Chiral Vanadyl(V) Complexes Enable Efficient Asymmetric Reduction of β-Ketoamides: Application toward (S)-Duloxetine

Article abstract of DOI:10.1021/acs.joc.0c00221

High-valent chiral oxidovanadium(V) complexes derived from 3,5-substituted-N-salicylidene-l-tert-leucine were used as catalysts in asymmetric reduction of N-benzyl-β-ketoamides. Among six different solvents, three different alcohol additives, and two different boranes examined, the use of pinacolborane in tetrahydrofuran (THF) with a t-BuOH additive led to the best results at -20 °C. The corresponding β-hydroxyamides can be furnished with yields up to 92percent and an enantiomeric excess (ee) up to 99percent. We have successfully extended this catalytic protocol for the synthesis of an (S)-duloxetine precursor.

Full text of DOI:10.1021/acs.joc.0c00221

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Article
Chiral Vanadyl(V) Complexes Enable Efficient Asymmetric
Reduction of #-Ketoamides: Application towards (S)-Duloxetine
Chien-Tien Chen, Nabin Ch. Maity, rachit agarwal, Chien-Fu Lai, Yi-Ya Liao, and Wei-Ru Yu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c00221 • Publication Date (Web): 22 Apr 2020
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Page 1 of 14
The Journal of Organic Chemistry
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Chiral Vanadyl(V) Complexes Enable Efficient Asymmetric Reduction
of -Ketoamides: Application towards (S)-Duloxetine
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Chien-Tien Chen,* Nabin Ch. Maity, Rachit Agarwal , Chien-Fu Lai, Yiya Liao and Wei-Ru Yu
Department of Chemistry, National Tsing Hua University, No. 101, Section 2, Kuang-Fu Road, Hsinchu 30013, Taiwan
KEYWORDS. Oxidovanadium, pinacolborane, -hydroxyamides, antidepressant.
O
O
10 mol%
Br
N
O
O
V
O
OH
R'
O
O
OH
O
R' = 2,5-Me2C6H4
tBuOH
R
N
R
N
H
H
HBPin, THF
-20 oC, 22-26h
R = aryl, heteroaryl
R = 1o-3o alkyl
Ar
62-92% (85-99% ee)
75-90% (56-98% ee; except R = Me)
ABSTRACT: High valent chiral oxidovanadium(V) complexes derived from 3,5-substituted-N-salicylidene-L-tert-leucine were used
as catalysts in asymmetric reduction of N-benzyl--keto-amides. Among 6 different solvents, 3 different alcohol additives and 2
different boranes examined, the use of pinacolborane in THF with t-BuOH additive led to the best results at -20 oC. The corresponding
-hydroxy-amides can be furnished with yields up to 92% and ee up to 99%. We have successfully extended this catalytic protocol
for the synthesis of (S)-duloxetine precursor.
1. INTRODUCTION
catalysts bearing chiral amine and/or phosphine ligands that
were first developed by Noyori are available.3 These catalysts
efficiently hydrogenate ketones by using hydrogen to produce
the corresponding alcohols with enantiopurity of 95% in many
cases.4 Excellent TON (Turnover Number) and enantiomeric
excess (ee) for asymmetric hydrogenation of -keto esters can
be realized.5
Enantiomerically pure alcohols and amides are profoundly
used in the pharmaceuticals, flavours, fragrances and fine
chemicals industries.1 Enantiopure -oxo-amides/nitriles and
gamma amino alcohols are important building blocks for the
synthesis of natural products and pharmaceutically active
compounds. Such as Fluoxetine, Duloxetine and Nisoxetine
which serve as serotonin specific reuptake inhibition whereas
Ritonavir and Lopinavir serve as anti HIV(Figure 1).2 For the
synthesis of the optically active alcohols, various ruthenium(II)
CF3
Wills and co-worker carried out asymmetric transfer
hydrogenation of acetyl ketones and diketones with
Ru(II)/TsDPEN-derived catalyst with excellent yields and ees
in most cases.6 Zhang et al. designed a series of chiral
diphosphine ligands with ruthenium(II) for the asymmetric
hydrogenation of -keto esters which had given alcohols with
ees up to 99%.7 By using ruthenium complexes equipped with
chiral 2,2'-binap ligands, Lin and co-workers achieved chiral -
hydroxy-esters with ees up to 99.8% for the asymmetric
hydrogenation of -aryl-keto esters.8 Zhou and co-workers
developed chiral iridium(I) complexes of SpiroPAP ligand
which had led to excellent enantioselectivities (up to 99.9% ee)
and extremely high TON (1,230,000) for the asymmetric
hydrogenation of -keto esters.9 Touati and co-workers
successfully demonstrated that chiral SYNPHOS and
DIFLUORPHOS ligands with ruthenium(II) can be efficiently
used in the asymmetric reduction of -keto-amides with good
to excellent enantioselectivities (up to 99%).10
S
HN
O
O
N
O
N
H
N
H
Me
O
iPr
OH HN
O
Fluoxetine
O
Duloxetine
O
Me
HN
O
O
N
H
S
N
H
Lopinavir
Dual NE and 5-HT
reuptake inhibitor
Nisoxetine
Ph
N
S
S
Me
Me
OH
Ph
O
Me
N
H
O
N
N
N
H
O
O
Me
Me
Ritonavir
Figure 1. The chiral anti-depressant drugs derived from the
enantioselective synthesis of -hydroxy-amides
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O
O
OH
Previous work
H
N
1
2
3
4
5
6
7
8
N
O
O
OH
O
Rh/Ir complexes
silanes
H
R
O
O
Cl
N
O
V
O
tBu
N
Bn
Ir
Ar
OR
80-99% ee
O
N
Ar
OR
1a
1b
1c
: R = t-Bu
N
I
N
N
O
O
Rh
N
V
: R = 2,5-Me2C6H4
: R = o-biphenyl
O
Zn complexes
silanes
Br
O
O
O
OH
O
I
O
5
Br
O
O
H
5
N
N
O
Me
3
Ph
NHBn
Ph
NHBn
Ph
Ph
H
Me
Zn
26% ee
3
: R = tBu
R
2a
This work
O
Figure 2. Vanadyl(V) complexes as catalysts
V(O)L3
complexes
O
OH
O
O
O
N
O
V
O
boranes
R
NHBn Br
O
Me
R
NHBn
O
H
9
R = Ar, heteroaryl, alkyl
2. RESULTS AND DISCUSSION
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Both HBCat and HBPin were selected as reducing agents (3
equiv) and the reactions were catalyzed by various vanadyl
complexes (Figure 2). When catalyst 1a was first tested with N-
benzyl-benzoylacetamide (3a) in THF at -20 oC for 24h (Table
1), it was found that HBCat (45%, 6% ee) was much inferior to
HBPin (70%, 53% ee) both in terms of yields and ees for
product-(S)-4a (entries 1 and 2) presumably due to its
background reaction. The imine-reduced catalyst 2a from 1a led
to comparable or better yields (75 and 81%) and ees (55 and
75%) in CH2Cl2 and THF (entries 3 and 5), respectively. The
reduction in strong coordination solvents like CH3CN led to
reduced yields by 20-26% and lower ee (55%, entry 4). On the
other hand, the reduction in nonpolar toluene led to the -
hydroxy-amide but with very poor ee of 6% in 87% yield (entry
6) due to poor substrate solubility. The use of a mixed
toluene/THF solvent (1/1) could maintain a similar yield (84%)
but with diminished ee to 60% (entry 7). Notably, the ee of the
product was further improved to 80% when the reduction was
Scheme 1. Asymmetric reduction of -keto eaters and amides.
Alternatively, asymmetric reductions of -keto-esters by bio-
enzymatic means in aqueous11 or organic phase were also
workable.12 Gotor and co-workers successfully carried out the
bio-catalyzed asymmetric reductions of -keto-amides with
good to excellent yields and ees (up to 99%).13 Gandolfi and co-
workers further extended their uses for the synthesis of
Duloxetine precursor.14 The biocatalytic reduction of -keto-
nitriles led to Duloxetine (S)-precursor with good to excellent
enantioselectivities (up to 99%). Toste and co-workers carried
out asymmetric hydrosilylation of aldehydes/ketones15-18 and
imines19 with good yields and enantioselectivities.
Enantioselective hydrosilylation of -keto-esters was also a
promising protocol for the synthesis of enantioenriched -
hydroxy esters by chiral Rh(I)-NHC complexes (Scheme 1).20
Asymmetric hydroboration of ketones constitutes a beneficial
strategy for the synthesis of enantio-enriched alcohols in view
of the weaker O-B bond relative to the O-Si bond in the
hydrosilylation. Since the seminal works by Itsuno21 and
Corey22 on the asymmetric reduction of ketones with chiral
amino alcohol-based borane reagents, enormous progress has
been made in that aspect. Hydroboration reagents like
catecholborane (HBCat), pinacolborane (HBPin) and etc. are
easily available reagents which tolerate a variety of diverse
functional groups.23 Ghorai and co-workers utilized cinchona-
derived thioureas or squaramides for intramolecular oxa-
Michael to enones by incipient borates from reduction of an
aldehyde by HBPin.24 Du and coworkers explored H3N-BH3-
mediated asymmetric reduction of imines in 84-95% ees by
using HB(C6F5)2/chiral tert-butylsulfinamide adduct as
catalyst.25
o
performed at -40 C albeit with 14% drop in yield (entry 8).
When the reduction was done at ambient temperature, the
product yield reached 92% but with a dramatic drop in product
ee to 24% (entry 9).
Table 1. Effects of catalysts and solvents on the asymmetric
reduction of N-benzyl-benzoylacetamidea
O
O
OH O
10 mol%
catalyst
N
N
H
H
borane, solvent
t oC, Ar, 24h
3a
4a
(S)-
entr
y
t,
yield ee,
cat.
borane
solvent
c
oC
, %b
%
1
2
3
4
5
6
1a
1a
2a
2a
2a
2a
HB(cat)
HB(pin)
HB(pin)
HB(pin)
HB(pin)
HB(Pin)
THF
THF
THF
-20 45
-20 70
-20 81
6
While there are considerable examples of asymmetric
reductions of -keto esters but there are very few reports on the
asymmetric reduction of the -keto amides by 3d-high valent,
oxometallic complexes with boranes. In view of economic and
environmental viewpoints, they are much more attractive than
the rare earth families. Carpentier had carried out asymmetric
hydrosilylation of -keto amides with chiral Zinc(II)-diamine
complexes with only 28% ee (Scheme 1).26
53
75
51
55
6
CH3CN -20 55
CH2Cl2
toluene
-20 75
-20 87
THF/tol
uene
(1:1)
7
2a
HB(pin)
-20 84
-40 70
60
As part of our continuing interests in asymmetric aerobic
oxidation/coupling events by chiral vanadyl(V) catalysts that
are stable to moisture and air, we began to evaluate their
catalytic reduction profiles. Herein, we have disclosed, for the
first time, oxidovanadium(V) complexes derived from N-
salicyliden-L-tert-leucine towards practical asymmetric
reduction of -keto amides by HBPin to afford nearly
enantiopure -hydroxy amides (Scheme 1).
8
9
2a
2a
HB(pin)
HB(pin)
THF
THF
80
24
26
92
aReaction conditions: catalyst (10 mol%), solvent (1 mL),
substrate (0.1 mmol), HBCat/HBPin (3 equiv.). bIsolated yield.
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The Journal of Organic Chemistry
determined via HPLC using Daicel CHIRALPAK AD-H
cEnantiomeric excess (ee) determined by HPLC analysis on a
d
1
Daicel CHIRALPAK® AD-H column.
column. Yield was determined via H NMR of the reaction
1
2
mass at -40 oC.
To facilitate the O-B bond cleavage of original reduction
product, we further tested the effect of alcohol additives (Table
2). The color of catalyst solution changed from dark brown to
burgundy red upon addition of an alcohol. The product ees
dropped significantly with decreasing steric of the additive
presumably due to competing coordination with the substrate-
3a to the vanadyl(V) center. Among the three alcohols (MeOH,
i-PrOH, and t-BuOH) examined, t-butanol gave the best result
(82% yield and 85% ee, entry 3). On the other hand, MeOH and
i-PrOH furnished the product, (S)-4a with similar yields but
with ees of 35% and 65%, respectively (entries 1-2). To prove
the role of alcohol additive as a proton donor for O-B to O-H
exchange, CD3OD was used to replace MeOH. Deuterium
incorporation both to the alcohol and one of the C2 proton was
observed (see ESI). The D-migration indicated that there was a
substantial keto-enol tautomerization of the -keto amide
reactant during the reaction.
