Novel and practical asymmetric synthesis of β2,3-amino esters using asymmetric Michael addition of chiral amine

Article abstract of DOI:10.1016/j.tet.2017.02.037

A practical method for the synthesis of chiral β^2,3-amino esters having various substituents was developed, which is characterized by an asymmetric Michael addition reaction of a chiral lithium amide with trisubstituted (E)-α,β-unsaturated esters. We found that a highly face-selective protonation occurred by the quick addition of water to the enolate intermediate derived from the Michael addition reaction to afford N-protected β^2,3-amino esters in moderate to excellent yields. This finding was made possible by the facile preparation of geometrically pure trisubstituted (E)-α,β-unsaturated esters, which was established recently by our group. The subsequent deprotection of the amino group in the Michael adduct by using N-iodosuccinimide (NIS) efficiently provided β^2,3-amino esters having various substituents.

Full text of DOI:10.1016/j.tet.2017.02.037

Tetrahedron xxx (2017) 1e8
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel and practical asymmetric synthesis of
asymmetric Michael addition of chiral amine
b
2,3-amino esters using
,
Minoru Ozeki a *, Honoka Egawa a, Toshiki Takano a, Hideki Mizutani a, Narumi Yasuda a,
,
Kenji Arimitsu a, Tetsuya Kajimoto a b, Shinzo Hosoi a, Hiroki Iwasaki a, Naoto Kojima a,
,
**
Manabu Node a, Masayuki Yamashita a
a Department of Pharmaceutical Manufacturing Chemistry, Kyoto Pharmaceutical University, 1 Shichono-cho, Misasagi, Yamashina-ku, Kyoto 607-8412,
Japan
b Medicinal Organic Chemistry Laboratory, College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-higashi, Kusatsu, Shiga 525-8577, Japan
a r t i c l e i n f o
a b s t r a c t
A practical method for the synthesis of chiral b
2,3-amino esters having various substituents was devel-
Article history:
Received 26 December 2016
Received in revised form
14 February 2017
Accepted 17 February 2017
Available online xxx
oped, which is characterized by an asymmetric Michael addition reaction of a chiral lithium amide with
trisubstituted (E)- -unsaturated esters. We found that a highly face-selective protonation occurred by
the quick addition of water to the enolate intermediate derived from the Michael addition reaction to
afford N-protected
2,3-amino esters in moderate to excellent yields. This finding was made possible by
the facile preparation of geometrically pure trisubstituted (E)- -unsaturated esters, which was estab-
a,b
b
a,b
lished recently by our group. The subsequent deprotection of the amino group in the Michael adduct by
Keywords:
b
Asymmetric Michael addition
Face-selective protonation
Chiral amine
using N-iodosuccinimide (NIS) efficiently provided
b
2,3-amino esters having various substituents.
2,3-Amino acid
© 2017 Elsevier Ltd. All rights reserved.
Trisubstituted (E)-a,b-unsaturated ester
1. Introduction
amine in their asymmetric syntheses.3,5 Moreover, Hawkings et al.
reported an asymmetric Michael addition reaction that used chiral
lithium amide having a binaphthyl skeleton as the chiral reagent.6
b
-Amino acid is one of the most important structural units in
organic chemistry because it appears in a number of biologically
active natural products and pharmaceutical compounds.1 b2,3
Amino acids bearing substituents at both and positions are
constituents of biologically active natural products and -peptide
foldamers of protein mimetics.2,3 A large number of methods for
the asymmetric synthesis of
2,3-amino acid derivatives have been
reported to date.2 The asymmetric Michael addition of an amine
derivative to trisubstituted -unsaturated esters is one of the
most straightforward and powerful methods to obtain optically
pure
2,3-amino acid derivatives. As a pioneering work, Davies et al.
reported the synthesis of
2,3-amino acid derivatives by the
asymmetric Michael addition of N-benzyl-N- -methylbenzyl-
-unsatu-
€
Fülop et al. reported a diastereoselective Michael addition reaction
-
of an achiral lithium amide with a chiral terpene derivative as the
a
b
Michael acceptor.7 Concerning catalytic asymmetric aza-Michael
b
additions using trisubstituted
strates, few were reported to date except for the reactions with low
enatioselctivities.8 However, only a few trisubstituted (E)-
-un-
a,b-unsaturated esters as the sub-
b
a,b
saturated esters were employed as applicable substrates in those
reports. Because few practical synthetic methods for geometrically
pure trisubstituted (E)-a,b-unsaturated esters are available,
a,b
b
detailed studies of the Michael addition reaction using versatile
trisubstituted acceptors have not been performed. Thus, the
b
a
development of an asymmetric synthesis of b
2,3-amino acid de-
amine-derived chiral lithium amide to trisubstituted
a,
b
rivatives possessing various substituents remains a challenging
task in synthetic organic chemistry.
