Chiral primary amino amide alcohol organocatalyst for the asymmetric Michael addition of 4-hydroxycoumarin with α,β-unsaturated ketones

Article abstract of DOI:10.3987/COM-14-S(K)83

Chiral primary amino amide organocatalysts were designed and synthesized as new organocatalysts for the enantioselective Michael addition of 4-hydroxycoumarin with α,β-unsaturated ketones to produce chiral warfarin (up to 56% ee with up to 92% yield).

Full text of DOI:10.3987/COM-14-S(K)83

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HETEROCYCLES, Vol. 90, No. 2, 2015
HETEROCYCLES, Vol. 90, No. 2, 2015, pp. 1124 - 1134. © 2015 The Japan Institute of Heterocyclic Chemistry
Received, 10th July, 2014, Accepted, 28th August, 2014, Published online, 11th September, 2014
DOI: 10.3987/COM-14-S(K)83
CHIRAL PRIMARY AMINO AMIDE ALCOHOL ORGANOCATALYST
FOR
THE
ASYMMETRIC
MICHAEL
ADDITION
OF
4-HYDROXYCOUMARIN WITH !,"-UNSATURATED KETONES
Jun Kumagai,a Yoshihito Kohari,a Chigusa Seki,a Koji Uwai,a Yuko
Okuyama,b Eunsang Kwon,c and Hiroto Nakano*a
a
Division of Sustainable and Environmental Engineering, Graduate School of
Engineering, Muroran Institute of Technology, 27-1 Mizumoto, Muroran
050-8585, Japan, E-mail: catanaka@mmm.muroran-it.ac.jp
b
Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai
981-8558, Japan, E-mail: yoku@tohoku-pharm.ac.jp
c
Research and Analytical Center for Giant Molecules, Graduate School of
Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578,
Japan, E-mail: ekwon@m.tohoku.ac.jp
Abstract – Chiral primary amino amide organocatalysts were designed and
synthesized as new organocatalysts for the enantioselective Michael addition of
4-hydroxycoumarin with !,"-unsaturated ketones to produce chiral warfarin (up
to 56% ee with up to 92% yield).
INTRODUCTION
Asymmetric organocatalysis has emerged as an important and rapidly growing area of synthetic organic
chemistry, and excellent covalent and non-covalent organocatalysts have been developed for use in a
wide range of reactions.1 The asymmetric Michael addition is one of the most important and efficient
* Dedicated to Prof. Dr. Isao Kuwajima on the occasion of his 77th birthday

HETEROCYCLES, Vol. 90, No. 2, 2015
1125
methods for C–C bond formation in organic synthesis,2 and the reaction of 4-hydroxycoumarin 1 with an
!,"-unsaturated ketone, benzylideneacetone 2, using an organocatalyst is a straightforward method to
access chiral warfarin 3 which is an effective and relatively safe agent for preventing thrombosis and
embolism.3 Although several efficient organocatalyst4 for this reaction have been developed by several
groups in recent years, it is difficult to obtain chiral warfarins with satisfactory high enantioselectivity.
Therefore, it is still desirable and challenging to develop an effective catalytic system for this conversion.
Chiral amine-based molecules, especially primary amine organocatalysts shows efficient asymmetric
catalytic activity in this procedure. We designed a series of chiral primary amino amide alcohols 7a-n
with one covalent site and two non-covalent sites in the molecule as an organocatalyst (Scheme 2). The
reaction using these designed amino amide alcohol catalyst might proceed through the transition state X
which is figured in Scheme 2. Since 4-hydroxycoumarins are fixed by the hydrogen bonding interactions
with both the hydroxy group and the amide group on the imine intermediate, theꢀcoumarins might attack
the less sterically crowded face of olefin part on the imine intermediate rather than the sterically crowded
face that is masked by the combination of the bulky diphenyl group and the two substituents (R1 and R2)
at the ! and " positions on the imine intermediate.
We describe herein the catalytic ability of the newly designed primary amino amide alcohol
organocatalyst for the asymmetric Michael addition of 4-hydroxycoumarins with !,"-unsaturated ketones
affording chiral warfarins.