3
4
5
6
7
8
9
To gain further insight into the effect of other ether type
solvents, TBME (tert-butylmethyl ether, entry 6) and DME
(1,2-dimethoxyethane, entry 7) were examined. Poorer
chemical yields and ees were observed (75- 77%, 89-90% ee).
Since the coordination ability of THF sits right between TBME
and DME, it seems there exists a delicate balance for the solvent
to help breaking the dimeric form of HBPin but not to interfere
with the substrate coordination to the vanadyl(V) center.
Acetone, both a more polar solvent and a competitive ketone,
led to (S)-4a with a similar ee of 91% but with reduced yield to
64% (entry 8). The reduction in CH3CN led to further reduced
yield to 20% and lower ee (80%, entry 9). Similar solvent effect
was also found in -borylation of -enaldimines by Pujol.27
The use of nonpolar CH2Cl2 led to moderate yield of 58% and
reduced ee to 83% (entry 10). Lowering catalyst loading from
10% to 5% in THF resulted in lowering of both the yield and
the ee to 74% and 94%, respectively (# in entry 4). Notably, no
reaction took place in absence of any catalyst (entry 11),
indicating a negligible background reduction. Further lowering
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With the optimized reaction conditions in hand, further catalyst
variation was carried out. Out of the four catalysts examined,
catalyst-1b bearing 2,5-dimethylphenyl group at C3 of the
salicylidene template led to the best result (86% yield, 97% ee,
entry 4). Conversely, catalyst 1a gave the worst result (70%,
53% ee in entry 2, Table 1). Increasing the steric bulk at C3 (i.e.,
o-biphenyl) as in catalyst-1c led to a decrease in yield (by 19%)
and ee (by 13%), entry 5. The result indicated that 
interaction between the benzoyl group in 3a with the C3 aryl
group in catalysts 1b and 1c may play an important role.
Furthermore, the o-biphenyl unit in 1c that can provide an extra
shielding underneath the salicylidene unit did not help in
improving the enantiofacial control.
o
of the reaction temperature to -40 C in THF did not help in
improving both yield and ee of the product (96% ee, entry 12).
This optimal protocol with catalyst 1b was extended to -keto
amides bearing various 3-aryl, -alkynyl, and -alkyl groups.
Highly enantio-enriched (S)--hydroxy amides 4a-q were
furnished except the 3-methyl case (R = Me) due to size and
priority change based on CIP (Cahn-Ingold-Prelog) rule (Table
3). For substituted phenyl family, substrates bearing electron
donating p-methyl- and p-methoxy-phenyl groups (entries 2 -
3) reacted slightly slower than those with electron-withdrawing
p-chloro- and p-bromo-phenyl ones (entries 4-5). With a fixed
reaction time of 24 h, the former two cases led to the
corresponding products in 82-85% yields with 98-99% ees as
compared to those of the latter two cases with 89-92% yields
with 96-99% ees. For electron withdrawing groups but with
coordinating ability like NO2, both the reduction yield (79%)
and ee (79%) dropped significantly (entry 6). The substantial
amount of enol form (38% at rt) in 3f may be responsible for
the reduced yield and ee (see ESI†).28
Table 2. Effects of catalysts, solvents, and alcohol additives on
the asymmetric reduction of N-benzyl-benzoylacetamidea
OH
O
O
O
10 mol%
catalyst
N
N
H
H
HBPin, solvent
20 C, Ar
4a
(S)-
entry Cat. solvent
additive yield, %b
ee, %c
1
2
3
2a
2a
2a
THF
THF
THF
MeOH
i-PrOH
tBuOH
85
80
82
35
65
85
Table 3. Substrate scope for asymmetric reduction of -keto
amides by catalyst 1ba
O
O
OH
O
10 mol%
1b
catalyst
R
N
86(74#)
67
97(94#)
84
R
N
4
5
1b
1c
1b
1b
1b
1b
1b
---
1b
THF
t-BuOH
t-BuOH
t-BuOH
t-BuOH
H
H
HBPin, THF
20 C, Ar, 22-26h
THF
3a q
-
4a q
-
6
TBME
DME
75
90
entry
R
yield,c %
86 (4a)
85 (4b)
82 (4c)
ee,d %
7
77
89
1
2
3
4
5
6
7
8
C6H5
97
98
99
8
acetone t-BuOH
CH3CN t-BuOH
64
91
p-MeC6H4
p-MeOC6H4
p-ClC6H4
p-BrC6H4
p-NO2C6H4
m-MeOC6H4
2-Np
9
20
80
10
11
12
CH2Cl2
t-BuOH
t-BuOH
t-BuOH
58
83
92/88e (4d) 96/98 e
THF
THFd
~0
-
89 (4e)
79 (4f)
43 (4g)
90 (4h)
99
79
88
98
81
96
aCatalyst (10 mol%), #catalyst (5 mol%); solvent (1 mL),
substrate (20 mg, 0.08 mmol), additive (1.0 equiv.), HBPin (3
equiv.). bIsolated yield. cEnantiomeric excess (ee) was
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9b
1-Np
65/83f (4i)
60 (4j)
85/90f
90
ester. Asymmetric reduction of 3k’ under optimal reaction
conditions led to (S)-N-methyl-3-hydroxy-3-(thiophin-2-
1
2
3
4
5
6
7
8
O
yl)propanamide29 4k’ in moderate, 45% yield and slightly
diminish enantioselectivity, 90% ee due to smaller N-methyl as
compared to N-benzyl (Scheme 2).31 Its structure was confirmed
by X-ray crystallographic analysis after recrystallization
(Figure S2). It depicts that the single stereocenter has S-
conformation and through retrosynthetic strategy that
enantiopure (S)-4k’ proved to be an excellent building block for
the synthesis of (S)-Duloxetine. Only the (S)-enantiomer of
Duloxetine is pharmaceutically active for the treatment of
anxiety, diabetes related pain, chronic musculoskeletal etc.30
Since it has been proposed that N,N-disubstitution can be used
to modify amide-O-metal coordination,31a N,N-dimethyl-3-oxo-
3-phenylpropanamide (3r) was prepared and tested for a similar
asymmetric reduction, the corresponding -hydroxyamide (S)-
4r was isolated in 63% yield and 96% ee (Scheme 2).
10
S
11
65/71 (4k)
95/93
12
13
14
15
16
17
o-MeOC6H4
PhCC
CH3
18 (4l)
56 (4m)
75 (4n)
90 (4o)
84 (4p)
82 (4q)
88
11
14
98
56
80
9
PhCH2CH2
i-Pr
10
11
12
13
14
15
16
17
18
19
20
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23
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26
27
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t-Bu
aSubstrate (0.08 mmol), dry THF (1.0 mL), t-BuOH (1.0 equiv),
catalyst (10 mol%), HBPin (3.0 equiv). Isolated yield. 2.5
equiv of t-BuOH was used. Enantiomeric excess (ee) was
determined by HPLC on Diacel CHIRALPAK AD-H or AS-H
column. Configurations were found to be S or determined by
analogy.12 e2.00 mmol scale reaction. fThe second data
c
b
d
1-Np
O
O
10 mol%
catalyst
OH
O
O
ref 26
1b
S
S
S
N
H
N
HBPin, THF
10 C, 48h
N
H
45%
(90% ee)
H
4k'
3k'
o
corresponds to reaction at -5 to 0 C for 48h.
O
O
10 mol%
catalyst
OH
O
1b
For aryl substrates bearing m- or o-methoxy-phenyl groups, the
reduction yields dropped to 43 and 18%, respectively,
presumably due to increasing steric interactions with the 2,5-
dimethylphenyl unit in catalyst 1b. Nevertheless, the
asymmetric inductions were maintained at 88% ee in both cases
(entries 7 and 12). For naphthyl and heteroaryl series (entries 8-
11), the 1-naphthyl case showed much poorer yield (23%) and
ee (85%) than those (90% and 98% ee) in the 2-naphthyl system
presumably due to increasing steric effects during the
coordination to the vanadyl center in the former case. An
additional 24 h of the reaction time at  oC led to an improved
yield to 83% with further increased ee to 90%. Evidently, a
facile stereo-electronic between the substrate and the catalyst
was paramount for its bidentate coordination to the vanadyl
center for smooth and secured enantiofacial preference in
reduction. The reduction proceeded slower in the heteroaryl
systems (entries 10-11) than the aromatic substrate (entry 1). By
increasing reaction temperature to −10 oC, the product yield in
4k was 65% and the ee can be maintained at 95%. (entry 11).
N
N
HBPin, THF
10 C, 48h
63%
(96% ee)
3r
4r
Scheme 2. Representative N-methyl and N,N-dimethyl analogs
3. Proposed Origin of Enantiofacial Control
Nonlinear effect study was performed with 25%, 50% and 75%
ee of the catalyst-1b. The results show a linear correlation
(Table S1). Therefore, the catalytic reduction system works in
a monomeric species. Notably, the mixing of either V(O)(i-
OPr)3 ( -626 ppm) or catalyst 1b ( -559.4 ppm) with 3 equiv
of HBPin only led to broadening of their signals with slight
upfield shifts by 2 ppm in their 51V NMR spectra. To explain
the origin of enantiocontrol in the asymmetric reduction, we
proposed two favourable reductant-directed, coordination
modes (Figure 3) based on our X-ray crystal structure of a
vanadyl(V) complex/N-benzyl-mandelamide adduct.31b The
amide carbonyl group was coordinated anti to the V=O unit in
such a way that N-benzyl moiety was positioned underneath the
salicylidene template as in catalyst-1b (Figure 3a). As a result,
the -keto unit would rotate clockwise and away from the 2,5-
dimethylphenyl group at C3 and the vanadyl-bound methoxide
in 1b. The bulky HBPin would deliver the hydride from Re-face
of the ketone moiety to give the resulting alcohol in S-
configuration (mode-I).
o
Further bringing the reaction to −5 C, the optimal reduction
yield and ee of the product (S)-4k were 71% and 93% ee. The
analogous furan case (entry 10) can be performed at −20 oC in
24h, leading to (S)-4j in 60% and 90% ee.
The propargyl derivative (entry 13) gave very poor results
(56% and ee ~11%) due to negligible steric interaction between
the catalyst-1b and the substrate-3m. The cylindrical -cloud in
the CC bond may interfere with ketone coordination to the
vanadyl center, thus hampering the reduction. For 3-alkyl
family, the asymmetric inductions were much inferior but can
be improved with increasing steric from methyl (14% ee), i-
propyl (56% ee) to t-butyl (80% ee). The chemical yields fell in
the range of 75-84%. Nevertheless, high chemical yield (90%)
and ee (98%) can be secured in the 2-phenethyl case (entry 15).
This result indicated that the zig-zag motion of the ethylene
linker may still orient the phenyl ring to interact with the 2,5-
dimethylphenyl unit.
We have successfully extended this protocol for the synthesis
of Duloxetine precursor. The requisite starting material 3k’
could be readily synthesized from the corresponding methyl
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doublets, doublet of triplets, and multiplet, respectively.
mode-I
O
O
1
2
3
4
5
6
7
8
Infrared spectra were recorded on a FTIR spectrometer. Peaks
are reported in units of cm-1 with the following relative
intensities: br (broad), s (strong 67–100%), m (medium 33–67
%), or w (weak 0 – 33%). Mass spectra were recorded with an
ionization voltage of 70 or 20 eV unless otherwise stated.