rated esters.4 Several research groups have used Davies' chiral
We have developed an asymmetric Michael addition reaction of
chiral amine 1 with various
practical method for the preparation of trisubstituted (E)-
saturated esters.10 Using both studies as background, we report
herein a practical asymmetric synthesis of
2,3-amino esters having
a,b
-unsaturated esters9 as well as a
a,b-un-
* Corresponding author.
** Corresponding author.
b
E-mail address: ozekim@mb.kyoto-phu.ac.jp (M. Ozeki).
http://dx.doi.org/10.1016/j.tet.2017.02.037
0040-4020/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ozeki M, et al., Novel and practical asymmetric synthesis of
addition of chiral amine, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.02.037
b
2,3-amino esters using asymmetric Michael

2
M. Ozeki et al. / Tetrahedron xxx (2017) 1e8
Table 1
various substituents, which is characterized by the asymmetric
Asymmetric Michael addition reaction of chiral amine 1 with trisubstituted (E)-
unsaturated esters 2.
a,b-
Michael addition reaction of chiral amine 1 with trisubstituted (E)-
a,b-unsaturated esters.
2. Results and discussion
In the asymmetric synthesis of
b
2,3-amino esters using the
Michael addition reaction, it is necessary to use geometrically pure
trisubstituted (E)- -unsaturated esters as the Michael acceptor to
a,b
achieve high stereoselectivity. In this regard, we have recently re-
ported a highly practical and E-stereoselective synthesis of trisub-
stituted
a,b-unsaturated esters having diverse substituents
Entry
R1
R2
Yield (%)
dra
(Scheme 1).10 This method consists of an aldol reaction, an acety-
lation of a hydroxyl group, and an E1cB elimination reaction using
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base. In the pre-
1
a
a
b
c
d
e
f
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
97
19
95
95
97
94
88
95:5
e
2b
3
4-Cl-Ph
4-CF3-Ph
4-Me-Ph
4-MeO-Ph
94:6
92:8
94:6
94:6
93:7
4
5
6
7
sent study, we decided to employ the trisubstituted (E)-a,b-un-
saturated esters as the Michael acceptor.
First, we performed the asymmetric Michael addition reaction
of chiral lithium amide 1-Li with
a
,
b-unsaturated ester 2a in THF
at ꢀ50 ꢁC. The attack of 1-Li on the
b-position of 2a and the sub-
8
9
g
Me
Me
65
68
92:8
91:9
sequent face-selective protonation of the enolate intermediate by
the quick addition of water proceeded to afford Michael adduct 3a
having two contiguous chiral centers in excellent yield (97%) with
high diastereoselectivity (major isomer/minor isomers ¼ 95/5)
(Table 1, entry 1). It is worth noting that the quick addition of water
to the enolate intermediate for the rapid quenching of the reaction
was crucial to obtain a satisfactory yield while avoiding the retro-
Michael reaction. Actually, a decrease in yield was observed when
water was added in the usual manner to quench the reaction
(Table 1, entry 2). Next, the asymmetric Michael addition reaction
using substrates 2b-e having either an electron-donating group or
an electron-withdrawing group on the aromatic ring resulted in the
production of desired Michael adducts 3b-e in excellent yields with
high diastereoselectivities (Table 1, entries 3e6). The reactions
h
10
11
12
13
14
i
j
k
l
m
Ph
Ph
Ph
Ph
Et
99
73
98
93
ec
94:6
92:8
92:8
82:18
e
Bn
i-Pr
Ph
Me
c-Hex
a
Selectivities were determined by 1H NMR spectroscopy.
The reaction was quenched by the normal addition of water.