R1
H2N
O
R2
hydrogen bonding
Ph
Ph
N
H
Ph
O
R
O
steric
influence
O
N
Ph
OH
"
H
covalent site
R2
O
non-covalent
hydrogen bonding
site
O
H
H
!
R1
N
amino amide alcohol
organocatalyst 7
R
imine intermediate
R"
Transition State X
Scheme 2. Concept of catalyst design
RESULTS AND DISCUSSION
Catalysts 7a-o bearing two substituents, aliphatic and/or aromatic group, at the ! and " positions in the
molecule were easily prepared by the condensation of N-Cbz-amino acids 4 with the corresponding amino
alcohols 5a or amino silyl ether 5b in the presence of stoichiometric amounts of HOBt and EDC followed
by the debenzyloxycarbonylation of the N-Cbz amino amide alcohols 6a-o using H2 and Pd-C (5%) at up
to 98% yields, respectively (Scheme 3). We first examined the Michael addition of common

1126
HETEROCYCLES, Vol. 90, No. 2, 2015
7a : R1 = Ph, R2 = Ph,
7b : R1 = Ph, R2 = i-Pr,
7c
R3 = H,
R3 = H,
R1
HN
O
68%
90%
87%
R2
R1
HN
O
HOBt
EDC
R2
H2N
Ph
Ph
Ph
Ph
+
: R1 = Ph, R2 = Me, R3 = H,
N
H
OR3
CH2Cl2
0 oC to rt
20 h
OH
: R1 = Bn, R2 = Ph, R3 = H,
72%
83%
76%
7d
7e
OR3
Cbz
Cbz
5a: R3=H
5b: R3=TMS
: R1 = Bn, R2 = i-Pr, R3 = H,
7f : R1 = Bn, R2 = Me,
R3 = H,
R3 = H,
6a-m, o
4
7g : R1 = t-Bu, R2 = Ph,
92%
67%
91%
75%
98%
50%
85%
R1
O
: R1 = t-Bu, R2 = i-Pr, R3 = H,
: R1 = t-Bu, R2 = Me, R3 = H,
R2
7h
7i
H2
5% Pd-C
!
Ph
7j : R1 = i-Bu, R2 = Ph,
R3 = H,
"
H2N
N
H
Ph
MeOH
50 oC
24 h
: R1 = i-Bu, R2 = i-Pr, R3 = H,
: R1 = i-Bu, R2 = i-Bu, R3 = H,
OR3
7k
R2
R2
7l
7m
7a-m,o:
7n:
1
2
R3 = H,
: R = i-Bu, R = Me,
7n : R1 = i-Bu, R2 = i-Bu, R3 = H,
54%
28%
: R1 = i-Bu, R2 = i-Bu,
3
7o
R = TMS,
Scheme 3. Preparations of amino amide alcohol organocatalysts
4-hydroxycoumarin 1 with benzylideneacetone 2 using the obtained amino amide alcohols 7a-n as
organocatalysts (Table 1). The reaction of 1 (1 equiv) with 2 (1.2 equiv) was carried out at room
temperature in THF (8 equiv) in the presence of 20 mol% of catalysts 7a-n and 20 mol% of additives to
afford the chiral warfarin 3, respectively (entries 1-14). As a result of these reactions, all catalysts showed
a catalytic activity and afforded warfarin 3 in moderate to fairly good chemical yields (56-91%, entries
1-14). However, satisfactory enantioselectivity was not observed under these reaction conditions. The
best enantioselectivity was 43 % ee with 85% yield in the case of using the catalyst 7l which was bearing
two iso-butyl moieties at ! and " positions on the molecule (entry 12). The use of stereoisomer 7n (!:
[S], ": [R]) of catalyst 7l (!: [S], ": [S]) caused a drop in the enantioselectivity (31% ee, entry 14),
although the highest chemical yield (91%) was observed. The same reaction using amino amide silyl
ether catalyst 7o in which the hydroxyl group was protected by a trimethylsilyloxy (TMS) group brought
about a great decrease in the chemical yield and enantioselectivity (65%, 15% ee, entry 15) in comparison
with those of the corresponding amino amide alcohol catalyst 7l with free hydroxy group (86%, 43% ee,
entry 15). This difference may be due to the loss of the ability for hydrogen bonding to
