Highly enantioselective synthesis of anti aryl β-hydroxy α-amino esters via DKR transfer hydrogenation

Article abstract of DOI:10.1016/j.tetlet.2011.01.146

An efficient preparation of highly enantiomerically enriched aryl β-hydroxy α-amino esters via dynamic kinetic resolution (DKR), asymmetric transfer hydrogenation of α-amino β-keto esters is described. The anti β-hydroxyl α-amino esters were obtained both in high yields and high diasteroselectivity. The observed high anti selectivity is inconsistent with the previous results in literature. The absolute stereochemistry of the aryl β-hydroxy α-amino esters was unambiguously confirmed via chemical derivatization as well as Vibrational Circular Dichroism (VCD) techniques.

Full text of DOI:10.1016/j.tetlet.2011.01.146

Tetrahedron Letters 52 (2011) 1685–1688
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly enantioselective synthesis of anti aryl b-hydroxy a-amino esters
via DKR transfer hydrogenation
Zhuqing Liu a, , C. Scott Shultz a, , Candice A. Sherwood a, Shane Krska a, Peter G. Dormer a,
⇑
⇑
Richard Desmond a, Claire Lee b, Edward C. Sherer c, Joseph Shpungin d, James Cuff b, Feng Xu a
a Department of Process Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA
b Department of Analytical Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA
c Chemistry Modeling and Informatics, Merck Research Laboratories, Rahway, NJ 07065, USA
d Scientific Computing, Merck Research Laboratories, Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient preparation of highly enantiomerically enriched aryl b-hydroxy a-amino esters via dynamic
Received 9 December 2010
Revised 25 January 2011
Accepted 28 January 2011
kinetic resolution (DKR), asymmetric transfer hydrogenation of
anti b-hydroxyl -amino esters were obtained both in high yields and high diasteroselectivity. The
observed high anti selectivity is inconsistent with the previous results in literature. The absolute stereo-
chemistry of the aryl b-hydroxy -amino esters was unambiguously confirmed via chemical derivatiza-
tion as well as Vibrational Circular Dichroism (VCD) techniques.
a-amino b-keto esters is described. The
a
a
Keywords:
Ó 2011 Published by Elsevier Ltd.
Dynamic kinetic resolution
Asymmetric transfer hydrogenation
Enantioselectivity
anti b-Hydroxyl a-amino ester
Vibrational Circular Dichroism (VCD)
1. Introduction
to a complete conversion and afforded 3 in 85% ee and 14:1 diaste-
reoselectivity; similarly 15:1 diastereoselectivity was observed
when Ts-DPEN-Ru/HCO2H/NEt3 system was applied without opti-
mization (Scheme 1). Surprisingly, the preliminary data showed
the relative stereochemistry observed was inconsistent with the
results reported in prior publications,4a,c where syn b-hydroxyl
Recently, asymmetric hydrogenation via dynamic kinetic reso-
lution (DKR) has received significant attention in both industry
and academia, due to its attractive capability to simultaneously
set up two adjacent stereogenic centers in a single transformation
from racemic substrates.1 The use of chiral ruthenium catalysts for
a-amino ester 2 was claimed to form under similar conditions.
DKR asymmetric hydrogenation of
reported by Noyori.2 High diastereo- and enantio-selectivities of
syn b-hydroxyl -amino esters were obtained under these condi-
a
-amino b-keto esters was first
Thus, studies on elucidation of the relative stereochemistry of
product 3 via derivatization and alternative synthesis were initi-
ated. Product 3, obtained from transfer hydrogenation, was con-
verted into alcohol 5 by protection with 2,2-dimethoxypropane
in the presence of BF3ÁEt2O followed by a reduction of the corre-
sponding ester 4 with lithium borohydride in THF. The observed
NOE effect between the aromatic protons and CH2 protons in 5
clearly showed an anti relationship of benzyl alcohol and NHBoc
amine, which confirmed the anti relative stereochemistry of the
DKR reduction product 3.5
To further verify the anti stereochemistry of 3 by eliminating a
concern about the possibility of epimerization during the forma-
tion of 4 under acidic conditions, ester 3 was reduced to amino diol
6 by LiAlH4 in tetrahydrofuran at 0 °C (Scheme 2). However, diol 6
did not match either with tert-butyl[((1S,2S)-1,3-dihydroxy-1-phe-
nylpropan-2-yl)]carbamate (7) or its enantiomer ent-7 on achiral
HPLC (see Supplementary data), both of which were prepared from
commercially available (1R,2R)-2-amino-1-phenylpropan-1,3-diol,
a
tions; however, prolonged reaction time and high pressure were
required.2 Since then, a number of modified conditions applying
transition metal catalysts for DKR asymmetric hydrogenation of
a
-amino b-keto esters have been developed.3 Despite these efforts,
only a few asymmetric transfer hydrogenation reactions of a-ami-
no b-keto esters have been reported to date.4
During our course of studies on the synthesis of amino alcohols,
we became interested in preparing amino alcohol esters such as 2
via DKR asymmetric transfer hydrogenation. Treatment of ketone 1
with (RuCl2C6H6)2/(À)-pseudoephedrine/HCO2H/NEt3 in i-PrOH led
⇑
Corresponding authors. Tel.: +1 732 594 2369; fax: +1 732 594 1570 (Z.L.); tel.:
+1 908 473 5268 (C.S.S.).
E-mail addresses: zhuqing_liu@merck.com (Z. Liu), Scott_Shultz@merck.com
(C. Scott Shultz).
0040-4039/$ - see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2011.01.146