Substrate 2m was recovered in 61% yield.
b
c
using Michael acceptors 2f-h having a heteroaromatic ring at the b-
position afforded desired products 3f-h in moderate to good yields
with high diastereoselectivities (Table 1, entries 7e9). Moreover,
The absolute configuration of major isomer 3 was determined
by X-ray diffraction analysis of crystalline Michael adduct 3b
(Fig. 1).11 The major products of 3a and 3c-l in Table 1 were sup-
posed to have the same stereochemistry as 3b based on careful
comparison of the 1H NMR spectrum of the major adducts with
those of the minor products in each case.12
we examined the influence of the substituent at the a-position of
the Michael acceptor by replacing the methyl group with bulkier
substituents (Table 1, entries 10e13). We had expected that a
decrease in reactivity and an increase in diastereoselectivity caused
A plausible transition state of the present asymmetric Michael
addition reaction is shown in Fig. 2. The asymmetric Michael
addition reaction would proceed via a six-membered ring transi-
tion state formed by coordinating lithium ion to the carbonyl ox-
ygen of the substrate, generating the Z-enolate intermediate as a
result of the s-cis conformation of the substrate.9b,13 Subsequent
face-selective protonation of the enolate intermediate would
preferentially occur from the bottom face of the enolate interme-
diate due to the steric repulsion by the N-benzyl group on the
amino group.9b Meanwhile, the Michael addition reaction of 1-Li
by the bulky substituent at the a-position would be observed in the
asymmetric Michael addition reaction. Contrary to our expectation,
the chemical yields remained good to excellent and the same or a
slight decrease in diastereoselectivity was observed in all cases
(Table 1, entries 10e13). Finally, the reaction with a Michael
acceptor having an aliphatic substituent at the
b-position was
attempted (Table 1, entry 14). However, none of the desired Michael
adducts were obtained and instead, starting material 2m was
recovered in 61% yield. This was unexpected because the asym-
metric Michael addition reaction of 1-Li with a similar Michael
acceptor (R1 ¼ c-Hex, R2 ¼ H) afforded a Michael adduct in excellent
yield with excellent diastereoselectivity in our previous report.9a
with Michael acceptor 2 having an aliphatic substituent at the
b-
position, i.e., Michael acceptor 2m, did not procced as mentioned
Scheme 1. Our developed practical and stereoselective synthesis of trisubstituted (E)-a,b-unsaturated esters.
Please cite this article in press as: Ozeki M, et al., Novel and practical asymmetric synthesis of
addition of chiral amine, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.02.037
b
2,3-amino esters using asymmetric Michael

M. Ozeki et al. / Tetrahedron xxx (2017) 1e8
3
Table 2
Conversion of Michael adducts 3 into b
2,3-amino ester derivatives 4.
Entry
R1
R2
Time (h)
Yield (%)
1
2
3
a
b
c
d
e
f
Ph
Me
Me
Me
Me
Me
Me
19
18
18
17
17
17
80
90
67
74
62
64
4-Cl-Ph
4-CF3-Ph
4-Me-Ph
4-MeO-Ph
4
5a
6
7
8
g
Me
Me
21
82
h
e
e
Fig. 1. X-ray crystal structure of Michael adduct 3b.
9
i
j
k
l
Ph
Ph
Ph
Ph
Et
19
21
24
24
77
69
71
61
10
11
12
Bn
i-Pr
Ph
above (Table 1, entry 14). This phenomenon could be rationalized as
follows:
for it to be used as a substrate of the Michael addition reaction13b,c
however, the steric repulsion between the tert-butyloxy group and
the substituent at the -position would shift the conformational
equilibrium of 2 to the s-trans conformation. In the case that a
proton exists as found in 2m, the -proton would be easily
a,b-Unsaturated ester 2 should have the s-cis conformation
a
;
6 eq of NIS was used.
a
substituents, which involved the asymmetric aza-Michael addition
to the (E)- -trisubstituted Michael acceptor and the subsequent
g-
a,b
g
face-selective protonation of the enolate intermediate derived from
the Michael addition reaction. The practical application of the
present method to the synthesis of
enhanced by combining our developed asymmetric aza-Michael
addition reaction and the stereoselective synthesis of trisubsti-
tuted (E)-a,b-unsaturated esters. Moreover, we found that the quick
abstracted by 1-Li from the stable s-trans conformation. Thus,
starting material 2m would be recovered.