4-hydroxycoumarin 1 or the steric influence of the bulkier trimethylsilyloxy group on the molecule,
although the reasons are not clear. To further improve the enantioselectivity, the reactions using 7l were
examined at lower temperatures of both 0 °C and -30 °C (entries 17 and 18). However, satisfactorily
results were not observed under each temperatures for enantioselectivity and chemical yield. Next, to
optimize the reaction conditions using the best catalyst 7l, we examined the effect of reducing the molar
ratio of 7l. However, the decrease of catalytic loading of 7l to 10 mol% resulted in a substantial decrease
in the chemical yield (46%) with a slight decrease in enantioselectivity (33% ee, entry 16). Furthermore,
the effects of additives such as CF3CO2H, CCl3CO2H, and hexafluoroisopropyl alcohol (HFIP) in this
reaction were investigated, respectively (entries 19-21). An additive has generally used for the

HETEROCYCLES, Vol. 90, No. 2, 2015
1127
improvement of the chemical yield and enantioselectivity in the Michael reaction for warfarin.4b,c,f,g,i,j,m
Unfortunately, these additives did not work more effectively than MeCO2H and the chemical yields were
significantly decreased under these reaction conditions. We examined the reactions of 1 (1 equiv) with 2
(1.2 equiv) carried out at room temperature in THF (8 equiv) in the presence of 20 mol% of catalyst 7l
without any additive (entries 22-24). An increase in enantioselectivity was observed with good chemical
yield (53%, 50% ee, entry 22). Furthermore, extending the reaction time from 24 to 72 h led to a great
increase in the chemical yield (86%) with 52% ee (entry 26). After 7l was identified as effective
Table 1. The effect of the catalyst in the Michael addition
OH
O
OH
O
O
catalyst
7a-o
+
O
O
O
1
2
[R]-3
catalyst
(mol%)
ee
temp
(°C)
time
(h)
yield
(%)a
additive
solvent
(%)b
entry
rt
//
7a (20)
1
2
3
4
5
6
7
8
MeCO2H
24
//
67
77
73
74
76
75
67
56
84
67
85
86
78
91
65
46
32
15
24
22
35
53
65
86
92
64
51
75
49
51
73
43
19
24
42
17
24
13
17
10
41
42
43
26
31
-15
33
41
40
32
30
20
50
51
52
37
25
22
29
34
27
27
THF
//
7b ( //
7c ( //
7d ( //
7e ( //
7f ( //
7g ( //
7h ( //
7i ( //
7j ( //
7k ( //
7l ( //
7m( //
7n ( //
7o ( //
)
)
)
)
)
)
)
)
)
)
)
)
)
)
//
//
//
//
//
//
//
//
//
//
//
//
//
//
//
//
//
//
//
//
//
//
//
//
//
//
9
//
//
//
//
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
38
29
30
31
//
//
//
//
//
//
//
//
//
//
//
//
//
//
//
//
//
//
//
//
//
//
//
//
7l (10)
7l (20)
//
//
//
0
-30
rt
//
//
//
//
7l ( //
7l ( //
7l ( //
7l ( //
7l ( //
7l ( //
7l ( //
7l ( //
7l ( //
7l ( //
7l ( //
7l ( //
7l ( //
7l ( //
)
)
)
)
)
)
)
)
)
)
)
)
)
)
//
//
//
CF3CO2H
CCl3CO2H
HFIPc
//
//
//
//
//
//
//
//
-
-
-
-
-
-
-
-
-
-
//
//
//
48
72
//
//
//
//
//
Et2O
CH2Cl2
MeCN
benzene
toluene
EtOH
2-PrOH
//
//
//
//
//
//
//
//
//
//
//
//
a Isolated yield. b The ee was determined by chiral HPLC using a Daicel AD-H column
( n-hexane : 2-propanol = 80 : 20 ). c Hexafluoroisopropyl alcohol.