Elemental analyses were obtained by the Department of
Chemistry, National Tsing Hua University, Taiwan or
Department of Photonics, National Chiao Tung University,
Taiwan. Fast atom bombardment (FAB) and electrospray
ionization (ESI) mass spectra were recorded with data reported
in the form m/e (intensity relative to base peak). Analytical TLC
was performed on silica gel plates. Visualization was
accomplished with UV light (254 nm) or with KMnO4 staining
agents. Column (flash) chromatography was performed using
32–63 m silica gel. Analytical high pressure liquid
chromatography (HPLC) was performed with a built-in
photometric detector ( = 220 nm or 254 nm) using a Chiralpak
AS-H, AD-H (0.46 cm  25cm). Solvents for HPLC analyses
were of spectroscopic grade and filtered before use. All
enantiomeric excess determinations for optically enriched
products were correlated with the corresponding racemic
samples by HPLC analyses on chiral columns. Solvents for
extraction and chromatography were reagent grade. Optical
[α]T
H
B
O
O
N
N
O
O
O
B
O
V
Br
V
Br
O
O
R'
O
R'
O
O
O
O
O
H
O
Me
O
HN
R
R
HN
Re-face
attack
1b
1c
: R = Ph, R' = H
steric hindrance
: R = R' = Me
mode-II
9
O
O
10
11
12
13
14
B
O
N
O
O
H
V
Re face
attack
Ar
Br
O
O
R'
O
N
H
R
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 3. Chem 3D presentations for the proposed origins of
enantiofacial controls in the asymmetric reduction catalyzed by
1b: (a) mode-I; (b) mode-II
Alternatively, the HBPin may first interact with the vanadyl
methoxide 1b to form pinacol-bound, vanadyl-activated
hydride, in which would bring the bidendate, -keto unit in the
substrate in close proximity. Under such circumstance, there
may exist a sandwich type,  interaction among the
salicylidene template in 1b and N-benzylunit in the substrate.
The vanadyl-activated hydride would attack to the Re face of
the benzoyl moiety thru a 6-membered ring, cyclic transition
state assembly (mode-II, Figure 3b).
rotations are reported as follows:
(c = g/100mL, solvent).
D
Toluene, Tetrahydrofuran (THF) and 1,2 Dimethoxyethane
(DME) were dried over sodium benzophenone-ketyl
intermediate under N2 atmosphere and distilled before use.
Dichloromethane (DCM) were dried over CaH2 and distilled
before use. i-Pr2NH was distilled from calcium hydride prior to
use. Chlorobenzene was distilled from anhydrous K2CO3 prior
to use. tert-Butanol (t-BuOH) was dried over flame dried
molecular sieves and distilled before use. Acetone was dried
over dry CaSO4 and distilled before use. 4,4,5,5-Tetramethyl-
1,3,2-dioxaborolane (Pinacolborane), Catecholborane and N-
benzyl-3-oxobutanamide (3n) were brought from Acros
Organics and are used as such without any further purification.
All reaction products were isolated as chromatographically pure
materials. All the chemicals were brought from Sigma Aldrich
or Acros Organics and are used as such without any
purification. Racemic -hydroxy amide were synthesized by
reduction of the corresponding -keto amides using half
equivalent sodium borohydride (NaBH4) at 0 oC. Subsequently,
the product was purified over silica gel chromatography using
hexane-ethyl acetate as eluents to get the racemic -hydroxy
amide. Catalysts were synthesized according to our previously
reported procedure.31,32
4. Conclusion
We have developed an efficient method for enantioselective
reduction of N-benzyl--ketoamides catalyzed by air stable
chiral oxidovanadium(V) complexes in THF at -20 oC. With a
judicious choice of HBPin as a reductant and t-BuOH as a turn-
over additive. The resultant reduced products were furnished in
good to excellent yields and with enantioselectivities of 85-99%
ee except in -p-nitrophenyl, -propargyl, and -alkyl ketoamides.
Nevertheless, the 2-phenethyl and t-butyl cases could make up
to a satisfactory level of asymmetric inductions in 98% and 80%
ee. To best of our knowledge, this new protocol was the best
non-rare earth, high oxidation state, metal complex catalyzed
asymmetric reduction of -keto amides. The optimal catalytic
protocol was successfully applied to Duloxetine precursor
synthesis in 90% ee. Two preferential modes of BPin-directed
substrate coordination were proposed to explain the origin of
high level enantiocontrols. Further studies on the applications
of this catalyst class for asymmetric reductions of different
functional substrate family are currently underway and will be
reported in due course.
2. General synthetic procedures for the preparation of substrates:
Experimental Section
2.1 Method-a: Substrates were synthesized by modifying
previously reported synthetic procedure.33,34 To a flame dried
two-necked round bottom flask was charged with NaH (28
mmol) under argon. The sodium hydride (60% in mineral oil)
was washed with dry toluene (2  20 mL). Again the flask was
charged with toluene (70 mL) and dimethyl carbonate (20
mmol) and the solution was heated to reflux. The appropriate
ketone (10 mmol) dissolved in dry toluene (10 mL) was added
dropwise to the reaction mixture (caution: hydrogen gas
evolution was vigorous). The reaction was allowed to stir for
1. Materials and Methods:
1H NMR and 13C NMR spectra were recorded on 400 MHz 1H
(100 MHz 13C) spectrometers in deutero chloroform with
chloroform or deutero methanol with methanol as an internal
reference unless otherwise stated. Chemical shifts are reported
in ppm (). Coupling constants, J, are reported in Hz. The
abbreviations s, d, t, pent, quint, sext, dd, ddd, dt, and m stand
for the resonance multiplicities singlet, doublet, triplet, pentet,
quintet, sextet, doublet of doublets, doublet of doublet of
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additional four hours after the evolution of hydrogen gas 2.3 Method-c: Propargyl derivative was synthesized via the
modified procedure reported previously.36 In a flame dried two
necked round flask was charged with dry THF (80 mL) and dry
i-Pr2NH (diisoproylamine, 1.7 g, 17.02 mmol) under argon
atmosphere. Temperature of the solution was lowered to 20 C
and n-BuLi (10.64 mL of 1.6 M solution in hexane, 17.02
mmol) was injected via syringe slowly. After stirring for 10
min, N-benzylacetamide dissolved in THF (10 mL) was added
dropwise via syringe. The reaction temperature was slowly
raised to room temperature and was allowed to stirred for 30
min at ambient temperature. The mixture was cooled to 78 °C
and ethyl phenylpropiolate (1.3 gm, 7.4 mmol) in THF (5 mL)
was added dropwise. The resulting solution was slowly raised
to 0 °C and the solution was stirred for 2 h at this temperature,
then quenched with cooled saturated NH4Cl (30 mL) solution.
Organic layer was separated and the aqueous layer was
extracted with EtOAc (2  20 mL). The combined organic layer
was washed successively with 1 N HCl (40 mL), water (2  30
mL), brine (2  30 mL), then dried over anhydrous MgSO4,
filtered and evaporated under reduced pressure. The residue was
purified by silica gel chromatography (hexane/EtOAc = 75/25)
to afford 0.4 g (20%) of the desire -keto amide. (Precaution:
N-benzyl-3-hydroxy-5-phenylpent-4-ynamide is thermally
highly unstable and is needed to be stored in refrigerator).
1
2
3
4
5
6
7
8
ceased. The reaction was cooled to room temperature; water (20
mL) and glacial acetic acid (3 mL) were added successively. Ice
cold water was added until the solid was dissolved completely.
The toluene layer was separated, and the aqueous phase was
extracted with ethyl acetate (2  30 mL). The combined organic
layers were washed successively with water (2  50 mL) and
brine (3  50 mL), dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (EtOAc in hexane) or
crystallization or directly used in the next step.
9
10
11
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13
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59
60
To a solution of -keto ester (8.6 mmol) in degassed ethanol
(30 mL) was rapidly added solid DMAP (317 mg, 2.6 mmol)
and the solution was heated to refluxed under argon atmosphere
for 1 h. Distilled benzyl amine (1.1 gm, 10.3 mmol) dissolved
in ethanol (5 mL) was injected drop wise via syringe. The
reaction mixture was refluxed for 24 h and the solvent was
removed under reduced pressure. The solid residue was washed
with water (3  50 mL) and brine (3  30 mL) successively.
Finally, the solvent was evaporated under reduced pressure and
the residue was purified by silica gel column chromatography
(eluent: ethyl acetate in hexane) to afford the -keto amide in
70–92% yield.
2.2 Method-b: Substrates were synthesized by modifying the
synthetic procedure reported previously.35 To a flame dried
two-necked round bottom flask was charged with NaH (28
mmol, 60% dispersion in mineral oil) under argon. The NaH
was washed with dry DME (2  20 mL). Again the flask was
charged with DME (70 mL) and methyl acetate (20 mmol)
(caution: hydrogen gas evolution was vigorous). The mixture
was heated to reflux. The appropriate methyl ester (10 mmol)
dissolved in dry DME (10 mL) was added drop wise to the
reaction mixture. The reaction was allowed to stir additional
four hours after the evolution of hydrogen gas ceased. When the
reaction was cooled to room temperature, water (20 mL) and
glacial acetic acid (3 mL) were added successively. Ice cold
water was added until the solid was dissolved completely. The
DME layer was separated, and the aqueous phase was extracted
with ethyl acetate (2  30 mL). The combined organic layer was
washed successively with water (2  50 mL) and brine (3  50
mL), then dried over anhydrous MgSO4. After evaporation of
the solvent, the residue was purified on silica gel column
chromatography (eluent: ethyl acetate in hexane) to afford the
-keto ester with 80–90% yield.
2.4
Synthesis
of
N-methyl-3-oxo-3-(thiophen-2-
yl)propanamide: In a flame dried two necked round flask, dry
i-Pr2NH (0.9 gm, 8.8 mmol) was dissolved into dry THF (30
mL) under argon atmosphere. Temperature of the solution was
lowered to 20 C and n-Butyllithium (5.5 mL of 1.6 M solution
in hexane, 8.8 mmol) was injected into the flask via syringe
slowly. After stirring for 10 min at this temperature, N-
methylacetamide37 (0.3 gm, 4.2 mmol) dissolved in THF (5 mL)
was added dropwise into the reaction mixture via syringe. The
reaction temperature was slowly raised to room temperature and
was allowed to stir for 30 min at ambient temperature. The
mixture was cooled to  C and methyl thiophene-2-
carboxylate (0.5 gm, 3.5 mmol) in THF (5 mL) was added
dropwise. The resulting solution was slowly raised to room
temperature and was stirred for 3 h at room temperature, then it
was quenched with cold saturated NH4Cl (20 mL) solution.
Organic layer was separated and the aqueous layer was
extracted with EtOAc (2  20 mL). The combined organic
layers were washed successively with 1 N HCl (10 mL), water
(2  50 mL), brine (2  50 mL), then dried over anhydrous
MgSO4, filtered and evaporated under reduced pressure. The
residue was purified by silica gel chromatography
(hexane/EtOAc = 10/90) to afford 0.3 g (46%) of the title
product as white solid.
To a solution of -keto ester (8.6 mmol) in degassed ethanol
(30 mL) was rapidly added solid DMAP (317 mg, 2.6 mmol)
and the solution was heated to refluxed under argon atmosphere
for 1 h. Freshly distilled Benzyl amine (1.1 gm, 10.3 mmol)
dissolved in ethanol (5 mL) was injected drop wise inside the
flask via syringe. The reaction mixture was refluxed for 24 h
and the solvent was removed under reduced pressure. The solid
residue was extracted in ethyl acetate (50 mL) and the organic
layer was washed with water (3  50 mL) and brine (3  30 mL)
successively and then dried over anhydrous MgSO4, filtered and
evaporated under reduced pressure. The residue was purified on
silica gel column chromatography (eluent: ethyl acetate in
hexane) to afford the -keto amide with 70–92% yield.
2.5 Synthesis of N-benzyl-3-oxo-5-phenylpentanamide: Step
I:38 In a flame dried two necked round bottom flask (250 mL),
dry i-Pr2NH (10.9 g, 0.1 mol) was taken with dry THF (50 mL)
under argon atmosphere at  C and n-BuLi (63 mL of 1.6 M
solution in hexane, 0.1 mol) was added slowly to the reaction
mixture at  C. Methyl acetoacetate (4.6 g, 40 mmol) was
added into the reaction mixture slowly at this temperature.
Temperature of the reaction mixture was slowly raised to 0 C
and it was stirred for additional 1 h at this temperature.