1686
Z. Liu et al. / Tetrahedron Letters 52 (2011) 1685–1688
Scheme 1.
ent-7 in hand, a chiral Supercritical Fluid Chromatography (SFC) as-
say to separate these isomers was developed. Clearly, the diol 6
prepared from derivatization of the transfer hydrogenation prod-
uct co-eluted with 6 prepared from AD-mix b (see Supplementary
data). In conclusion, the absolute stereochemistry of the anti b-hy-
droxyl a-amino ester 3 obtained under our DKR transfer hydroge-
nation conditions was (2R,3 R). This is inconsistent with the
previously reported assignment of stereochemistry of 2.t4a In that
publication the stereochemistry of 2 was assigned by the compar-
ison of optical rotation, a method that has some limitations in
determining the absolute stereochemistry of substrates containing
more than one stereogenic center.
To further confirm the absolute stereochemical assignment,
Vibrational Circular Dichroism (VCD) measurements were applied
on ester 3.10a VCD is a useful method for determining the absolute
configuration of chiral molecules.10b As a result, VCD measure-
ments also confirmed the assignments of absolute stereochemistry
from chemical derivation (Fig. 1).
With the establishment of the absolute stereochemistry of the
transfer hydrogenation product 3, we turned our attention to opti-
mization of the reaction conditions. Thus, the Ts-DPEN-RuCl2/
HCO2H/NEt3 system was applied.4b,c We were pleased to find that
significant improvement of the ee from our initial results with the
Ts-DPEN-Ru/HCO2H/NEt3 system were achieved by using CH2Cl2 as
a co-solvent, although the diastereoselectivity eroded slightly to
ca. 8:1 (Table 1, entry 3). However, the diastereoselectivity could
be remedied by either changing the ratio of HCO2H:NEt3 to 1:3
(Table 1, entry 4) or by performing a slow addition of formic acid
over 5 h (Table 1, entry 5). It was believed that the slow addition
Scheme 2.
or its corresponding enantiomer, in the presence of (Boc)2O in
methanol, respectively. The mismatch of 6 to syn 7 and ent-7 is
in agreement with the anti stereochemistry assignment for 3.6
At this point, studies were required to unambiguously deter-
mine the absolute stereochemistry of 3. Due to difficulties encoun-
tered from attempts to obtain X-ray quality single crystals of
derivatives of 3, we decided to correlate the absolute stereochem-
istry of 3 to alcohol 6, which could be synthesized alternatively by
applying the well-established Sharpless dihydroxylation protocol.7
Therefore, treatment of (E)-ethyl cinnamate with AD-mix b led to
the formation of syn-diol 9, which was transformed into amino diol
12 following Halies’s procedure (Scheme 3).8,9 Selective reaction of
diol 9 with nosyl chloride afforded nosylate 10, which was then
treated with sodium azide and provided azide 11 through SN2 dis-
placement. Reduction of azide 11 with lithium aluminum hydride
gave fully reduced amino diol 12, which was protected with
(Boc)2O to afford NHBoc diol 6. Similarly, ent-6 was synthesized
starting with the treatment of the corresponding (E)-ethyl cinna-
mate with AD-mix
a. With all four diastereomers 6, ent-6, 7, and
Scheme 3.
Figure 1. Measured and calculated VCD spectra for 3.

