Enantioselective Synthesis of α-Hydroxy Amides and β-Amino Alcohols from α-Keto Amides

Article abstract of DOI:10.1002/chem.201503569

Synthesis of enantiomerically enriched α-hydroxy amides and β-amino alcohols has been accomplished by enantioselective reduction of α-keto amides with hydrosilanes. A series of α-keto amides were reduced in the presence of chiral Cu^II/(S)-DTBM-SEGPHOS catalyst to give the corresponding optically active α-hydroxy amides with excellent enantioselectivities by using (EtO)₃SiH as a reducing agent. Furthermore, a one-pot complete reduction of both ketone and amide groups of α-keto amides has been achieved using the same chiral copper catalyst followed by tetra-n-butylammonium fluoride (TBAF) catalyst in presence of (EtO)₃SiH to afford the corresponding chiral β-amino alcohol derivatives.

Full text of DOI:10.1002/chem.201503569

DOI: 10.1002/chem.201503569
Communication
&
Synthetic Methods
Enantioselective Synthesis of a-Hydroxy Amides and b-Amino
Alcohols from a-Keto Amides
N. Chary Mamillapalli and Govindasamy Sekar*[a]
Dedicated to Prof. T. K. Chandrashekar on his 60th birthday
Abstract: Synthesis of enantiomerically enriched a-hy-
droxy amides and b-amino alcohols has been accom-
plished by enantioselective reduction of a-keto amides
with hydrosilanes. A series of a-keto amides were reduced
in the presence of chiral CuII/(S)-DTBM-SEGPHOS catalyst
to give the corresponding optically active a-hydroxy
amides with excellent enantioselectivities by using
(EtO)3SiH as a reducing agent. Furthermore, a one-pot
complete reduction of both ketone and amide groups of
a-keto amides has been achieved using the same chiral
copper catalyst followed by tetra-n-butylammonium fluo-
ride (TBAF) catalyst in presence of (EtO)3SiH to afford the
corresponding chiral b-amino alcohol derivatives.
Enantiomerically enriched a-hydroxy amides and b-amino alco-
hols are very important classes of chiral compounds that have
been extensively used as chiral ligands in the asymmetric syn-
thesis[1] of drug candidates in pharmaceutical industry
(Figure 1).[2] Oxidative kinetic resolution of racemic a-hydroxy
amides,[3] asymmetric ring opening of a,b-epoxy amides,[4] and
enzymatic resolution of a-hydroxy amides[5] are the most
common methods to synthesize chiral a-hydroxy amides. Car-
Figure 1. Biologically important chiral a-hydroxy amides and b-amino alco-
hols.
pentier and Motreux reported an enantioselective hydrogena-
tion of N-benzyl-2-oxo-2-phenylacetamide catalyzed by a chiral
rhodium amidophosphine–phosphinite catalyst for the synthe-
sis of chiral a-hydroxy amides (Scheme 1a).[6] Later, Agbossou-
Niedercorn, Motreux and co-workers reported the rhodium-cat-
alyzed enantioselective hydrogenation of isatin with chiral tri-
enantioselectivity.[15] Recently, Riant and co-workers reported
an efficient chiral CuII/(S)-BINAP complex for the enantioselec-
tive hydrosilylation of simple ketones; however, in the case of
a-keto esters, the asymmetric reduction reaction provided the
corresponding a-hydroxy ester with moderate selectivity.[15b]
Despite this recent progress in the enantioselective hydrosilyla-
tion of simple ketones, enantioselective hydrosilylation of a-
keto amides by Cu catalysis for the synthesis of chiral a-hy-
droxy amides has not been established to date.
carbonyl (h6-arene)chromium diphosphanes as
a ligand
(Scheme 1b).[7] Significant research efforts have been devel-
oped for the enantioselective reduction of simple ketones
using hydrosilanes in the presence of various chiral metal cata-
lysts, including Rh,[8] Ru,[9] Fe,[10] Co,[11] Ni,[12] Ti,[13] and Zn.[14] Im-
portantly, copper-catalyzed enantioselective reduction of
simple ketones by using hydrosilanes has emerged as an effi-
cient method for the synthesis of chiral alcohols with high
As part of our ongoing research into the synthesis of chiral
alcohols[16] and the chemoselective reduction of a-keto amides
by using metal[17] and metal-free[18] catalysts, we report herein
the first catalytic enantioselective reduction of a-keto amides
with hydrosilanes to afford chiral a-hydroxy amides by using
a chiral copper catalyst. Furthermore, a one-pot enantioselec-
tive complete reduction of both ketone and amide groups of
a-keto amides using the same chiral copper complex followed
by tetra-n-butylammonium fluoride (TBAF) as a catalyst is dem-
[a] N. C. Mamillapalli, Prof. G. Sekar
Department of Chemistry
Indian Institute of Technology Madras
Chennai-600036 (India)
E-mail: gsekar@iitm.ac.in
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503569.