Temperature of the reaction mixture was again lowered to -78
C and the benzyl bromide (7.5 g, 44 mmol) was added to the
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reaction mass slowly. Subsequently the reaction mixture was solvent under reduced pressure. The residue was extracted with
1
2
3
4
5
6
7
8
brought to room temperature and was stirred for 14 h at room
temperature. After that the reaction was quenched by saturated
NH4Cl solution (20 mL) and the organic layer was separated.
The aqueous layer was extracted with diethyl ether (2  50 mL)
and the combined organic layers were washed with brine (2 
50 mL) and finally dried over anhydrous MgSO4. The solvent
was evaporated under reduced pressure and the residue was
purified by silica gel column chromatography (hexane/ethyl
acetate = 4/1) to afford 6.7 g (82%) of methyl 3-oxo-5-
phenylpentanoate as light yellow oil.
ethyl acetate (10 mL) and the organic layer was washed with
water and drying over anhydrous MgSO4. The solvent was
evaporated under reduced pressure and then the product (S)-3-
hydroxy-N-methyl-3-(thiophen-2-yl)propanamide was isolated
by silica gel column chromatography (eluent: 80% ethyl acetate
in hexane).
5. General procedure for deuterium exchange reaction: In
an oven dried Schlenk tube, N-benzyl-3-oxo-3-phenyl
propanamide (20 mg, 0.08 mmol) was taken along with the
catalyst 1b (4 mg, 0.008 mmol) under argon atmosphere. Dry
THF (1 mL) and CD3OD (3 equiv.) were injected into the tube
via syringe and the reaction mass was stirred for 10 minutes at
room temperature before cooling the Schlenk tube at 10 C. H-
B(pin) (3 equiv., in 200 L dry THF) was injected slowly into
the reaction tube via syringe. The reaction mixture was allowed
to come room temperature and was stirred for additional 14
hours at ambient temperature. After that the reaction solvent
was evaporated under reduced pressure and the N-benzyl-3-
hydroxy-3-phenyl propanamide was isolated from the residue
by flash chromatography with silica gel column
chromatography (hexane/ethyl acetate = 2/3) to afford 18 mg
(91%) of the desire deuterated -hydroxy amide as white solid.
6. Synthesis of the catalysts: Catalyst were synthesized
according to the procedure previously reported.31,32
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51
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60
Step II:39 A flame dried two necked round bottom flask (50 mL)
was charged with dry chlorobenzene (50 mL) along with methyl
3-oxo-5-phenylpentanoate (2 g, 9.7 mmol). Catalytic amount of
Ti(Oi-Pr)4 (0.3 g, 0.97 mmol) was added to the reaction mixture
and was stirred for 30 min. Benzyl amine (1.1 g, 10.7 mmol)
was added to the reaction mixture slowly. The reaction mixture
°
was refluxed at 130 C for 24 h. After that solvent was
evaporated and the solid residue was extracted with ethyl
acetate (50 mL). Organic layer was washed successively with
water (2  50 mL) and brine (2  50 mL) and finally dried over
anhydrous MgSO4. The solvent was evaporated under vacuum
and the residue was purified by silica gel chromatography
(hexane/ethyl acetate = 2/3) as eluents to afford 0.9 g (33%) of
N-benzyl-3-oxo-5-phenylpentanamide as white solid.
Data for catalyst 1a: 1H NMR (CD3OD, 400 MHz)  8.53 (bs,
1H), 7.65 (d, J = 2.4 Hz, 1H), 7.62 (d, J = 2.4 Hz, 1H), 4.14 (s,
1H), 3.34 (s, OCH3), 1.44 (s, 9H), 1.19 (s, 9H); 51V NMR
(CD3OD, 105 MHz)  567.7; 13C{1H} NMR (CD3OD, 100
MHz)  167.7, 142.3, 137.0, 136.3, 135.1, 134.7, 123.8, 111.9,
84.7, 49.8, 38.3, 37.2, 36.3, 29.9, 28.1, 27.4; IR (KBr) 2965 (s),
2913 (m), 2869 (m), 1663 (s), 1615 (s, C=N), 1578 (m), 1548
(m, COO), 1480 (w), 1429 (m), 1368 (m), 1320 (m), 1297 (s),
3. General reaction procedure for the asymmetric reduction
of -keto amides: In an oven dried Schlenk tube, the -keto
amide (0.08 mmol) was taken along with catalyst (0.008 mmol)
under argon atmosphere. The respective dry solvent (1 mL) was
injected into the Schlenk tube via syringe. After stirring the
reaction mixture for 15 minutes at ambient temperature, the
schlenk tube was put into the cooling bath. The reducing agent
(0.24 mmol) diluted by the dry reaction solvent was added to
the reaction mixture via flame dried syringe slowly over 1 h
(caution: HB(pin) and HB(cat) are highly moisture sensitive).
After the reaction was over (checked by TLC), double distilled
water was injected into the Schlenk tube via syringe to quench
the reducing agent. The reaction mixture was stirred for 30 min
under room temperature followed by removable of the organic
solvent under reduced pressure. The residue was extracted with
ethyl acetate (2 mL) and the organic layer was washed with
water and drying over anhydrous MgSO4. The solvent was
evaporated under reduced pressure and then the product -
hydroxy amide was isolated by silica gel column
chromatography (eluent: ethyl acetate in hexane).
1181 (m), 1055 (w), 1031 (w), 993 (m, V=O); [α]3D4+306.53 (c
0.1, CH3OH); TLC Rf 0.20 (CH3OH/CH2Cl2, 1/9); HRMS (ESI)
m/z: [M + H]+ Calcd for C18H26BrNO5V 466.0436; Found
466.0434.
Data for catalyst 2a: 1H NMR (CD3OD, 400 MHz) δ 7.39 (d,
J = 2.0 Hz, 1H), 7.25 (d, J = 2.4 Hz, 1H), 3.93 (d, J = 11.6 Hz,
1H), 3.73 (d, J = 11.2 Hz, 1H), 1.47 (s, 9H), 1.20 (s, 9H);
13C{1H} NMR (CD3OD, 100 MHz) δ 164.8, 140.4, 130.9,
130.5, 129.1, 128.4, 113.3, 76.0, 53.6, 37.2, 36.2, 30.6, 30.2,
27.2; 51V NMR (CD3OD, 105 MHz) δ 514.7, 528.3; IR (KBr)
3449 (br, w, NH), 2958 (m), 2872 (m), 1654 (s), 1463 (m), 1434
(s), 1409 (m), 1340 (m), 1267 (s), 1247 (s), 1053 (s), 970 (m,
V=O); [α]3D4+562.00 (c 0.1, CH3OH); TLC Rf 0.10
(iPrOH/Hexanes, 1/10); HRMS (ESI) m/z: [M + H]+ Calcd for
C18H28BrNO5V 468.0592; Found 468.0589.
4. Reaction procedure for the synthesis of the (S)-duloxetine
precursor:
(S)-3-hydroxy-N-methyl-3-(thiophen-2-
yl)propanamide: In an oven dried Schlenk tube, N-methyl-3-
oxo-3-(thiophen-2-yl)propanamide (0.4 mmol) was taken along
with catalyst (0.04 mmol) under argon atmosphere. Dry THF (4
mL) was injected into the Schlenk tube via syringe. After
stirring the reaction mixture for 15 minutes at ambient
temperature, the schlenk tube was put into the cooling bath. The
reducing agent (1.2 mmol) diluted by the dry reaction solvent
(400 L) was added to the reaction mixture via flame dried
syringe slowly over 1 h. After 72 h, double distilled water (100
L) was injected into the Schlenk tube via syringe to quench
the reducing agent. The reaction mixture was stirred for 30 min
under room temperature followed by removable of the organic
Data for catalyst 1b: 1H NMR (CD3OD, 400 MHz) δ 8.61 (s,
1H), 7.80 (s, 1H), 7.52 (s, 1H), 7.14 (d, J = 7.6 Hz, 1H), 7.07
(d, J = 7.6 Hz, 1H), 6.98 (s, 1H), 4.17 (s, 1H), 3.34 (s, OCH3),
2.31 (s, 3H), 2.22 (s, 3H), 1.20 (s, 9H); 51V NMR (CD3OD, 105
MHz) δ 559.4; 13C{1H} NMR (CD3OD, 100 MHz) δ 167.4,
140.5, 137.6, 136.2, 136.0, 135.0, 131.8, 130.7, 129.7, 123.4,
111.5, 84.7, 38.3, 28.1, 21.0, 19.8; IR (KBr) 3446 (br, w, NH),
2961 (m), 1687 (m), 1616 (s), 1553 (s), 1432 (s), 1314 (s), 1002
(m, V=O); [α]2D5+236.43 (c 0.1, CH3OH); TLC Rf 0.28
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(iPrOH/Hexanes, 1/5); HRMS (ESI) m/z: [M + H]+ Calcd for
C22H26BrNO5V 514.0429; Found 514.0434.
9.78 (s, 1H), 7.56 (d, J = 2.8 Hz, 1H), 7.47–7.40 (m, 5H), 7.22–
7.19 (m, 3H), 7.17–7.14 (m, 2H); 13C{1H} NMR (CDCl3, 100
MHz) δ 195.3, 157.8, 141.7, 141.1, 140.9, 134.6, 133.4, 133.1,
130.6, 130.1, 129.0, 128.5, 127.8, 127.1, 126.7, 121.3, 110.7;
TLC Rf 0.20 (CH2Cl2/Hexanes, 1/5); HRMS (ESI) m/z: [M +
H]+ Calcd for C19H14BrO2 353.017; Found 353.0172.
1
2
3
4
5
6
7
8
Data for catalyst 1c: 1H NMR (CD3OD, 400 MHz) δ 8.48 (s,
1H), 7.64 (d, J = 2.8 Hz, 1H), 7.45–7.40 (m, 4H), 7.31 (d, J =
2.4 Hz, 1H), 7.22–7.20 (m, 2H), 7.17–7.13 (m, 3H), 4.11 (s,
1H), 3.34 (s, OCH3), 1.14 (s, 9H); 51V NMR (CD3OD, 105
MHz) δ 557.9; 13C{1H} NMR (CD3OD, 100 MHz) δ 179.3,
167.1, 160.7, 143.1, 142.5, 141.3, 136.3, 135.9, 134.1, 132.1,
130.9, 130.4, 130.2, 129.2, 128.8, 127.9, 127.6, 123.4, 111.1,
84.6, 38.2, 28.0; IR (KBr) 3424 (br, w, NH), 2962 (m), 1700
(s), 1687 (s), 1616 (s), 1555 (s), 1428 (s), 1411 (s), 1311 (m),
8. Characterization data of the substrates and products:
N-Benzyl-3-oxo-3-phenylpropanamide (3a):40 The product
3a was obtained as white solid with 90% yield (1.96 g, 7.74
1
9
mmol) H NMR (CDCl3, 400 MHz) δ keto form (major) 8.00
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1267 (s), 1215 (s), 1141 (s), 1002 (m, V=O); [α]2D5+381.02 (c
0.1, CH3OH); TLC Rf 0.28 (iPrOH/Hexanes, 1/5); HRMS (ESI)
m/z: [M + H]+ Calcd for C26H26BrNO5V 562.0429; Found
562.0438.
(d, J = 8.0 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 7.6 Hz,
2H), 7.35–7.27 (m, 5H), 4.51 (d, J = 6.0 Hz, 2H), 4.01 (s, 2H);
enol form (minor) 5.50 (s, 1H); 13C{1H} NMR (CDCl3, 100
MHz) δ keto form (major) 195.9, 165.7, 137.8, 136.0, 134.0,
128.8, 128.6, 128.5, 127.6, 127.4, 45.2, 43.5; enol form (minor)
128.3, 125.6; TLC Rf 0.21 (EtOAc/Hexanes, 1/2); HRMS (ESI)
m/z: [M + Na]+ Calcd for C16H15NO2Na 276.1000; Found
276.0999.