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HETEROCYCLES, Vol. 90, No. 2, 2015
organocatalyst, we also examined solvent effects on this reaction. Commonly used both aprotic (Et2O,
CH2Cl2, MeCN, benzene, toluene) and protic (EtOH, 2-PrOH) solvents were screened, respectively
(entries 25-31). Only Et2O afforded a fairly good chemical yield (92%, entry 25), but other solvents gave
chiral warfarin 3 in moderate to good yields (49-75%, entries 26-31). Unfortunately, no improvements in
enantioselectivity were obtained when other catalysts 7a-k, m-o were used.
Under the optimized reaction conditions, a wide range of the Michael additions with 4-hydroxy-
coumarins 1, 8a-d5 and !,"-unsaturated ketones 2, 9a-h6 were investigated and the results are shown in
Table 2. In all the Michael additions, catalyst 7l was performed to afford the corresponding chiral
warfarins (up to 87%, up to 56% ee, entries 1-12). In particular, the reaction of 1 with bulkier aromatic
2-naphthylated !,"-unsaturated ketone 9g afforded the corresponding chiral warfarin 10g in moderate
enantioselectivity and good chemical yield (56%, 56% ee, entry 7).
Based on the observed enantiopurity (52% ee, entry 24, Table 1) of chiral warfarin 3 that was obtained
from the reaction of 1 with 2, a model of the enantioselective reaction under the condition without
additives was proposed as follows (Scheme 4). The reaction might be go through the transition state A
which is fixed by the two hydrogen bonding interactions of the hydroxy group on the imine intermediate
and the carbonyl group on the 4-hydroxycoumarin 1 and of the carbonyl group on the imine intermediate
and the hydroxy group on 1. Then 4-hydroxycoumarin might attack the si-face of the olefin part on the

HETEROCYCLES, Vol. 90, No. 2, 2015
1129
imine intermediate rather than the sterically crowded re-face that was masked by the combination of the
bulky diphenyl group and the two iso-butyl groups on the imine intermediate in the transition state A.
In conclusion, new chiral amino amide alcohol organocatalysts 7a-o were explored. The catalysts were
easily prepared from the condensation of cheaply and commercially available chiral amino acids with
amino alcohols in two steps. The Michael addition of 4-hydroxycoumarins with !,"-unsaturated ketones
using the explored catalyst 7l provided the corresponding Michael adduct 3 in moderate enantioselectivity
(up to 56% ee) and fairly good chemical yield (up to 92%). Further optimizations of the structure of the
catalyst 7 to increase enantioselectivity in this reaction are now in progress.
EXPERIMENTAL
1
IR spectra were measured with a JASCO FT/IR-400 spectrophotometer. H-NMR spectra were recorded
on a JEOL JNM-ECA 500 spectrometer with TMS as an internal standard. MS were taken on Hitachi
RMG-6MG and JEOL-JNM-DX 303 spectrometers. Optical rotations were measured with JASCO
DIP-360 digital polarimeter.
General procedure for the preparations of amino amide alcohol organocatalysts 7a-n
A solution of N-Cbz amino acid 4 (1 mmol) and amino alcohol 5a (1 mmol) were dissolved in CH2Cl2
(10 mL). To the solution, EDC (1.4 mmol) and HOBT (1 mmol) was added and the solution was stirred at
o
0 C for 1 h and room temperature for another 20 h. The reaction mixture was quenched with aqueous
HCl (0.1 N) and extracted with AcOEt. The combined organic layer was washed with a saturated aqueous
NaHCO3, brine, dried over anhydrous Na2SO4, and filterated. The filtrate was concentrated under reduced
pressure to give the crude product which was used for the next step without further purification. To a
solution of crude N-Cbz amino amide alcohols 6a-n in MeOH (10 mL) was added 5 % Pd/C (10 wt%)
o
under hydrogen atmosphere and the mixture stirred at 50 C for 24 h. The reaction mixture was filtered

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HETEROCYCLES, Vol. 90, No. 2, 2015
and the solvent was evaporated under reduced pressure to give the residue. The residue was purified by
column chromatography on silica gel (AcOEt : hexane = 1 : 2) to afford the amino amide alcohol 7a-n.
Compounds 7j-l7 were known compounds and were identified by spectral data which were in good
agreement with those reported.
