 0.02mmol) was dissolved in degassed dichloro-
methane (10 mL) in a glovebox and divided equally among 10 vials.
To each of the vials was added 1 (0.2mmol, substrate/catalyst 100:1)
and the resulting mixture was transferred to an autoclave, which was
then charged with H2 (50 atm). The hydrogenation was performed at
508C for 24 h. After carefully releasing the hydrogen gas, the solvent
was removed under reduced pressure. The crude product was purified
through a plug of silica gel (eluting with a mixture of Hex/EtOAc,
10:1) to afford the aryl glycine 2. The enantiomeric excess was
determined by HPLC on a chiral stationary phase.
Received: April 19, 2006
Revised: July 11, 2006
Published online: August 28, 2006
Keywords: amino acids · asymmetric catalysis ·
.
enantioselectivity · hydrogenation · reduction
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