7. Characterization data of the catalyst precursors31,32
5-Bromo-3-(tert-butyl)-2-hydroxybenzaldehyde: 1H NMR
(CDCl3, 400 MHz) δ 11.72 (s, 1H), 9.81 (s, 1H), 7.57 (d, J = 2.4
Hz, 1H), 7.52 (d, J = 2.4 Hz, 1H), 1.40 (s, 9H); 13C{1H} NMR
(CDCl3, 100 MHz) δ 195.9, 160.1, 141.0, 136.9, 133.5, 121.5,
111.0, 35.0, 28.9; TLC Rf 0.50 (EtOAc/Hexanes, 1/10); HRMS
(ESI) m/z: [M]+ Calcd for C11H13BrO2 256.0099; Found
256.0101.
(S)-N-Benzyl-3-hydroxy-3-phenylpropanamide (4a):41a The
product 4a was obtained as white solid with 86% yield (17 mg,
0.0688 mmol).1H NMR (CDCl3, 400 MHz) δ 7.35–7.27 (m, 8H),
7.21–7.19 (m, 2H), 6.14 (bs, 1H, NH), 5.14–5.13 (m, 1H), 4.43
(dd, J = 3.2, 5.6 Hz, 2H), 4.08 (s, 1H), 2.60 (m, 2H); 13C{1H}
NMR (CD3OD, 100 MHz) δ 173.2, 145.2, 139.7, 129.4, 128.5,
(S)-2-((5-Bromo-3-(tert-butyl)-2-hydroxybenzyl)-amino)-
1
3,3-dimethylbutanoic acid: H NMR (CD3OD, 400 MHz) δ
128.4, 128.0, 127.0, 72.1, 46.7, 43.9; [α]2549.5 (c 0.43, CHCl3);
7.24 (d, J = 2.0 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H), 4.07 (d, J =
13.6 Hz, 1H), 3.65 (d, J = 13.6 Hz, 1H), 2.90 (s, 1H), 1.36 (s,
9H), 1.00 (s, 9H); 13C{1H} NMR (CD3OD, 100 MHz) δ 176.6,
157.0, 140.6, 130.9, 130.1, 126.2, 111.9, 71.7, 51.6, 35.7, 34.0,
D
TLC Rf 0.20 (EtOAc/Hexanes, 1/1); HRMS (ESI) m/z: [M +
H]+ Calcd for C16H18NO2 256.1338; Found 256.1342. HPLC
analysis: tR 12.07 min (S-isomer), 14.99 min (R-isomer)
(Chiralpak AD-H, hexanes/iPrOH, 90/10, 1.0 mL/min, λ = 254
nm) for 97% ee.
N-Benzyl-3-oxo-3-(p-tolyl)propanamide (3b):40 The product
3b was obtained as white solid with 81% yield (1.86 g, 6.97
mmol).1H NMR (CDCl3, 400 MHz) δ keto form (major) 7.89
(d, J = 8.4 Hz, 2H), 7.52 (bs, 1H, NH), 7.34–7.26 (m, 7H), 4.50
(d, J = 5.6 Hz, 2H), 3.97 (s, 2H), 2.42 (s, 3H); enol form (minor)
5.47 (s, 1H); 13C{1H} NMR (CDCl3, 100 MHz) δ 195.6, 165.8,
145.1, 137.9, 133.7, 129.5, 128.6, 127.6, 127.4, 45.0, 43.6, 21.7;
TLC Rf 0.21 (EtOAc/Hexanes, 1/2); HRMS (ESI) m/z: [M +
Na]+ Calcd for C17H17NO2Na 290.1157; Found 290.1152.
29.8, 27.6; [α]2831.33 (c 0.1, CH2Cl2); TLC Rf 0.30
D
(CH3OH/CH2Cl2, 1/10); HRMS (ESI) m/z: [M]+ Calcd for
C17H26BrNO3 371.1096; Found 371.1097.
2-Hydroxy-2',5'-dimethyl-[1,1'-biphenyl]-3-
carbaldehyde:31,32 1H NMR (CDCl3, 400 MHz) δ 11.31 (s, 1H),
9.97 (s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H),
7.19 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 7.09 (d, J =
7.6 Hz, 1H), 7.03 (s, 1H), 2.36 (s, 3H), 2.16 (s, 3H); 13C{1H}
NMR (CDCl3, 100 MHz) δ 196.7, 158.8, 138.2, 136.0, 135.1,
133.6, 133.0, 131.1, 130.5, 129.8, 128.8, 120.5, 119.6, 20.9,
19.4; TLC Rf 0.33 (Ether/Hexanes, 1/15); HRMS (ESI) m/z: [M
+ H]+ Calcd for C15H15O2 227.1072; Found 227.1067.
5-Bromo-2-hydroxy-2',5'-dimethyl-[1,1'-biphenyl]-3-
carbaldehyde:31,32 1H NMR (CDCl3, 400 MHz) δ 11.2 (s, 1H),
9.90 (s, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H),
7.18 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 6.99 (s, 1H),
2.35 (s, 3H), 2.15 (s, 3H); 13C{1H} NMR (CDCl3, 100 MHz) δ
195.6, 157.9, 140.5, 135.3, 134.8, 134.6, 133.7, 130.3, 129.9,
129.2, 121.5, 111.1, 20.9, 19.3; TLC Rf 0.40 (Ether/Hexanes,
1/15); HRMS (ESI) m/z: [M + H]+ Calcd for C15H14BrO2
305.0177; Found 305.0172.
(S)-N-benzyl-3-hydroxy-3-(p-tolyl)propanamide (4b): The
product 4b was obtained as white solid with 85% yield (18 mg,
1
0.068 mmol). H NMR (CD3OD, 400 MHz) δ 7.25–7.17 (m,
5H), 7.13–7.09 (m, 4H), 5.04 (dd, J = 8.4, 5.8 Hz, 1H), 4.31 (dd,
J = 48.8, 15.2 Hz, 2H), 2.62 (ddd, J = 22.0, 14.0, 8.0 Hz, 2H),
2.31 (s, 3H); 13C{1H} NMR (CD3OD, 100 MHz) δ 173.3, 142.1,
139.7, 138.3, 130.0, 129.3, 128.4, 127.0, 128.0, 72.0, 46.6, 43.9,
21.1; [α]2642.0 (c 0.05, CHCl3); TLC Rf 0.21 (EtOAc/Hexanes,
D
1/1); HRMS (ESI) m/z: [M + H]+ Calcd for C17H20NO2
270.1494; Found 270.1492. HPLC analysis: tR 12.00 min (S-
isomer), 14.40 min (R-isomer) (Chiralpak AD-H,
hexanes/iPrOH, 90/10, 1.0 mL/min, λ = 254 nm) for 98% ee.
2-Hydroxy-[1,1':2',1''-terphenyl]-3-carbaldehyde:31,32
1H
NMR (CDCl3, 400 MHz) δ 11.16 (s, 1H), 9.86 (s, 1H), 7.48–
7.45 (m, 3H), 7.44–7.43 (m, 2H), 7.24 (dd, J = 7.6, 1.6 Hz, 1H),
7.18–7.15 (m, 5H), 6.88 (t, J = 7.6 Hz, 1H); 13C{1H} NMR
(CDCl3, 100 MHz) δ 196.6, 158.9, 141.7, 141.3, 139.1, 134.7,
132.9, 130.9, 130.6, 130.2, 129.2, 128.1, 127.7, 127.0, 126.5,
120.4,119.2; TLC Rf 0.10 (CH2Cl2/Hexanes, 1/5); HRMS (ESI)
m/z: [M + H]+ Calcd for C19H15O2 275.1072; Found 275.1067.
5-Bromo-2-hydroxy-[1,1':2',1''-terphenyl]-3-
N-Benzyl-3-(4-methoxyphenyl)-3-oxopropanamide
(3c):
The product 3c was obtained as crystalline white solid with 73%
yield (1.78 g, 6.28 mmol). 1H NMR (CDCl3, 400 MHz) δ keto
form (major) 7.97 (d, J = 8.8 Hz, 2H), 7.55 (s, 1H, NH), 7.34–
7.26 (m, 5H), 6.95 (d, J = 9.2 Hz, 2H), 4.49 (d, J = 6.0 Hz, 2H),
3.94 (s, 2H), 3.88 (s, 1H); enol form (minor) 5.43 (s, 1H);
13C{1H} NMR (CDCl3, 100 MHz) δ 194.3, 165.9, 164.3, 137.9,
carbaldehyde:31,32 1H NMR (CDCl3, 400 MHz) δ 11.01 (s, 1H),
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128.4, 128.0, 122.1, 71.5, 46.5, 43.9; [α]2537.3 (c 0.5, CHCl3);
131.0, 129.1, 128.6, 127.6, 114.0, 55.5, 44.9, 43.5; TLC Rf 0.21
D
(EtOAc/Hexanes, 1/2); HRMS (ESI) m/z: [M + Na]+ Calcd for
C17H17NO3Na 306.1106; Found 306.1102.
1
2
3
4
5
6
7
8
TLC Rf 0.21 (EtOAc/Hexanes, 1/1); HRMS (ESI) m/z: [M +
H]+ Calcd for C16H17BrNO2 334.0443; Found 334.0443. HPLC
analysis: tR 12.23 min (S-isomer), 18.18 min (R-isomer)
(Chiralpak AD-H, hexanes/iPrOH, 90/10, 1.0 mL/min, λ = 254
nm) for 99% ee.
(S)-N-Benzyl-3-hydroxy-3-(4-methoxyphenyl)propanamide
(4c):41a The product 4c was obtained as white solid with 82%
1
yield (18 mg, 0.065 mmol). H NMR (CDCl3, 400 MHz) δ
7.31–7.24 (m, 5H), 7.23 (d, J = 2.0 Hz, 2H), 7.17–7.15 (m, 2H),
6.83 (d, J = 8.8 Hz, 2H), 6.48 (bs, 1H, NH), 5.00 (dd, J = 8.8,
3.2 Hz, 1H), 4.36 (d, J = 5.6 Hz, 2H), 4.17 (bs, 1H, OH), 3.77
(s, 3H), 2.59–2.50 (m, 2H); 13C{1H} NMR (CD3OD, 100 MHz)
δ 173.2, 160.6, 139.6, 137.0, 129.3, 128.3, 128.0, 114.7, 71.8,
N-Benzyl-3-(4-nitrophenyl)-3-oxopropanamide (3f): The
product 3f was obtained as crystalline white solid with 80%
yield (2.05 g, 6.88 mmol). 1H NMR (CDCl3, 400 MHz) δ keto
form (major) 8.33 (d, J = 8.8 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H),
8.17 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 7.38–7.27
(m,5H), 4.56 (d, J = 6.0 Hz, 1H), 4.49 (d, J = 6.0 Hz, 1H), 4.02
(s, 1H); enol form (minor) 5.60 (s, 1H); 13C{1H} NMR (CDCl3,
100 MHz) δ keto form (major) 193.9, 164.9, 150.6, 148.8, 137.5,
129.6, 126.5, 123.9, 123.6, 91.3, 43.7, 43.2; enol form (minor)
171.1, 166.6, 140.3, 140.2, 137.4, 128.7, 128.7, 127.7, 127.6,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
55.6, 46.6, 43.8; [α]2531.5 (c 0.7, CHCl3); TLC Rf 0.20
D
(EtOAc/Hexanes, 1/1); HRMS (ESI) m/z: [M + H]+ Calcd for
C17H20NO3 286.1443; Found 286.1445. HPLC analysis: tR
16.88 min (S-isomer), 19.90 min (R-isomer) (Chiralpak AD-H,
hexanes/iPrOH, 90/10, 1.0 mL/min, λ = 254 nm) for 99% ee.
46.3; [α]2538.3 (c 0.4, CHCl3); TLC Rf 0.20 (EtOAc/Hexanes,
N-Benzyl-3-(4-chlorophenyl)-3-oxopropanamide (3d):40 The
product 3d was obtained as white solid with 92% yield (2.27 g,
7.91 mmol). 1H NMR (CDCl3, 400 MHz) δ keto form (major)
7.91 (t, J = 2.4 Hz, 1H), 7.88 (t, J = 2.0 Hz, 1H), 7.44 (t, J = 2.4
Hz, 1H), 7.42 (t, J = 2.0 Hz, 1H), 7.32–7.29 (m, 3H), 7.26 (m,
1H), 7.25–7.24 (m, 1H), 4.45 (d, J = 5.6 Hz, 2H), 3.90 (s, 2H);
enol form (minor) 5.51 (s, 1H); 13C{1H} NMR (CDCl3, 100
MHz) δ keto form (major) 194.6, 165.2, 140.7, 137.7, 134.4,
130.0, 129.2, 128.7, 127.6, 127.5, 45.5, 43.7; enol form (minor)
127.0; TLC Rf 0.21 (EtOAc/Hexanes, 1/2); HRMS (ESI) m/z:
[M + Na]+ Calcd for C16H14ClNO2Na 310.0611; Found
310.0604.