(S)-2-Amino-N-((S)-2-hydroxy-1,2,2-triphenylethyl)-2-phenylacetamide (7a)
o
23
White crystal (AcOEt), mp 188-189 C, [!]D -27.3 (c 0.21, CHCl3). IR (neat) cm-1: 3304, 3058, 3029,
1
13
1636. H-NMR (CDCl3) ": 7.55-6.93 (m, 20H), 6.01-5.98 (m, 1H), 4.37-4.36 (d, 1H, J = 6.6). C-NMR
(CDCl3) ": 172.2, 144.2, 137.4, 128.8, 128.6, 128.5, 128.4, 128.1, 127.9, 127.8, 127.5, 127.2, 127.0,
126.9, 126.0, 125.6, 80.9, 77.3, 77.1, 76.8, 59.9, 21.1, 14.2. Ms m/z: 422. HRMS (EI) calcd for
(C28H26N2O2): 422.1994, Found: 422.1994. Anal. Calcd for (C28H26N2O2): C 79.59, H 6.20, N 6.63, O
7.57, Found: C 79.48, H 6.33, N 6.60, O 7.46.
(S)-2-Amino-N-((S)-1-hydroxy-3-methyl-1,1-diphenylbutan-2-yl)-2-phenylacetamide (7b)
o
23
White crystal (AcOEt), mp 153-154 C, [!]D -24.5 (c 1.02, CHCl3). IR (neat) cm-1: 3309, 2960, 1644.
13
1H-NMR (CDCl3) ": 7.48-7.15 (m, 15H), 4.82-4.80 (m, 1H), 4.35 (s, 1H), 0.87-0.58 (m, 6H). C-NMR
(CDCl3) ": 129.1, 128.9, 128.6, 128.5, 128.4, 128.2, 128.1, 127.0, 125.3, 125.2, 125.0, 81.9, 77.3, 77.1,
76.8, 67.0, 58.2, 28.8, 22.8, 17.5. Ms m/z: 388. HRMS (EI) calcd for (C25H28N2O2): 388.2151, Found:
388.2161.
(S)-2-Amino-N-((S)-1-hydroxy-1,1-diphenylpropane-2-yl)-2-phenylacetamide (7c)
o
23
White crystal (AcOEt), mp 150-151 C, [!]D -15.0 (c 1.00, CHCl3). IR (neat) cm-1: 3297, 2942, 1652.
1H-NMR (CDCl3) ": 7.48-7.02 (m, 15H), 4.99-4.93 (m, 1H), 4.31 (s, 1H), 1.16-1.15 (d, 3H, J = 6.6 Hz).
13C-NMR (CDCl3) ": 144.4, 136.2, 128.9, 128.5, 128.3, 128.1, 127.2, 127.0, 125.5, 125.3, 80.3, 77.3,
77.1, 76.8, 67.0, 51.1, 16.1. Ms m/z: 360. HRMS (EI) calcd for (C23H24N2O2): 360.1838, Found:
360.1837.
(S)-2-Amino-N-((S)-2-hydroxy-1,2,2-triphenylethane)-3-phenylpropanamide (7d)
White crystal (AcOEt), mp 194-195 oC, [!]D22 -201.2 (c 0.83, CHCl3). IR (neat) cm-1: 3311, 2956, 1644.
1H-NMR (CDCl3) ": 8.29-8.27 (d, 1H, J = 8.4 Hz), 7.71-6.01 (m, 20H), 6.03-6.01 (d, 1H, J = 9.2 Hz),
13
3.47-3.41 (m, 1H), 3.04-3.00 (m, 1H), 2.54-2.50 (m, 1H), 1.09 (brs, 2H). C-NMR (CDCl3) ": 173.6,
144.5, 144.4, 137.8, 137.7, 129.3, 128.7, 128.3, 128.1, 127.9, 127.5, 127.2, 127.0, 126.7, 126.1, 125.7,
81.0, 77.3, 77.1, 76.8, 59.1, 56.3, 40.5. Ms m/z: 437 [M+H]+. HRMS (EI) calcd for (C29H28N2O2+H)+:
437.2229, Found: 437.2216. Anal. Calcd for (C29H28N2O2): C 79.79, H 6.46, N 6.42, O 7.33, Found: C
79.56, H 6.41, N 6.50, O 7.39.