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Table 1. Optimization of the copper-catalyzed enantioselective reduction
of a-keto amides.[a]
Scheme 1. Asymmetric reduction of a-keto amides. a) ref. [6]; b) ref. [7];
c) this work. X=chloride or trifluoroacetate; AMPP: Aminophosphine-phos-
phinite.
Entry
Ligand
Silane
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
L1
L2
L3
L4
L5
L4
L4
L4
L4
L4
L4
L4
L4
PMHS
PMHS
PMHS
PMHS
PMHS
PhSiH3
Ph2SiH2
Ph3SiH
TMDSO
(Et)3SiH
(EtO)3SiH
Me(EtO)3SiH
(EtO)3SiH
95
93
98
90
95
98
95
26
95
90
97
95
–
20
36
55
85
10
86
89
20
85
94
99
96
–
onstrated for the synthesis of the corresponding chiral b-
amino alcohol derivatives (Scheme 1c).
To initiate the optimization, 2-oxo-N-2-diphenylacetamide
1a was selected as model substrate and the enantioselective
reduction reaction was carried out with 5 mol% of CuF2 and
ligand (S)-BINAP (L1) in toluene at room temperature in the
presence of polymethylhydrosiloxane (PMHS). From this reac-
tion, the desired product a-hydroxy amide 2a was isolated in
95% yield, with a 20% enantiomeric excess of the (R)-enantio-
mer[19] (Table 1, entry 1).
9
10
11
12
13[d]
[a] Reaction conditions: 1a (0.25 mmol) in toluene (0.7 mL). [b] Yields
refer to isolated products. [c] ee was determined by HPLC using Diacel
chiralCEL OB-H column. [d] Reaction was carried out without CuF2.
TMDSO: tetramentyldisiloxane.
We then tested the reaction with L1 replaced by several
other chiral phosphine ligands, such as (S)-SEGPHOS (L2), (S)-P-
PHOS (L3), (S)-DTBM-SEGPHOS (L4), and (S,S)-DIOP (L5).
Among these ligands, only L4 led to an increase in the ee to
85%, with 90% yield (Table 1, entry 4). The other phosphine li-
gands afforded the product 2a in very good yields, but with
lower selectivity (Table 1, entries 2–5). With a view to further
improving the ee, L4 was used as a ligand and optimization
was carried out by replacing PMHS with various hydrosilanes,
including PhSiH3, Ph2SiH2, and Ph3SiH.[20] The selectivity and
yields were slightly improved with PhSiH3 and Ph2SiH2 (Table 1,
entries 6 and 7), whereas the use of bulky hydrosilane Ph3SiH
gave 2a in only 26% yield with 20% ee (Table 1, entry 8). Alkyl
and alkoxy hydrosilanes provided very good yields and excel-
lent enantioselectivities (Table 1, entries 9–12). In particular, in
the presence of (EtO)3SiH, the reaction gave 97% yield with
99% ee (Table 1, entry 11). Lowering the amount of copper cat-
alyst from 5 mol% to 2.5 mol% provided lower selectivity
(64% ee).
the absence of copper catalyst; in this case, the reduction reac-
tion did not take place at all (Table 1, entry 13). Replacement
of CuF2 with other copper salts, such as CuCl2, CuBr2, and
Cu(OAc)2, led to inferior results.[21,22] Similarly, replacement of
toluene with other solvents, such as THF, MeOH and dichloro-
methane led to less selectivity.[23]
With the optimized reaction conditions in hand, the sub-
strate scope of this reduction reaction was studied (Table 2).
Ortho, para, and meta substituents on the phenyl ring attached
to the amide group had almost no effect on the selectivity of
the enantioselective reduction (Table 2, 2b–f) and these sub-
strates were reduced with greater than 95% ee. However, the
presence of an electron-withdrawing group did influence the
enantioselective reduction. In case of N-(4-nitrophenyl)-2-oxo-
2-phenylacetamide there is no reduction at all but in case of
To identify the role of the copper catalyst in the enantiose-
lective reduction reactions, a blank reaction was carried out in
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stitution. Substrates incorporating a para-methoxy group on
the ketone-attached aromatic ring (1i) or a benzyl group at-
tached to the amide (1j) gave ee values of 85% and 80%, re-
spectively.[24] To explore the synthetic utility of this protocol,
we investigated the enantioselective reduction of 1a on
2.5 mmol scale. The reduction reaction provided the corre-
sponding product (R)-2a in 90% yield with 94% enantiomeric
excess.