D
1/2); HRMS (ESI) m/z: [M + H]+ Calcd for C16H15N2O4
299.1032; Found 299.1025.
(S)-N-Benzyl-3-hydroxy-3-(4-nitrophenyl)propan-amide
(4f): The product 4f was obtained as white solid with 79% yield
(19 mg, 0.063 mmol). 1H NMR (CD3OD, 400 MHz) δ 8.14 (d,
J = 8.8 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.25–7.12 (m, 5H),
5.21–5.17 (m, 1H), 4.30 (dd, J = 46.8, 14.8 Hz, 2H), 2.64 (ddd,
J = 22.0, 14.0, 8.0 Hz, 2H); 13C{1H} NMR (CD3OD, 100 MHz)
δ 172.5, 153.0, 148.6, 139.7, 129.4, 128.5, 128.1, 128.0, 124.4,
71.2, 46.5, 43.9; TLC Rf 0.20 (EtOAc/Hexanes, 1/1); HRMS
(ESI) m/z: [M + Na]+ Calcd for C16H16N2O4Na 323.1008;
Found 323.0997. HPLC analysis: tR 10.47 min (S-isomer),
18.55 min (R-isomer) (Chiralpak AD-H, hexanes/iPrOH, 85/15,
1.0 mL/min, λ = 254 nm) for 79% ee.
(S)-N-Benzyl-3-(4-chlorophenyl)-3-hydroxypropanamide
(4d):40,41a The product 4d was obtained as crystalline white solid
1
with 92% yield (21 mg, 0.07 mmol). H NMR (CD3OD, 400
MHz) δ 7.35–7.19 (m, 7H), 7.09 (dd, J = 8.0, 1.6 Hz, 2H), 5.07
(dd, J = 13.6, 7.6 Hz, 1H), 4.30 (dd, J = 14.8, 54.8 Hz, 2H), 2.61
(ddd, J = 21.6, 13.6, 8.0 Hz, 2H); 13C{1H} NMR (CD3OD, 100
MHz) δ 172.9, 144.0, 139.6, 134.1, 129.4, 129.4, 128.7, 128.4,
N-Benzyl-3-(3-methoxyphenyl)-3-oxopropanamide
(3g):
The product 3g was obtained as white solid with 82% yield
(1.99 g, 7.05 mmol). 1H NMR (CDCl3, 400 MHz) δ keto form
(major) 7.57 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 2.0 Hz, 1H), 7.45
(s, 1H, NH), 7.39 (t, J = 8.0 Hz, 1H), 7.34–7.26 (m, 5H), 7.15
(ddd, J = 8.2, 2.8, 0.8 Hz, 1H), 4.50 (d, J = 5.6 Hz, 2H), 3.98 (s,
2H), 3.85 (s, 1H); enol form (minor) 5.50 (s, 1H); 13C{1H}
NMR (CDCl3, 100 MHz) δ keto form (major) 195.7, 165.6,
159.8, 137.8, 137.4, 129.8, 128.6, 127.6, 127.4, 121.2, 120.6,
112.4, 55.4, 45.3, 43.5; enol form (minor) 129.3, 118.0 116.5,
110.8; TLC Rf 0.22 (EtOAc/Hexanes, 1/1); HRMS (ESI) m/z:
[M + Na]+ Calcd for C17H17NO3Na 306.1106; Found 306.1102.
128.0, 71.4, 46.6, 43.9; [α]2554.5 (c 0.4, CHCl3); TLC Rf 0.21
D
(EtOAc/Hexanes, 1/1); HRMS (ESI) m/z: [M + H]+ Calcd for
C16H17ClNO2 290.0948; Found 290.0951. HPLC conditions: tR
11.70 min (S-isomer), 17.26 min (R-isomer) (Chiralpak AD-H,
hexanes/iPrOH, 90/10, 1.0 mL/min, λ = 254 nm) for 96% ee.
N-Benzyl-3-(4-bromophenyl)3-oxopropanamide (3e):40 The
product 3e was obtained as crystalline white solid with 84%
yield (2.39 g, 7.22 mmol). 1H NMR (CDCl3, 400 MHz) δ keto
form (major) 7.86 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H),
7.33–7.28 (m, 5H), 4.49 (d, J = 5.6 Hz, 2H), 3.95 (s, 2H); enol
form (minor) 5.48 (s, 1H); 13C{1H} NMR (CDCl3, 100 MHz) δ
keto form (major) 194.7, 165.2, 137.7, 134.8, 132.1, 131.6,
130.0, 128.6, 127.6, 127.5, 45.5, 43.6; enol form (minor) 129.4,
127.2; TLC Rf 0.13 (EtOAc/Hexanes, 1/2); HRMS (ESI) m/z:
[M + Na]+ Calcd for C16H14BrNO2Na 354.0106; Found
354.0105.
(S)-N-Benzyl-3-hydroxy-3-(3-methoxyphenyl)propanamide
(4g): The product 4g was obtained as white solid with 43% yield
1
(10 mg, 0.034 mmol). H NMR (CD3OD, 400 MHz) δ 7.62–
7.19 (m, 5H), 7.13–7.11 (m, 1H), 6.95–6.93 (m, 2H), 6.81 (ddd,
J = 3.2, 2.4, 0.8 Hz, 1H), 5.06 (dd, J = 8.0, 6.0 Hz, 1H), 4.32
(dd, J = 44.4, 14.8 Hz, 2H), 3.76 (s, 3H), 2.62 (ddd, J = 21.6,
13.6, 8.0 Hz, 2H); 13C{1H} NMR (CD3OD, 100 MHz) δ 173.2,
161.2, 146.8, 139.6, 130.4, 129.4, 128.3, 128.0, 119.2, 114.0,
112.5, 72.1, 55.5, 46.7, 43.9; [α]2651.2 (c 0.1, CHCl3); TLC Rf
(S)-N-Benzyl-3-(4-bromophenyl)-3-hydroxypropanamide
(4e):40 The product 4e was obtained as white solid with 89%
D
0.20 (EtOAc/Hexanes, 1/1); HRMS (ESI) m/z: [M + Na]+ Calcd
for C17H19NO3Na 308.1263; Found 308.1259. HPLC analysis:
tR 18.32 min (S-isomer), 21.53 min (R-isomer) (Chiralpak AD-
H, hexanes/iPrOH, 90/10, 1.0 mL/min, λ = 254 nm) for 88% ee.
1
yield (23 mg, 0.071 mmol). H NMR (CD3OD, 400 MHz) δ
7.45 (d, J = 8.4 Hz, 2H), 7.29–7.17 (m, 5H), 7.08 (dd, J = 7.6,
0.8 Hz, 2H), 5.05 (t, J = 7.2 Hz, 1H), 4.30 (dd, J = 57.6, 15.2
Hz, 2H), 2.61 (ddd, J = 21.6, 13.6, 7.6 Hz, 2H); 13C{1H} NMR
(CD3OD, 100 MHz) δ 172.8, 144.5, 139.6, 132.4, 129.4, 129.0,
N-Benzyl-3-(naphthalen-2-yl)-3-oxopropanamide (3h): The
product 3h was obtained as white solid with 85% yield (2.21 g,
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7.31 mmol). 1H NMR (CDCl3, 400 MHz) δ keto form (major)
(S)-N-Benzyl-3-(furan-2-yl)-3-hydroxypropanamide (4j):
1
2
3
4
5
6
7
8
8.55 (s, 1H), 8.03–7.97 (m, 2H), 7.92–7.87 (m, 2H), 7.66–7.62
(m, 1H), 7.60–7.56 (m, 1H), 7.53–7.50 (m, 1H), 7.34–7.27 (m,
1H), 4.52 (d, J = 5.6 Hz, 2H), 4.13 (s, 2H); enol form (minor)
5.65 (s, 1H); 13C{1H} NMR (CDCl3, 100 MHz) δ 195.8, 165.7,
137.8, 135.9, 133.4, 132.3, 130.9, 129.8, 128.7, 128.6, 127.7,
127.6, 127.4, 127.0, 123.5, 45.4, 43.6; TLC Rf 0.20
(EtOAc/Hexanes, 1/3); HRMS (ESI) m/z: [M + Na]+ Calcd for
C20H17NO2Na 326.1157; Found 326.1153.
The product 4j was obtained as white solid with 60% yield (11
mg, 0.048 mmol). 1H NMR (CD3OD, 400 MHz) δ 7.42 (dd, J =
1.6, 0.8 Hz, 1H), 7.29–7.20 (m, 5H), 6.34 (dd, J = 3.2, 1.6 Hz,
1H), 6.28 (d, J = 3.2 Hz, 1H), 5.10 (t, J = 6.8 Hz, 1H), 4.35 (d,
J = 10.4 Hz, 2H), 2.75–2.73 (m, 2H); 13C{1H} NMR (CD3OD,
100 MHz) δ 172.7, 157.2, 143.2, 139.6, 129.4, 128.4, 128.0,
111.1, 107.1, 65.4, 43.9, 43.1; [α]2611.0 (c 0.2, CHCl3); TLC
D
Rf 0.20 (EtOAc/Hexanes, 1/1); HRMS (ESI) m/z: [M + Na]+
Calcd for C14H15NO3Na 268.0950; Found 268.0951. HPLC
analysis: tR 22.18 min (S-isomer), 32.91 min (R-isomer)
(Chiralpak AS-H, hexanes/iPrOH, 80/20, 1.0 mL/min, λ = 220
nm) for 90% ee.
(S)-N-Benzyl-3-hydroxy-3-(naphthalen-2-yl)propan-amide
(4h): The product 4h was obtained as white solid with 90%
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yield (21 mg, 0.072 mmol). H NMR (CD3OD, 400 MHz) δ
7.82–7.79 (m, 4H), 7.53 (dd, J = 8.8, 1.6 Hz, 1H), 7.48–7.44
(m, 2H), 7.10–7.06 (m, 1H), 7.04–7.00 (m, 2H), 6.94 (d, J = 7.2
Hz, 2H), 5.26 (dd, J = 7.6, 6.4 Hz, 1H), 4.28 (dd, J = 70.4, 15.2
Hz, 2H), 2.75 (ddd, J = 21.6, 14.0, 8.0 Hz, 2H); 13C{1H} NMR
(CD3OD, 100 MHz) δ 173.1, 142.4, 139.5, 134.7, 134.5, 129.2,
129.2, 129.0, 128.6, 128.1, 127.9, 127.1, 126.8, 125.9, 125.2,
N-Benzyl-3-oxo-3-(thiophen-2-yl)propanamide (3k): The
product 3k was obtained as light brown solid with 77% yield
(1.71 g, 6.62 mmol). 1H NMR (CDCl3, 400 MHz) δ 7.83 (dd, J
= 3.6, 0.8 Hz, 1H), 7.74 (dd, J = 4.8, 0.8 Hz, 1H), 7.50 (bs, 1H,
NH), 7.35–7.25 (m, 5H), 7.17 (d, J = 4.8, 4.0 Hz, 1H), 4.49 (d,
J = 5.6 Hz, 2H), 3.94 (s, 2H); 13C{1H} NMR (CDCl3, 100 MHz)
δ 188.4, 165.1, 143.2, 137.8, 135.6, 133.8, 128.6, 128.6, 127.6,
127.4, 45.7, 43.6; TLC Rf 0.25 (EtOAc/Hexanes, 1/2); HRMS
(ESI) m/z: [M + Na]+ Calcd for C14H13NO2SNa 282.0565;
Found 282.0557.