HETEROCYCLES, Vol. 90, No. 2, 2015
1131
(S)-2-Amino-N-((S)-1-hydroxy-3-methyl-1,1-diphenylbutan-2-yl)-3-phenylpropanamide (7e)
o
21
White crystal (AcOEt), mp 165-166 C, [!]D -95.6 (c 0.93, CHCl3). IR (neat) cm-1: 3313, 2953, 1637.
1H-NMR (CDCl3) ": 7.71-7.69 (d, 1H, J = 9.7 Hz), 7.69-7.04 (m, 5H), 4.82-4.80 (m, 1H), 3.43-3.41 (m,
1H), 3.07-3.04 (m, 1H), 2.48-2.39 (m, 1H), 0.89-0.85 (m, 6H). 13C-NMR (CDCl3) ": 146.6, 145.6, 129.3,
128.8, 128.4, 128.2, 128.0, 126.9, 126.8, 125.6, 125.4, 81.9, 77.3, 77.1, 76.8, 56.6, 40.8, 28.8, 23.0, 18.2.
Ms m/z: 403 [M+H]+. HRMS (EI) calcd for (C26H30N2O2+H)+: 403.2386, Found: 403.2397.
(S)-2-Amino-N-((S)-1-hydroxy-1,1-diphenylpropane-2-yl)-3-phenylpropanamide (7f)
o
20
White crystal (AcOEt), mp 167-168 C; [!]D -85.8 (c 0.99, CHCl3). IR (neat) cm-1: 3325, 2970, 1644.
1H-NMR (CDCl3) ": 7.60-7.59 (d, 1H, J = 8.9 Hz), 7.51-7.09 (m, 15H), 4.99-4.93 (m 1H), 3.38-3.36 (m,
13
1H), 3.04-3.00 (m, 1H), 2.38-2.32 (m, 1H), 1.15-1.13 (d, 3H, J =6.6 Hz). C-NMR (CDCl3) ": 174.2,
145.5, 144.9, 137.9, 129.3, 128.7, 128.4, 128.2, 127.0, 126.9, 126.8, 125.8, 125.7, 80.6, 77.3, 77.1, 76.8,
56.3, 51.7, 40.7, 15.8. Ms m/z: 375 [M+H]+. HRMS (EI) calcd for (C24H26N2O2+H)+: 375.2073, Found:
375.2072.
(S)-2-Amino-N-((S)-1-hydroxy-1,1,2-triphenylethane)-3,3-dimethylbutanamide (7g)
White crystal (AcOEt), mp 210-211 oC, [!]D21 -215.5 (c 0.90, CHCl3). IR (neat) cm-1: 3325, 2969, 1645.
1H-NMR (CDCl3) ": 7.75-7.73 (m, 1H), 7.62-6.61 (m, 2H), 7.37-7.06 (m, 13H), 6.09-6.04 (m, 1H),
13
2.96-2.95 (m, 1H), 0.99 (brs, 2H), 0.81 (s, 9H). C-NMR (CDCl3) ": 172.9, 144.3, 128.8, 128.4, 128.1,
127.9, 127.5, 127.2, 127.1, 125.9, 125.5, 81.0, 77.3, 77.1, 76.8, 64.5, 59.1, 34.1, 26.6. Ms m/z: 402.
HRMS (EI) calcd for (C26H30N2O2): 402.2307, Found: 402.2301.
(S)-2-Amino-N-((S)-1-hydroxy-3-methyl-1,1-diphenylbutan-2-yl)-3,3-dimethylbutanamide (7h)
o
21
White crystal (AcOEt), mp 240-241 C, [!]D -70.7 (c 0.41, CHCl3). IR (neat) cm-1: 3422, 2969, 1647.
1H-NMR (CDCl3) ": 7.55-7.04 (m, 10H), 5.08-5.00 (m, 1H), 2.80 (s, 1H), 0.87 (s, 9H), 0.83 (s, 6H).