Z. Liu et al. / Tetrahedron Letters 52 (2011) 1685–1688
1687
Table 1
Optimization of dynamic kinetic resolution (DKR) transfer hydrogenation of 1
Entries
Ligand
Solvent
Conditions
Conv (%)
dra
ee (anti)a
1
2
3
4
5
Ts-DPEN
Ts-DPEN
Ts-DPEN
Ts-DPEN
Ts-DPEN
HCO2H:NEt3 (5:2)
HCO2H:NEt3 (3:4)
CH2CI2
CH2CI2
CH2CI2
100
100
77
100
100
15:1
21:1
8:1
28:1
31:1
45%
42%
75%
80%
82%
HCO2H:NEt3 (5:2)
HCO2H:NEt3 (1:3)
Addition of HCO2H over 5 h
HCO2H:NEt3 (5:2)
6
7
F5PhSO2DPEN
F5PhSO2DPEN
CH2CI2
CH2CI2
HCO2H:NEt3 (5:2)
Addition of HCO2H over 5 h
HCO2H:NEt3 (5:2)
100
100
40:1
42:1
73%
91%
a
SFC conditions: Chiralpak IC column, 250 Â 4.6 mm, 5 lm particle size, modified with MeOH, 2 mL/min, 35 °C, 200 bar, UV detector: k 210 nm.
of formic acid or the use of more NEt3 allowed better balancing of
the kinetics of the epimerization vs. the enantioselective reduction
in this DKR process. Finally, we found that utilization of the more
electron deficient perfluorophenyl ligand gave an even further
boost in selectivity (entry 7) under our optimized conditions.4b,c
With the optimized reaction conditions in hand, we further ex-
plored the generality of the reaction scope. A variety of different
substrates were studied (Table 2). The reaction proceeded
smoothly for substrates with both electron donating (Table 2, en-
tries 2, 5, and 8), and electron withdrawing groups (Table 2, entries
4 and 6) with excellent ee and diastereoselectivity. Moderate enan-
tio- and diastereo-selectivities were obtained when the phenyl
group was replaced with a furyl group (Table 2, entry 7). In addi-
tion, the sense of asymmetric induction was not affected when
Boc protection on nitrogen was replaced with a Cbz group (Table
2, entries 5 and 9).11 The absolute stereochemistry of the product
3h from entry 9 (Table 2) was also confirmed on chiral SFC after
converting it to the corresponding Boc protected product 3d
through hydrogenation and Boc protection with Pd/C in MeOH in
the presence of (Boc)2O.
Table 2
Exploration of substrate scope
In summary, an asymmetric method for the preparation of anti
b-hydroxyl
ported. Our results showed that anti b-hydroxyl
were obtained from performing DKR asymmetric transfer hydroge-
nation on -amino b-keto esters under these conditions. The abso-
a-amino esters via DKR transfer hydrogenation is re-
a-amino esters
a
lute stereochemistry of the products was unambiguously
elucidated by both chemical derivatization and VCD spectroscopy.
Entry
1
Substrate
Yielda (%)
90
drb
eeb (%)
91
2. Typical experimental procedures
41.3:1
To a N2 degassed solution of
a-amino b-keto ester 1 (200 mg,
0.65 mmol) and [(R,R)-C6F5SO2DPEN]RuCl2(p-cymene)2 (6.9 mg,
0.00976 mmol) in dichloromethane (1 mL) was added triethyl-
amine (0.09 mL, 0.65 mmol). The reaction solution was heated to
2
3
89
90
24.2
23.7
92
84
35 °C and
a N2 degassed solution of formic acid (0.06 mL,
1.63 mmol) in dichloromethane (1 mL) was added via syringe
pump over 5 h. The resulting reaction solution was agitated for
additional 13–17 h at 35 °C. The crude mixture was purified by sil-
ica gel chromatography eluting with Hex/EtOAc (5:1–2:1) to afford
3 (181 mg, 90%). 1H NMR (400 MHz, CDCl3): d 7.35–7.21 (m, 5H),
5.37 (d, J = 8.0 Hz, 1H), 5.14 (br s, 1H), 4.65 (br s, 1H), 4.09 (dd,
J = 14.2, 7.1 Hz, 2H), 1.41 (s, 9H), 1.11 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d 170.0, 156.4, 139.5, 128.3, 128.0, 126.2, 80.6,
75.0, 74.0, 61.7, 61.0, 60.5, 59.9, 28.4, 14.0; HRMS m/z: Calcd for
4
5
96
87
23.1
27.0
97
90
C
16H23NaNO5: 332.1474; found: 332.1473.
6
7
8
89
99
80
>99:1
6:1
80
72
92
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.01.146.
28.9:1
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