72.4, 46.6, 43.8; [α]2540.3 (c 0.6, CHCl3); TLC Rf 0.20
D
(EtOAc/Hexanes, 1/1); HRMS (ESI) m/z: [M + H]+ Calcd for
C20H20NO2 306.1494, Found 306.1492. HPLC analysis: tR
19.56 min (S-isomer), 28.20 min (R-isomer) (Chiralpak AD-H,
hexanes/iPrOH, 90/10, 1.0 mL/min, λ = 254 nm) for 98% ee.
N-Benzyl-3-(naphthalen-1-yl)-3-oxopropanamide (3i): The
product 3i was obtained as white solid with 70% yield (1.82 g,
6.02 mmol). 1H NMR (CDCl3, 400 MHz) δ keto form (major)
8.65 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 7.6 Hz, 1H), 7.91–7.89 (m,
1H), 7.62–7.60 (m, 1H), 7.56–7.51 (m, 2H), 7.36–7.28 (m, 5H),
4.53 (d, J = 5.6 Hz, 2H), 4.09 (s, 2H); enol form (minor) 5.31
(s, 1H); 13C{1H} NMR (CDCl3, 100 MHz) δ keto form (major)
199.2, 165.6, 137.8, 134.4, 134.0, 130.3, 130.1, 129.4, 128.7,
128.6, 128.4, 127.6, 127.4, 126.7, 125.5, 124.4, 49.0, 43.7; enol
form (minor) 133.9, 127.8; TLC Rf 0.20 (EtOAc/Hexanes, 1/3);
HRMS (ESI) m/z: [M + Na]+ Calcd for C20H17NO2Na 326.1157;
Found 326.1155.
(S)-N-Benzyl-3-hydroxy-3-(thiophen-2-yl)propan-amide
(4k): The product 4k was obtained as white solid with 71%
1
yield (15 mg, 0.057 mmol). H NMR (CD3OD, 400 MHz) δ
7.30 (dd, J = 5.2, 1.2 Hz, 1H), 7.28–7.24 (m, 2H), 7.22–7.16
(m, 3H), 6.97 (dt, J = 3.6, 0.8 Hz, 1H), 6.93 (dd, J = 4.8, 3.6 Hz,
1H), 5.35 (dd, J = 8.0, 6.0 Hz, 1H), 4.34 (dd, J = 32.8, 15.2 Hz,
2H), 2.73 (ddd, J = 22.0, 14.0, 8.0 Hz, 2H); 13C{1H} NMR
(CD3OD, 100 MHz) δ 172.7, 149.2, 139.7, 129.4, 128.4, 128.0,
127.5, 125.4, 124.7, 68.0, 46.8, 43.9; [α]2550.3 (c 0.05, CHCl3);
D
TLC Rf 0.20 (EtOAc/Hexanes, 1/1); HRMS (ESI) m/z: [M +
H]+ Calcd for C14H16NO2S 262.0902; Found 262.0901. HPLC
analysis: tR 14.05 min (S-isomer), 22.97 min (R-isomer)
(Chiralpak AS-H, hexanes/iPrOH, 70/30, 1.0 mL/min, λ = 254
nm) for 95% ee at -20°C and 93% ee at -5 to 0°C.
(S)-N-Benzyl-3-hydroxy-3-(naphthalene-1-yl)propan-
amide (4i): The product 4i was obtained as white solid with
83% yield (20 mg, 0.066 mmol). 1H NMR (CD3OD, 400 MHz)
δ 8.22 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.77 (d, J =
8.0 Hz, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.52–7.42 (m, 3H), 7.26–
7.16 (m, 5H), 5.93 (dd, J = 8.4, 4.8 Hz, 1H), 4.35 (d, J = 3.2 Hz,
2H), 2.80–2.70 (m, 2H); 13C{1H} NMR (CD3OD, 100 MHz) δ
173.5, 141.0, 139.7, 135.3, 131.5, 129.8, 129.4, 128.9, 128.4,
N-Benzyl-3-(2-methoxyphenyl)-3-oxopropanamide (3l): The
product 3l was obtained as white solid with 74% yield (1.80 g,
1
0.64 mmol). H NMR (CDCl3, 400 MHz) δ 7.69 (dd, J = 7.6,
1.6 Hz, 1H), 7.50 (t, J = 6.8 Hz, 1H), 7.44 (bs, 1H, NH), 7.34–
7.27 (m, 5H), 7.01 (t, J = 7.6 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H),
4.50 (d, J = 6.0 Hz, 1H), 4.03 (s, 2H), 3.88 (s, 1H); 13C{1H}
NMR (CDCl3, 100 MHz) δ 179.7, 166.4, 158.7, 138.1, 134.4,
130.4, 128.4, 127.5, 127.1, 120.6, 115.1, 55.3, 49.8, 43.3; TLC
Rf 0.25 (EtOAc/Hexanes, 2/3); HRMS (ESI) m/z: [M + Na]+
Calcd for C17H17NO3Na 306.1106; Found 306.1101.
128.0, 127.0, 126.5, 126.4, 124.2, 124.1, 68.7, 46.1, 44.0; [α]2D5
61.7 (c 0.4, CHCl3); TLC Rf 0.20 (EtOAc/Hexanes, 1/1);
HRMS (ESI) m/z: [M + Na]+ Calcd for C20H19NO2Na 328.1313;
Found 328.1311. HPLC analysis: tR 9.00 min (S-isomer), 12.60
min (R-isomer) (Chiralpak AD-H, hexanes/iPrOH, 85/15, 1.0
mL/min, λ = 254 nm) for 90% ee.
(S)-N-Benzyl-3-hydroxy-3-(2-methoxyphenyl)propanamide
(4l): The product 4l was obtained as white solid with 18% yield
(4 mg, 0.014 mmol). 1H NMR (CD3OD, 400 MHz) δ 7.44–7.42
(m, 1H), 7.29–7.19 (m, 6H), 6.94–6.91 (m, 2H), 5.42 (dd, J =
8.8, 4.0 Hz, 1H), 4.36 (s, 2H), 3.81 (s, 3H), 2.61 (ddd, J = 18.4,
14.4, 4.0 Hz, 2H); 13C{1H} NMR (CD3OD, 100 MHz) δ 173.8,
157.4, 139.8, 133.1, 129.4, 128.4, 128.0, 127.3, 121.5, 111.4,
N-Benzyl-3-(furan-2-yl)-3-oxopropanamide
(3j):
The
product 3j was obtained as colourless viscous liquid with 82%
yield (1.71 g, 7.05 mmol). 1H NMR (CDCl3, 400 MHz) δ keto
form (major) 7.62 (m, 1H), 7.48 (bs, 1H, NH), 7.31–7.26 (m,
5H), 6.55 (dd, J = 3.6, 1.6 Hz, 1H), 4.45 (d, J = 6.0 Hz, 2H);
enol form (minor) 5.53 (s, H); 13C{1H} NMR (CDCl3, 100 MHz)
δ 183.6, 165.3, 151.6, 147.5, 137.7, 128.4, 127.4, 127.2, 119.4,
112.6, 44.9, 43.4; TLC Rf 0.25 (EtOAc/Hexanes, 1/2); HRMS
(ESI) m/z: [M + Na]+ Calcd for C14H13NO3Na 266.0793; Found
266.0787.
66.7, 55.7, 44.7, 43.9; [α]2633.0 (c 0.03, CHCl3); TLC Rf 0.20
D
(EtOAc/Hexanes, 1/1); HRMS (ESI) m/z: [M + Na]+ Calcd for
C17H19NO3Na 308.1263; Found 308.1257. HPLC analysis: tR
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19.28 min (S-isomer), 22.46 min (R-isomer) (Chiralpak AD-H,
tR 34.41 min (R-isomer), 39.13 min (S-isomer) (Chiralpak AS-
hexanes/iPrOH, 90/10, 1.0 mL/min, λ = 254 nm) for 88% ee.
H, hexanes/iPrOH, 90/10, 1.0 mL/min, λ = 220 nm) for 98% ee.
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N-Benzyl-3-oxo-5-phenylpent-4-ynamide (3m): The product
3m was obtained as light yellow viscous liquid with 20% yield
(0.4 g, 1.4 mmol). H NMR (CDCl3, 400 MHz) δ keto form
N-Benzyl-4-methyl-3-oxopentanamide (3p):44 The product
3p was obtained as white solid with 76% yield (1.43 g, 6.53
mmol). 1H NMR (CDCl3, 400 MHz) δ 7.40 (bs, 1H, NH), 7.35–
7.26 (m, 5H), 4.46 (d, J = 5.6 Hz, 2H), 3.49 (s, 2H), 2.69 (hep,
J = 7.2 Hz, 1H), 1.12 (d, J = 7.2 Hz, 6H); 13C{1H} NMR (CDCl3,
100 MHz) δ 210.7, 165.5, 137.9, 128.6, 127.6, 127.4, 46.5, 43.5,
42.0, 17.7; TLC Rf 0.25 (Acetone/Hexanes, 1/2); HRMS (ESI)
m/z: [M + Na]+ Calcd for C13H17NO2Na 242.1157; Found:
242.1156.
1
(major) 7.56–7.54 (m, 1H), 7.50–7.46 (m, 1H), 7.40–7.36 (m,
2H), 7.32–7.27 (m, 6H), 4.47 (d, J = 5.2 Hz, 2H), 3.69 (s, 2H);
enol form (minor) 5.39 (s, 1H); 13C{1H} NMR (CDCl3, 100
MHz) δ keto form (major) 181.7, 164.6, 137.6, 133.1, 128.5,
128.2, 127.3, 119.0, 98.5, 93.7, 51.3, 43.4, 42.8; enol form
(minor) 170.8, 153.3, 153.2, 137.7, 137.7, 137.1, 132.3, 131.9,
131.1, 129.9, 129.4, 128.5, 128.3, 127.7, 127.5, 127.3, 120.9,
119.9, 91.6, 87.5, 85.0, 83.9, 82.7, 43.7, 30.7; TLC Rf 0.30
(EtOAc/Hexanes, 1/2); HRMS (ESI) m/z: [M + Na]+ Calcd for
C18H15NO2Na 300.1000; Found 300.0995.
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(S)-N-Benzyl-3-hydroxy-4-methylpentanamide (4p):41b The
product 4p was obtained as white solid with 84% Yield (15 mg,
1
0.0672 mmol). H NMR (CD3OD, 400 MHz) δ 7.29–7.28 (m,
4H), 7.25–7.19 (m, 1H), 4.37 (d, J = 2.4 Hz, 2H), 3.80–3.76 (m,
1H), 2.41–2.26 (m, 2H), 1.69–1.61 (m, 1H), 0.92 (dd, J = 6.8,
2.4 Hz, 6H); 13C{1H} NMR (CD3OD, 100 MHz) δ 174.6, 139.9,
129.4, 128.5, 128.1, 74.5, 44.0, 41.6, 34.9, 19.0, 17.8; [α]2D5
(S)-Benzyl-3-hydroxy-5-phenylpent-4-ynamide (4m): The
product 4m was obtained as white solid with 56% yield (12 mg,
1
0.0448 mmol). H NMR (CD3OD, 400 MHz) δ 7.36–7.34 (m,
2H), 7.32–7.27 (m, 5H), 7.21–7.15 (m, 3H), 4.97 (t, J = 7.2 Hz,
1H), 4.39 (dd, J = 53.2, 14.8 Hz, 2H), 2.75–2.65 (m, 2H);
13C{1H} NMR (CD3OD, 100 MHz) δ 172.1, 139.7, 132.6, 129.5,
129.4, 129.4, 128.4, 128.0, 132.9, 90.4, 85.4, 60.4, 45.5, 44.0;
18.4 (c 0.1, CHCl3); TLC Rf 0.23 (Acetone/Hexanes, 1/4);
HRMS (ESI) m/z: [M + Na]+ Calcd for C13H19NO2Na 244.1313;
Found 244.1308. HPLC analysis: tR 12.50 min (S-isomer),
14.82 min (R-isomer) (Chiralpak AD-H, hexanes/iPrOH, 95/5,
1.0 mL/min, λ = 254 nm) for 56% ee.