b
2,3-amino esters could be
Finally, we examined the conversion of Michael adducts 3 into
b
2,3-amino ester derivatives 4 by removing the bornyl group and
the benzyl group on the amino group. We had developed an
oxidative C-N bond cleavage reaction by treatment with NIS.9,14
Thus, Michael adducts 3 were subjected to the C-N bond cleavage
reaction using NIS in dichloromethane at room temperature,
addition of water to the enolate intermediate was crucial to achieve
high yields of the Michael adducts and avoid the retro-Michael
reaction. Finally, the Michael adducts were subjected to the
oxidative C-N bond cleavage reaction with NIS for the deprotection
affording desired
b
2,3-amino ester derivatives 4 in moderate to
good yields in almost all cases (Table 2, entries 1e7 and 9e12). As a
limitation of our method, it should be mentioned that 3h having an
indole substituent decomposed when its deprotection was
attempted.
of the amino group, and desired
moderate to good yields.
b
2,3-amino esters were obtained in
4. Experimental
3. Conclusions
4.1. General
In conclusion, we succeeded in developing a practical method
for the synthesis of chiral
b
2,3-amino esters having various
1H NMR spectra were recorded at 400 MHz and 13C NMR spectra
Fig. 2. Plausible transition state of the asymmetric Michael addition reaction of 1 with 2.
Please cite this article in press as: Ozeki M, et al., Novel and practical asymmetric synthesis of
addition of chiral amine, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.02.037
b
2,3-amino esters using asymmetric Michael

4
M. Ozeki et al. / Tetrahedron xxx (2017) 1e8
were recorded at 100 or 150 MHz on a Varian Unity INOVA-400,
JEOL JNM ECS-400 or JEOL JNM ECA-600 K spectrometer. Chemi-
cal shifts are reported in ppm relative to tetramethylsilane as the
internal reference. IR spectra were recorded in CHCl3 on a Shi-
madzu FTIR-8300. Absorptions are given in wavenumber (cmꢀ1).
Mass spectra were recorded on a JEOL JMS-SX 102A QQ or a JEOL
JMS-GC-mate spectrometer. Melting points were determined on a
micro hot-stage apparatus (Yanagimoto) and are uncorrected.
Elemental analysis was performed on a Perkin Elmer Series II
CHNS/O Analyzer 2400. Flash column chromatography was per-
Found: C, 78.47; H, 9.02; N, 2.86.
21
4.2.1.2. Minor isomer 1 of 3a. Colorless oil; [
a
]
þ64.4 (c ¼ 0.80,
D
CHCl3); 1H NMR (400 MHz, CDCl3):
d 7.36 (m, 10H), 3.86 (d,
J ¼ 13.4 Hz, 1H), 3.79 (d, A part of AB, JAB ¼ 11.5 Hz, 1H), 3.42 (dd,
J ¼ 7.3, 3.1 Hz,1H), 3.24 (s, 3H), 3.11 (dq, J ¼ 13.4, 6.8 Hz,1H), 2.84 (d,
B part of AB, JAB ¼ 11.5 Hz, 1H), 2.74 (d, A part of AB, JAB ¼ 13.7 Hz,
1H), 2.15 (d, B part of AB, JAB ¼ 13.7 Hz, 1H),1.78 (dq, J ¼ 12.8, 3.3 Hz,
1H), 1.62e1.43 (m, 4H), 1.49 (d, J ¼ 6.8 Hz, 3H), 1.25e1.17 (m, 1H),
1.01 (s, 9H), 0.94e0.85 (m, 1H), 0.90 (s, 3H), 0.56 (s, 3H); 13C NMR
formed on 63e210
mm silica gel. TLC analysis and preparative TLC
(100 MHz, CDCl3): d 174.8, 140.6, 136.7, 130.0 (2C), 129.9 (2C), 127.9
were performed on commercial glass plates with a 0.25 or 0.5 mm
thick silica gel layer, respectively. When necessary, compounds
were further purified by recycling HPLC (JAI LC-908) on a silica gel
column (Kusano Si-10) after column chromatography on silica gel.
Chiral amine 1 was synthesized from (S)-ketopinic acid according
to our previous report.9a
(2C), 127.4 (2C), 126.9, 126.7, 85.4, 79.6, 66.0, 55.4, 54.8, 52.9, 47.7,
46.0, 45.4, 43.7, 37.6, 31.1, 27.4 (3C), 27.2, 20.7, 20.5, 16.7; IR (CHCl3):
3018, 2936, 1717, 1601, 1454, 1367, 1155, 1094 cmꢀ1; MS (EI,
20 eV) m/z: 491 (Mþ, 0.1), 362 (100), 332 (1), 272 (1), 240 (1), 196
(1), 135 (9), 106 (4), 91 (5); HRMS calcd for C32H45NO3 (Mþ):
491.3399, found 491.3390.