Table 2. Substrate scope of the copper-catalyzed enantioselective reduc-
tion of a-keto amides.[a]
Entry
1
2
Yield
[%][b]
ee
[%][c]
Given that the enantiopure a-hydroxy amides 2 could po-
tentially be used as precursors for the preparation of biologi-
cally important chiral b-amino alcohols 3, the a-keto amide 1a
was subjected to enantioselective reduction under the opti-
mized reaction conditions to afford the product (R)-2a. The
thus-formed product (R)-2a was subjected to in situ reduction
of the amide group by treatment with 10 mol% of TBAF and
(EtO)3SiH as reducing agent, to provide the desired chiral b-
amino alcohol (R)-3a with 97% ee in a one-pot protocol
(Table 3, entry 1). By using this one-pot enantioselective com-
plete reduction, various a-keto amides were reduced to the
corresponding optically active b-amino alcohols (Table 3).[25]
Having achieved the enantioselective syntheses of the (R)-
enantiomers of 2a and 3a, we also successfully synthesized
the opposite (S)-enantiomers of these compounds with the
same yields and enantioselectivities by using the same enan-
tio- and chemoselective reduction and one-pot enantioselec-
tive complete reduction of a-keto amide 1a with the (R)-enan-
tiomer of ligand L4.
To investigate the possibility of racemization during TBAF-
catalyzed reduction of the chiral a-hydroxy amide, enantiomer-
ically pure a-hydroxy amide (R)-2a (99% ee) was subjected to
the amide reduction by treatment with 10 mol% of TBAF and
three equivalents of (EtO)3SiH in toluene at room temperature.
The reaction afforded enantiomerically pure b-amino alcohol
(R)-3a in 96% yield and without any racemization (99% ee;
Scheme 2).
1
2
3
97
95
96
99
97
97
4
93
96
5
6
7
8
9
97
95
98
94
96
97
96
84
86
85
10
93
80
[a] Reaction conditions: 1 (0.25 mmol) in toluene (0.7 mL). [b] Yields refer
to isolated products. [c] ee was determined by HPLC using Diacel chiral-
CEL OB-H or Diacel chiralPAK AD-H column.
Scheme 2. TBAF-catalyzed reduction of chiral a-hydroxy amide (R)-2a.
With regards to the reaction mechanism, it is expected that
the chiral copper catalyst undergoes oxidative addition with
the hydrosilane to yield the chiral copper hydride.[26] This
copper hydride may further coordinate with the keto group of
a-keto amides to transfer the hydride ion in an enantioselec-
tive manner to the keto group. Detailed mechanistic studies of
this copper-catalyzed enantioselective reduction of a-keto
amides, as well as its applications, are currently underway.
In summary, we have developed an efficient protocol for the
synthesis of enantiomerically enriched a-hydroxy amide by
enantioselective reduction of a-keto amides in the presence of
a chiral Cu catalyst and (EtO)3SiH as reducing agent. A one-pot
N-(4-cyanophenyl)-2-oxo-2-phenylacetamide, the asymmetric
reduction was gave corresponding racemic a-hydroxy amide
with lower yield.
With 2-oxo-2-phenyl-N-[4-(trifluoromethyl)phenyl] acetamide
(1g) as substrate, the ee was decreased to 84%. Similarly, the
less electronegative N-(4-chlorophenyl)-2-oxo-2-phenyl acet-
amide (1d) also gave a slightly reduced ee of 96%, whereas,
with a chloro group at the ortho position, the ee was further
reduced to 86% (2h), due to steric hindrance at the ortho sub-
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enantioselective complete reduction of a-keto amides, using
the chiral copper catalyst along with TBAF in the presence of
(EtO)3SiH, afforded the corresponding chiral b-amino alcohol,
with no racemization during the amide group reduction.
Acknowledgements
We thank DST (project No: SB/S1/OC-72/2013) and DST nano
mission (SR/NM/NS-1034/2012(G)) for financial support. NCM
thanks CSIR, New Delhi for senior research fellowship.
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Keywords: amides · amino alcohols · enantioselectivity ·
reduction · silanes
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[24] Enantioselective reduction of alkyl and tertiary amides afforded racemic
alcohols. In the case of primary amide, the reduction reaction did not
take place. Furthermore, in the reduction of a-keto ester, a drop of
enantioselectivity was observed.
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specific rotation value of 2a with literature reports.[3b,c]
[25] Only the first enantioselective reduction step of the keto group of the
a-keto amide influences the reduction reaction. The second step is
a simple achiral reduction of the amide group, which does not have
any influence on the first enantioselective reduction step.
[20] PhSiH3 is more bulky and less reactive than the secondary silane
(Ph2SiH2) and primary silane (PhSiH3). Similarly, alkoxy hydrosilanes
[(EtO)3SiH] and alkyl hydrosilanes (Et3SiH) are more reactive than Ph3SiH
due to the presence of alkyl or alkoxy groups instead of phenyl rings.
Owing to the lower reactivity of PhSiH3, enantioselective reduction of
the a-hydroxy amide with Ph3SiH afforded poor yield and lower enan-
tioselectivity.
[21] “CuH” is a hydride-transferring agent. In the presence of FÀ, the hydro-
silane may easily transfer the hydride to the copper catalyst, which may
explain the better results given with CuF2 as catalyst.
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[22] For details, see the Supporting Information, Table 1.
Received: September 7, 2015
[23] For details, see the Supporting Information, Table 2.
Published online on November 5, 2015
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