[α]251.5 (c 0.03, CHCl3); TLC Rf 0.22 (EtOAc/Hexanes, 1/1);
D
HRMS (ESI) m/z: [M + Na]+ Calcd for C18H17NO2Na 302.1157;
Found: 302.1153. HPLC analysis: tR 14.46 min (S-isomer),
21.85 min (R-isomer) (Chiralpak AS-H, hexanes/iPrOH, 75/25,
1.0 mL/min, λ = 254 nm) for 11% ee.
N-Benzyl-4,4-dimethyl-3-oxopentanamide (3q): The product
3q was obtained as white solid with 83% yield (1.66 g, 7.13
mmol). 1H NMR (CDCl3, 400 MHz) δ 7.43 (bs, 1H, NH), 7.33–
7.29 (m, 2H), 7.27–7.25 (m, 3H), 4.45 (d, J = 6.0 Hz, 2H), 3.52
(s, 2H), 1.15 (s, 9H); 13C{1H} NMR (CDCl3, 100 MHz) δ 212.1,
165.8, 137.9, 128.5, 127.5, 127.3, 45.0, 43.4, 43.2, 27.4, 25.7;
TLC Rf 0.25 (Acetone/Hexanes, 1/2); HRMS (ESI) m/z: [M +
H]+ Calcd for C14H20NO2 234.1494; Found 234.1489.
(R)-N-Benzyl-3-hydroxybutanamide (4n):42 The product 4n
was obtained as white solid with 75% yield (12 mg, 0.06 mmol).
1H NMR (CD3OD, 400 MHz) δ 7.31–7.26 (m, 4H), 7.24–7.19
(m, 1H), 4.36 (s, 2H), 4.20–4.12 (m, 1H), 2.41–2.29 (m, 2H),
1.19 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (CD3OD, 100 MHz) δ
(S)-N-Benzyl-3-hydroxy-4,4-dimethylpentanamide
173.8, 139.8, 129.4, 128.5, 128.1, 65.9, 46.2, 44.0, 23.3; [α]2D5
(4q):41a,44 The product 4q was obtained as white solid with 82%
1
yield (15 mg, 0.0656 mmol). H NMR (CD3OD, 400 MHz) δ:
5.2 (c 0.08, CHCl3); TLC Rf 0.24 (Acetone/Hexanes, 1/4);
HRMS (ESI) m/z: [M + Na]+ Calcd for C11H15NO2Na 216.1000;
Found 216.0992. HPLC analysis: tR 18.69 min (R-isomer),
21.14 min (S-isomer) (Chiralpak AD-H, hexanes/iPrOH, 95/5,
0.7 mL/min, λ = 254 nm) for 14% ee.
7.29 (d, J = 4.4 Hz, 4H), 7.24–7.19 (m, 1H), 4.38 (dd, J = 38.8,
24.0 Hz, 2H), 3.69 (dd, J = 10.4, 2.4 Hz, 1H), 2.44–2.21 (m,
2H), 0.90 (s, 9H); 13C{1H} NMR (CD3OD, 100 MHz) δ 175.2,
139.9, 129.4, 128.5, 128.1, 77.3, 44.1, 39.5, 35.7, 26.1; [α]2D5
N-Benzyl-3-oxo-5-phenylpentanamide (3o): The product 3o
was obtained as white solid with 33% yield (0.9 g, 3.20 mmol).
1H NMR (CDCl3, 400 MHz) δ keto form (major) 7.35–7.29 (m,
3H), 7.28–7.26 (m, 4H), 7.21–7.15 (m, 3H), 4.44 (d, J = 5.6 Hz,
2H), 3.41 (s, 2H), 2.89 (m, 4H); enol form (minor) 5.31 (s, 1H);
enol form (minor) 5.46 (s, 1H); 13C{1H} NMR (CDCl3, 100
MHz) δ 205.5, 165.3, 140.1, 137.7, 128.5, 128.4, 128.1, 127.5,
127.3, 126.1, 49.0, 44.9, 43.4, 29.1; TLC Rf 0.30
(EtOAc/Hexanes, 1/3); HRMS (ESI) m/z: [M + Na]+ Calcd for
C18H19NO2Na 304.1313; Found 304.1314.
25.3 (c 0.6, CHCl3); TLC Rf 0.23 (Acetone/Hexanes, 1/4);
HRMS (ESI) m/z: [M + H]+ Calcd for C14H22NO2 236.1651;
Found 236.1645. HPLC analysis: tR 20.54 min (S-isomer),
20.53 min (R-isomer) (Chiralpak AS-H, hexanes/iPrOH, 90/10,
0.9 mL/min, λ = 254 nm) for 80% ee.
N,N-dimethyl-3-oxo-3-phenylpropanamide (3r):46 The
product 3r was obtained as white solid with 76% yield (1.3 g,
6.70 mmol). 1H NMR (MeOD, 400 MHz) δ keto form (major)
8.00 (d, J = 8.0 Hz, 2H), 7.63 (t, J = 7.6 Hz, 1H), 7.51 (t, J =
7.6 Hz, 2H), 4.22 (d, J = 8.4 Hz, 1H), 3.05 (s, 3H), 2.98 (s, 3H);
enol form (minor) 7.82(d, J = 6.4 Hz, 2 H), 7.43(m, 3H), 6.00(s,
1H), 3.13 (s, 1H), 3.01 (s, 1H); 13C{1H} NMR (MeOD, 100
MHz) δ keto form (major) 195.9, 170.2, 137.5, 134.8, 129.8,
129.5, 126.9,46.1 38.3, 35.7; enol form (minor) 173.5, 171.5,
135.9, 131.7, 85.9, 45.8, 37.4, 35.2; TLC Rf 0.35
(EtOAc/Hexanes, 1/1); HRMS (ESI) m/z: [M + H]+ Calcd for
C11H13NO2 : 192.1025, found: 192.1027.
(R)-N-Benzyl-3-hydroxy-5-phenylpentanamide (4o):43 The
product 4o was obtained as white solid with 90% yield (20 mg,
1
0.072 mmol). H NMR (CD3OD, 400 MHz) δ 7.29–7.28 (m,
4H), 7.25–7.21 (m, 3H), 7.17–7.13 (m, 3H), 4.36 (d, J = 2.0 Hz,
2H), 4.03–3.97 (m, 1H), 2.80–2.59 (m, 2H), 2.39 (d, J = 6.4 Hz,
2H), 1.78–1.72 (m, 2H); 13C{1H} NMR (CD3OD, 100 MHz) δ
173.8, 143.3, 139.9, 129.5, 129.4, 129.3, 128.5, 128.1, 126.7,
69.2, 44.8, 44.0, 40.1, 32.8; [α]259.5 (c 0.4, CHCl3); TLC Rf
(S)-3-hydroxy-N,N-dimethyl-3-phenylpropanamide-4r:47
The product 4r was obtained as slight yellow oil with 63% yield
(24.3 mg, 12.57 mmol). 1H NMR (CDCl3, 400 MHz) δ 7.41-
D
0.22 (EtOAc/Hexanes, 3/7 HRMS (ESI) m/z: [M + Na]+ Calcd
for C18H21NO2Na 306.1470; Found 306.1469. HPLC analysis:
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7.34(m, 4H), 7.29(d, J = 7.2 Hz, 1H), 5.15(d, J = 8.8 Hz, 1H),
Author Contributions
3.84(s, 1H), 2.98(s, 6H), 2.74-261(m, 2H); 13C{1H} NMR
(CDCl3, 100 MHz) δ 172.2, 143.1, 128.4, 127.5, 125.7, 70.4,
1
2
3
4
5
6
7
8
The manuscript was written through contributions of all authors.
All authors have given approval to the final version of the
manuscript.
41.9, 37.1, 35.0; [α]2D5 −96.5 (c 0.60, CHCl3); TLC Rf 0.25
(EtOAc/Hexanes, 1/1); HRMS (ESI) m/z: [M + Na]+ Calcd for
C11H15NO2: 216.1001, found: 216.1002. HPLC conditions: tR
12.44 min (S-isomer, Major), 14.41 min (R-isomer, Minor)
(Chiralcel OD-H, hexanes/iPrOH, 90/10, 1.0 mL/min, λ = 254
nm) for 96% ee.
ACKNOWLEDGMENT
We thank the Ministry of Science and Technology of Taiwan
(MOST 104-2113-M-007-002-MY3 and MOST 107-2113-M-007-
026-MY3) for a generous financial support of this research.
N-Methyl-3-oxo-3-(thiophen-2-yl)propanamide (3k’):45 The
product 3k’ was obtained as white solid with 46% yield (0.3 g,
1.6 mmol). 1H NMR (400 MHz, CDCl3)  7.86 (dd, J = 4.0, 1.2
Hz, 1 H), 7.72–7.70 (m, 1 H), 7.14 (dd, J = 4.0, 4.8 Hz, 1 H),
3.87 (s, 2 H), 2.82 (d, 4.8 Hz, 3 H). 13C{1H} NMR (100 MHz,
CDCl3)  188.2, 165.9, 143.2, 135.4, 133.8, 128.4, 45.8, 26.2.
TLC Rf = 0.3 (EtOAc/Hexane = 4/1.5); HRMS (ESI) m/z: [M
+ Na]+ Calcd for C8H9NO2SNa 206.0252; Found 206.0248.
9
REFERENCES
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1. (a) Lin, G. Q.; You; Q. D. and Cheng, J. F. Chiral Drugs: Chemistry
and Biological Action. John Wiley & Sons, 2011; (b) Zuo, W. W.;
Morris, R. H. Synthesis and use of an asymmetric transfer
hydrogenation catalyst based on iron(II) for the synthesis of
enantioenriched alcohols and amines. Nat. Protoc. 2015, 10, 241-257
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(S)-3-Hydroxy-N-methyl-3-(thiophen-2-yl)propan-amide
(4k’):45 The product 4k’ was obtained as crystalline white solid
1
with 45% yield (33 mg, 0.18 mmol). H NMR (400 MHz,
CD3OD) : 7.29 (dd, J = 4.8, 1.2 Hz, 1 H), 6.97 (dt, J = 3.2, 1.2
Hz, 1 H), 6.93 (dd, J = 4.8, 3.6 Hz, 1 H), 5.33 – 5.29 (m, 1 H),
2.71 – 2.58 (m, 5 H). 13C{1H} NMR (100 MHz, CD3OD) :
173.5, 149.3, 127.5, 125.4, 124.5, 67.9, 46.8, 26.3. TLC Rf =
0.25 (EtOAc/Hexane = 4/1.5); [α]2D520.2 (1.3, CHCl3) for 90%
ee; HRMS (ESI) m/z: [M + Na]+ Calcd for C8H11NO2SNa:
208.0408; Found 208.0407; HPLC analysis: tR 17.3 major (S-
isomer), 22.3 minor (R-isomer) (Chiralpak AS-H,
hexanes/iPrOH, 85/15, 1.0 mL/min, λ = 254 nm), ee 90% for
(S)-isomer.
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Procedure for 2 mmol Scale preparation of (S)-N-Benzyl-3-
(4-chlorophenyl)-3-hydroxypropanamide (4d):
In an oven dried 50 mL Schlenk tube, 3d (0.575.4 g, 2 mmol)
was taken along with 1b catalyst (109.3 mg, 0.2 mmol) under
argon atmosphere. Dry THF (16 mL) was injected into the
Schlenk tube via syringe. After stirring the reaction mixture for
15 minutes at ambient temperature, the schlenk tube was put
into the cooling bath. The reducing agent (870μL, 6 mmol)
diluted by dry THF (4mL) was added to the reaction mixture
via flame dried syringe slowly over 1 h. After the reaction was
over (checked by TLC), distilled water (5mL) was injected into
the Schlenk tube via syringe to quench the reducing agent. The
reaction mixture was stirred for 30 min under room temperature
followed by extraction with ethyl acetate (20mL  3). Collected
organic solvent was dried with MgSO4 and concentrated under
reduced pressure. The residue was purified by flash column
chromatography (Hexanes/EA = 2:1) to afford the product 4d
as white solid (472 mg, 88% yield, 98% ee).
ASSOCIATED CONTENT
Supporting Information
NMR spectra, HPLC Chromatographs, crystal structure
preparation, and Crystal data for compound 4k’ (PDF).
AUTHOR INFORMATION
Corresponding Author

E–mail: ctchen@mx.nthu.edu.tw
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The Journal of Organic Chemistry
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