13C-NMR (CDCl3) ": 129.0, 128.2, 128.1, 126.7, 126.4, 126.1, 125.1, 124.7, 77.3, 77.1, 76.8, 65.0, 33.7,
29.9, 26.8. Ms m/z: 368. HRMS (EI) calcd for (C23H32N2O2): 368.2464, Found: 368.2448.
(S)-2-Amino-N-((S)-1-hydroxy-1,1-diphenylpropane-2-yl) -3,3-dimethylbutanamide (7i)
o
22
White crystal (AcOEt), mp 111-112 C, [!]D -39.0 (c 0.87, CHCl3). IR (neat) cm-1: 3253, 2969, 1652.
1H-NMR (CDCl3) ": 7.52-7.04(m, 10H), 5.06-5.00 (m, 1H), 2.92 (s, 1H), 1.52 (brs, 2H), 1.15-1.14 (d, 3H,
13
J = 6.6 Hz), 0.78 (s, 9H). C-NMR (CDCl3) ": 173.2, 153.3, 145.5, 145.0, 128.5, 128.3, 127.0, 126.9,
125.6, 125.5, 80.5, 77.3, 77.1, 76.8, 64.5, 51.6, 33.8, 26.5, 15.8. Ms m/z: 340. HRMS (EI) calcd for
(C21H28N2O2): 340.2151, Found: 340.2162.

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HETEROCYCLES, Vol. 90, No. 2, 2015
(S)-2-Amino-N-((S)-1-hydroxy-1,1-diphenylpropane-2-yl)-4-methylpentanamide (7m)
22
White crystal (AcOEt), mp 101-102oC, [!]D -34.6 (c 0.52, CHCl3). IR (neat) cm-1: 3308, 2969, 1644.
1H-NMR (CDCl3) ": 7.51-7.13 (m, 10H), 4.99-4.92 (m, 1H), 3.16-3.14 (m, 1H), 1.16-1.15 (d, 3H, J = 6.6),
13
0.83-0.79 (m, 6H). C-NMR (CDCl3) ": 175.6, 145.6, 145.0, 128.4, 128.2, 127.0, 126.8, 125.7, 125.6,
80.6, 77.3, 77.1, 76.8, 53.5, 51.8, 43.8, 24.7, 23.3, 21.4, 15.7. Ms m/z: 340. HRMS (EI) calcd for
(C21H28N2O2): 340.2151, Found: 340.2136. Anal. Calcd for (C21H28N2O2): C 74.08, H 8.29, N 8.23, O
9.40, Found: C 74.01, H 8.34, N 8.17, O 9.31.
(S)-2-Amino-N-((R)-1-hydroxy-4-methyl-1,1-diphenylpentan-2-yl)-4-methylpentanamide (7n)
o
23
White crystal (AcOEt), mp 162-163 C, [!]D -4.5 (c 0.22, CHCl3). IR (neat) cm-1: 3290, 2969, 1645.
1H-NMR (CDCl3) ": 7.54-7.50 (m, 4H), 7.44-7.7.29 (m, 3H), 7.24-7.11 (m, 3H), 4.94-4.90 (m, 1H),
13
3.20-3.18 (m, 1H), 0.99-0.79 (m, 12H). C-NMR (CDCl3) ": 175.9, 145.7, 145.1, 128.4, 128.1, 127.0,
126.6, 125.6, 81.3, 77.3, 77.1, 76.8, 54.3, 53.4, 43.6, 38.8, 25.2, 24.7, 24.0, 23.3, 21.6, 21.4. Ms m/z: 382.
HRMS (EI) calcd for (C24H34N2O2): 382.2620, Found: 382.2630.
