Rhodium-catalyzed enantioseletive hydrogenation of tetrasubstituted α-acetoxy β-enamido esters: A new approach to chiral α-hydroxyl-β-amino acid derivatives

Article abstract of DOI:10.1021/ja509005e

Asymmetric hydrogenation of tetrasubtitued α-acetoxy β-enamido esters with rhodium catalysts based on chiral diphosphine ligands provides an efficient and concise route to the synthesis of chiral α-hydroxyl-β-amino acid derivatives in excellent enantioselectivities. The products are valuable chiral building blocks in many biologically active compounds and have important applications in organic synthesis.

Full text of DOI:10.1021/ja509005e

Communication
pubs.acs.org/JACS
Rhodium-Catalyzed Enantioseletive Hydrogenation of
Tetrasubstituted α‑Acetoxy β‑Enamido Esters: A New Approach to
Chiral α‑Hydroxyl-β-amino Acid Derivatives
Qingli Wang, Wenhua Huang, Haoquan Yuan, Qin Cai, Liming Chen, Hui Lv,* and Xumu Zhang*
College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei 430072, China
S
* Supporting Information
opening of chiral epoxides,9 Sharpless aminohydroxylation,10
hetero-Diels−Alder reactions,11 asymmetric hydrosilylation,12
ABSTRACT: Asymmetric hydrogenation of tetrasub-
asymmetric Mannich reactions,13 asymmetric tandem-multi-
titued α-acetoxy β-enamido esters with rhodium catalysts
based on chiral diphosphine ligands provides an efficient
component reactions,14 and other transformations.15 However,
and concise route to the synthesis of chiral α-hydroxyl-β-
amino acid derivatives in excellent enantioselectivities. The
products are valuable chiral building blocks in many
biologically active compounds and have important
applications in organic synthesis.
asymmetric hydrogenation of α-acetoxy β-enamido esters, the
most straightforward access to construct chiral α-hydroxyl-β-
amino acid derivatives, has not been reported.
In the past decades, transition metal catalyzed asymmetric
hydrogenation of enamides has been certified as a powerful and
environmentally friendly methodology to obtain chiral amine
derivatives.16 However, most of the substrate scope was
confined to di- and trisubstituted enamides, especially for β-
acylamido acrylates (Scheme 1).17 While employing asym-
hiral α-hydroxy-β-amino acid moieties are versatile chiral
C
building blocks occurring in a variety of biologically active
natural products, for instance, the side chains of taxol1 and its
analogues, ( )-epi-cytoxazone,2 bestatin,3 KNI-227 and KNI-
272,4 KRI-1314,5 dideoxy-kanamycin A,6 amastatin,7 and
microginin8 (Figure 1). Thus, the synthesis of chiral α-
hydroxyl-β-amino acid derivatives has attracted considerable
interest and many approaches have been developed.
Representative synthetic methods include the following: ring
Scheme 1. Enantioselective Routes to Chiral β-Amino Acid
Derivatives
metric hydrogenation to make β-amino acids is an important
strategy and major advances have been made, reports on
asymmetric hydrogenation of tetrasubstituted acyclic β-
enamides to make α-substituted β-amino acids are rare. In
the literature, only a few special tetrasubstituted enamides have
been succefully hydrogenated.18 Finding the optimal catalyst
for asymmetric hydrogenation of tetrasubstituted enamides to
make α-hydroxyl-β-amino acid derivatives is a very challenging
test in asymmetric hydrogenation. Herein, we presented results
on asymmetric hydrogenation of tetrasubstituted enamides for
the concise synthesis of chiral α-hydroxyl-β-amino acid
derivatives.
Initially, asymmetric hydrogenation of (E)-ethyl 3-acetami-
do-2-acetoxy-3-phenyl acrylate (E)-1a19 was investigated by
using [Rh(NBD)(Sc,Rp)-DuanPhos]BF4 as the catalyst. To our
delight, we found (E)-1a was completely converted under 30
atm of H2 pressure in CH2Cl2 at room temperature for 24 h,
Figure 1. Structures of biologically active compounds containing an α-
hydroxyl-β-amino acid moiety.
Received: September 10, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja509005e | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
generating the desired product in good yield with excellent
enantioselectivity (Table 1, entry 1). Subsequently, we
Table 1. Solvent Screening for Rh-Catalyzed Asymmetric
Hydrogenation of (E)-Ethyl 3-acetamido-2-acetoxy-3-
a
phenylacrylate (E)-1a
b
c
entry
metal
solvent
conversion (%)
ee (%)
1
2
Rh(NBD)2BF4
Rh(NBD)2BF4
Rh(NBD)2BF4
Rh(NBD)2BF4
Rh(NBD)2BF4
Rh(NBD)2BF4
Rh(NBD)2BF4
Rh(NBD)2BF4
Rh(NBD)2BF4
Rh(COD)2BF4
CH2Cl2
EtOAc
IPA
>99
52
97
98
97
89
89
94
90
93
30
95
3
46
4
TFE
>99
60
5
THF
6
dioxane
MeOH
EtOH
toluene
CH2Cl2
52
Figure 2. Structures of the phosphine ligands for hydrogenation of
(E)-ethyl 3-acetamido-2-acetoxy-3-phenyl acrylate (E)-1a.
7
34
8
27
9
9
Table 2. Ligands and H2 Pressure Screening for Rh-
10
>99
a
Catalyzed Asymmetric Hydrogenation of (E)-Ethyl 3-