22
4.2. Typical procedure for the asymmetric Michael addition
4.2.1.3. Minor isomer 2 of 3a. Colorless oil; [
a
]
D
þ54.2 (c ¼ 0.26,
reaction of chiral amine 1 with trisubstituted (E)-
ester 2
a,
b
-unsaturated
CHCl3); 1H NMR (400 MHz, CDCl3):
d 7.52e7.19 (m, 10H), 4.04 (d,
J ¼ 11.7 Hz, 1H), 3.97 (d, A part of AB, JAB ¼ 12.8 Hz, 1H), 3.63 (dd,
J ¼ 7.3, 3.1 Hz, 1H), 3.29 (s, 3H), 3.24 (dq, J ¼ 11.7, 6.8 Hz,1H), 2.72 (d,
A part of AB, JAB ¼ 13.9 Hz, 1H), 2.71 (d, B part of AB, JAB ¼ 12.8 Hz,
1H), 2.08 (d, B part of AB, JAB ¼ 13.9 Hz,1H),1.75 (dq, J ¼ 12.8, 3.5 Hz,
1H), 1.58 (s, 9H), 1.57e1.52 (m, 3H), 1.50e1.32 (m, 1H), 1.12e1.05 (m,
1H), 0.89 (s, 3H), 0.86 (d, J ¼ 6.8 Hz, 3H), 0.84e0.79 (m, 1H), 0.49 (s,
A typical procedure for the asymmetric Michael addition reac-
tion is shown in the reaction of 1 and 2a. Major isomers of Michael
adducts 3 were isolated as single diastereomers by either recycling
HPLC on a silica gel column or recrystallization from hexane/ethyl
acetate.
3H); 13C NMR (100 MHz, CDCl3):
d 175.8, 140.4, 135.5, 130.4 (2C),
129.9 (2C), 127.8 (2C), 127.5 (2C), 126.9, 126.6, 84.6, 80.0, 66.5, 55.4,
54.5, 52.6, 47.7, 46.1, 45.6, 42.9, 35.7, 30.2, 28.3 (3C), 27.0, 20.6, 20.5,
16.9; IR (CHCl3): 3030, 2934, 1719, 1603, 1456, 1367, 1148,
1094 cmꢀ1; MS (EI, 20 eV) m/z: 491 (Mþ, 0.6), 362 (100), 272 (3),135
(8), 106 (5), 91 (6); HRMS calcd for C32H45NO3 (Mþ): 491.3399,
found 491.3395.
4.2.1. (2S,3S)-tert-Butyl 3-[(1S,2R)-2-methoxybornyl-10-
benzylamino]-2-methyl-3-phenylpropanoate (3a)
Butyllithium (2.6 M in hexane solution, 106
mL, 0.279 mmol) was
added dropwise to a solution of chiral amine
1
(76.3 mg,
0.279 mmol) in THF (1.8 mL) at ꢀ50 ꢁC under an argon atmosphere.
A solution of trisubstituted (E)-a,b-unsaturated ester 2a (40.6 mg,
22
0.186 mmol) in THF (1.2 mL) was added dropwise to the lithium
amide solution at the same temperature, and the reaction mixture
was stirred for 0.5 h. Water (2 mL) was quickly added to the reac-
tion mixture at ꢀ50 ꢁC, and the reaction mixture was allowed to
warm to room temperature. The resulting mixture was poured into
a saturated aqueous solution of sodium hydrogen carbonate and
extracted with ethyl acetate. The organic layer was washed with
brine, dried over anhydrous sodium sulfate, and concentrated un-
der reduced pressure. The residue was purified by column chro-
matography on silica gel (hexane-ethyl acetate, 30:1) to give 3a
(88.6 mg, 97%, major isomer/minor isomers ¼ 95/5). Obtained
diastereomeric mixture could be separated into each diastereomer
by preparative TLC, HPLC and recrystallization.