General procedure for the preparation of amino amide alcohol catalyst 7o
A solution of amino alcohol 5a (1 mmol) in CH2Cl2 (15 mL) was cooled down to -30 oC. To the solution,
Et3N (1.2 mmol) and hexamethyldisilazane (1.2 mmol) were added and the reaction mixture was stirred at
room temperature for 16 h. The solution was quenched with water and extracted with CHCl3. The
combined organic layer was washed with a brine, dried over anhydrous Na2SO4, and filtrated. The filtrate
was concentrated under reduced pressure to give the residue. The residue was purified by column
chromatography on silica gel (AcOEt : hexane = 1 : 4) to afford (S)-4-methyl-1,1-diphenyl-1-
trimethylsilyloxypentan-2-amine 5b. N-Cbz amino acid 4 (1 mmol) and (S)-4-methyl-1,1-diphenyl-1-
trimethylsilyloxypentan-2-amine 5b (1 mmol) were dissolved in CH2Cl2 (10 mL) and the solution was
o
cooled down to 0 C. EDC (1.4 mmol) and HOBT (1 mmol) was added to the solution and the solution
o
was stirred at 0 C for 1 h and room temperature for another 20 h. The solution was quenched with
aqueous HCl (0.1 N) and extracted with AcOEt. The combined organic layer was washed with a saturated
aqueous NaHCO3, brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give
the crude product 6o which was used for the next step without further purification. The solution of 6o in
MeOH (10 mL) was added 5 % Pd/C (10 wt%) under hydrogen atmosphere and the mixture stirred at 50
oC for 24 h. The reaction mixture was filtered and the solvents were evaporated under reduced pressure to
give the residue. The crude residue was purified by column chromatography on silica gel (AcOEt :
hexane = 1 : 2) to afford the amino amide silyl ether 7o.

HETEROCYCLES, Vol. 90, No. 2, 2015
1133
(S)-4-Methyl-1,1-diphenyl-1- trimethylsilyloxypentan-2-amine (5b)
Colorless oil, [!]D21 -63.5 (c 0.21, CHCl3). IR (neat) cm-1: 1249, 2953. 1H-NMR (CDCl3) ": 7.39-7.23 (m,
10H), 3.76-3.73 (m, 1H), 1.88-1.78 (m, 1H), 1.44-1.38 (m, 1H), 1.01-1.00 (d, 3H, J = 6.6 Hz), 0.84-0.82
13
(d, 3H, J = 6.6 Hz), -0.17 (s, 9H). C-NMR (CDCl3) ": 128.7, 128.2, 127.6, 127.5, 127.4, 127.2, 83.5,
50.7, 40.8, 24.5, 24.1, 22.8, 22.1, 21.4, 1.8. Ms m/z: 341. HRMS (EI) calcd for (C24H34N2O2): 341.2175,
Found: 341.2173.
(S)-2-Amino-N-((S)-4-methyl-1,1-dipheny-1-trimethylsilyloxypentan-2-yl)-4-methylpentanamide
(7o)
o
22
1
White crystal (AcOEt), mp 75-76 C; [!]D -83.3 (c 0.24, CHCl3). IR (neat) cm-1: 2969, 1669. H-NMR
(CDCl3) ": 7.41-7.20 (m, 10H), 5.09-5.00 (m, 1H), 3.24-3.19 (m, 1H), 1.03-0.72 (m, 12H), -0.12 (s, 9H).
13C-NMR (CDCl3) ": 174.7, 144.5, 128.8, 128.2, 127.8, 127.5, 127.4, 127.1, 83.8, 77.3, 77.1, 76.8, 53.7,
51.7, 44.3, 41.0, 24.7, 24.3, 23.5, 22.0, 21.4, 1.9, 0.9. Ms m/z: 455 [M+H]+. HRMS (EI) calcd for
(C24H34N2O2+H)+: 455.3094, Found: 455.3099.
General procedure for the asymmetric Michael reaction of 4-hydroxycoumarines 1, 8a-d to
!,"-unsaturated ketones 2, 9a-h
4-Hydroxycoumarines 1, 8a-d (0.1 mmol), !,#-unsaturated ketones 2, 9a-h (0.12 mmol), amino amide
alcohol catalysts 7a-o (0.02 mmol) with/without additives (0.02 mmol) were stirred in THF (0.8 mL) at
room temperature for the times shown in the Table 1. The reaction mixture was directly purified by
preparative TLC on silica gel (hexane : AcOEt = 3 : 1) to afford warfarin 3 and its analogs 10a-l. All
13
adducts were known compounds and were identified by spectral data (1H and C-NMR) which were in
good agreement with those reported.4 The enantiomeric excess (ee) were determined by HPLC (DAICEL
CHIRALPAK AD-H, 1.0 mL/min, n-hexane : 2-propanol = 80 : 20).4
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