Unless otherwise mentioned, all reactions were carried out with a
a
Acetamido-2-acetoxy-3-phenylacrylate (E)-1a
[Rh]/(Sc, Rp)-DuanPhos/substrate ratio of 1:1.1:20 in 1 mL of
solvent, at room temperature under hydrogen (30 atm) for 24 h.
b
c
Determined by 1H NMR spectroscopy. Determined by HPLC
analysis using a chiral stationary phase. NBD = 2,5-norbornadiene,
COD = 1,5-cyclooctadiene, TFE = trifluoroethanol, IPA =
isopropanol.
b
c
entry
ligand
JosiPhos
conversion (%)
ee (%)
investigated the solvent effect and found that different solvents
have great influence on the conversions and ee values. EtOAc
and isopropanol (IPA) gave high enantioselectivities but poor
conversions (Table 1, entries 2−3). Except for trifluoroethanol
(TFE) which showed high activity (Table 1, entry 3), both
ethereal solvents and alcoholic solvents gave lower conversions,
albeit with promising enantioselectivities (89−94% ee, entries
5−8). Metal precursor [Rh(COD)2]BF4 was also investigated.
Compared with [Rh(NBD)2]BF4, similar ee values and full
conversion were achieved when using [Rh(COD)2]BF4 as a
metal precursor.
1
2
3
4
5
6
7
8
>99
17
28
13
69
7
(S,S)-Me-DuPhos
TangPhos
>99
61
(S)-Binapine
(R)-QuinoxP
<5
3
(S)-BINAP
64
5
(S)-C3-TunePhos
(Sc,Rp)-DuanPhos
(Sc,Rp)-DuanPhos
(Sc,Rp)-DuanPhos
31
28
97
97
92
>99
92
d
9
e
10
>99
a
Unless otherwise mentioned, all reactions were carried out with a
[Rh(NBD)2]BF4/L/substrate ratio of 1:1.1:20 in CH2Cl2 at room
temperature under hydrogen (30 atm) for 24 h. Determined by H
NMR spectroscopy. Determined by HPLC analysis using a chiral
stationary phase. The hydrogenation was under 10 atm of H2
In order to further optimize the reaction conditions, a series
of chiral ligands (Figure 2) were screened carefully. As shown
in Table 2, chiral ferrocenyl ligand JosiPhos and electron-
donating P-chiral diphosphine ligand TangPhos exhibited the
same high reactivity with DuanPhos in this reaction and
afforded the expected product in quantitative yield but only
with moderate enantioselectivities (Table 2, entries 1 and 3).
Other chiral ligands, such as (S, S)-Me-DuPhos, (S)-Binapine,
(R)-QuinoxP, (R)-BINAP, and (S)-C3-TunePhos, showed poor
reactivity with decreased stereocontrol (Table 2, entries 2 and
4−7). Only the electron-donating P-chiral diphosphine ligand
(Sc,Rp)-DuanPhos developed in our group gave excellent
enantioselectivity and high activity in the hydrogenation of α-
acetoxy β-enamido ester (E)-1a (Table 2, entry 8). The effect
of H2 pressure for this reaction was also evaluated. Under a
lower hydrogen pressure of 10 atm, the enantioselectivity was
maintained but with a slightly lower conversion, while an
increase in the hydrogen pressure to 50 atm resulted in the ee
value reducing to 92% (Table 2, entries 9−10).
b
1
c
d
e
pressure. The hydrogenation was under 50 atm of H2 pressure.
shown in Table 3, (E)-1 compounds with different ester groups
were found to be good substrates to give desired α-acetoxy β-
amido esters in excellent yields with outstanding stereocontrol
(Table 3, entries 1−2). A wide range of β-aryl-α-acetoxy β-
enamido esters with electron-rich or -poor aryl groups were
examined. High yields and excellent enantioselectivities were
observed in most cases, regardless of the substitution position
(Table 3, entries 3−11). When the phenyl group was replaced
by the more sterically hindered 2-naphthyl substituent, the
reaction proceeded quite smoothly and gave the product in
96% yield with up to 95% ee (Table 3, entry 12). However, the
β-alkyl-substituted derivatives showed a somewhat lower ee
value albeit with good yields (Table 3, entries 13−14).
Under the optimized reaction conditions, a series of α-
acetoxy β-enamido esters were examined to evaluate the
substrate scope and generality of this catalytic reaction. As
To demonstrate the synthetic utility of the current
methodology, the taxol C13 side chain was synthesized as
shown in Scheme 2. The asymmetric hydrogenation product 2a
B
dx.doi.org/10.1021/ja509005e | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 3. Rh-Catalyzed Asymmetric Hydrogenation of α-
Acetoxy β-Enamido Esters (E)-1
ASSOCIATED CONTENT
* Supporting Information
■
a
S
Detailed experimental procedures and complete character-
izations of the substrates and hydrogenation products (NMR
spectra, HPLC chromatograms of racemic and enantioenriched
compounds and HRMS). This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: huilv@whu.edu.cn.
*E-mail: xumu@whu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the financial support by a grant from the
Wuhan University (203273463), “111” Project of the Ministry
of Education of China, and National Natural Science
Foundation of China (Grant Nos. 21372179, 21432007,
21402145).
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