4.2.1.4. Minor isomer 3 of 3a. Colorless oil; [
CHCl3); 1H NMR (400 MHz, CDCl3):
a]
ꢀ 67.1 (c ¼ 0.53,
D
d
7.45e7.16 (m, 10H), 4.01 (d,
J ¼ 11.2 Hz, 1H), 3.82 (d, A part of AB, JAB ¼ 14.3 Hz, 1H), 3.35 (d, B
part of AB, JAB ¼ 14.3 Hz, 1H), 3.23 (dd, J ¼ 7.3, 3.3 Hz, 1H), 3.14 (d, A
part of AB, JAB ¼ 14.3 Hz, 1H), 3.10 (dq, J ¼ 11.2, 7.0 Hz, 1H), 2.98 (s,
3H), 2.23 (d, B part of AB, JAB ¼ 14.3 Hz, 1H), 1.70e1.57 (m, 4H), 1.54
(s, 9H), 1.46 (dd, J ¼ 12.6, 7.3 Hz, 1H), 1.28e1.22 (m, 1H), 0.98e0.91
(m, 1H), 0.87 (s, 3H), 0.82 (d, J ¼ 7.0 Hz, 3H), 0.79 (s, 3H); 13C NMR
(100 MHz, CDCl3):
d 175.7, 140.9, 137.2, 129.9 (2C), 129.4 (2C), 127.8
(2C), 127.7 (2C), 126.8, 126.4, 85.1, 79.9, 68.2, 57.1, 54.6, 53.1, 47.7,
47.6, 45.1, 42.4, 37.4, 29.9, 28.2 (3C), 27.3, 20.9, 20.3,16.9; IR (CHCl3):
3017, 2936, 1720, 1601, 1495, 1454, 1367, 1151 cmꢀ1; MS (EI,
20 eV) m/z: 491 (Mþ, 0.4), 362 (100), 272 (3), 240 (3), 135 (10), 118
(5), 106 (12), 91 (7); HRMS calcd for C32H45NO3 (Mþ): 491.3399,
found 491.3392.
4.2.1.1. Major isomer of 3a. Colorless crystals; mp 89e91 ꢁC (hex-
20
ane-ethyl acetate); [
(400 MHz, CDCl3):
a]
ꢀ 115.8 (c ¼ 0.70, CHCl3); 1H NMR
D
d
7.47e7.45 (br d, J ¼ 7.1 Hz, 2H), 7.38e7.28 (m,
4.2.2. (2S,3S)-tert-Butyl 3-[(1S,2R)-2-methoxybornyl-10-
benzylamino]-3-(4-chlorophenyl)-2-methylpropanoate (3b)
Colorless crystals; mp 163e164 ꢁC (hexane-ethyl acetate);
4H), 7.27e7.17 (m, 4H), 3.82 (d, A part of AB, JAB ¼ 14.5 Hz, 1H), 3.51
(d, J ¼ 11.2 Hz, 1H), 3.47 (dd, J ¼ 7.3, 3.3 Hz, 1H), 3.39 (d, B part of AB,
JAB ¼ 14.5 Hz, 1H), 3.29 (d, A part of AB, JAB ¼ 13.8 Hz, 1H), 3.20 (s,
3H), 3.19 (dq, J ¼ 11.2, 6.6 Hz, 1H), 1.84e1.70 (m, 2H), 1.76 (d, B part
of AB, JAB ¼ 13.8 Hz, 1H), 1.68e1.59 (m, 2H), 1.55 (dd, J ¼ 13.0, 7.1 Hz,
1H), 1.36 (dq, J ¼ 11.2, 3.3 Hz, 1H), 1.29 (d, J ¼ 6.6 Hz, 3H), 1.05e1.00
(m, 1H), 0.98 (s, 3H), 0.97 (s, 9H), 0.75 (s, 3H); 13C NMR (100 MHz,
[a
]
27 ꢀ 164.1 (c ¼ 1.03, CHCl3); 1H NMR (400 MHz, CDCl3):
d 7.34 (br
D
d, J ¼ 7.8 Hz, 2H), 7.36e7.23 (m, 5H), 7.15 (br d, J ¼ 7.8 Hz, 2H), 3.82
(d, A part of AB, JAB ¼ 14.6 Hz, 1H), 3.50 (d, J ¼ 11.2 Hz, 1H), 3.46 (dd,
J ¼ 7.2, 3.2 Hz, 1H), 3.33 (d, B part of AB, JAB ¼ 14.6 Hz, 1H), 3.23 (d, A
part of AB, JAB ¼ 13.9 Hz, 1H), 3.21 (s, 3H), 3.16 (dq, J ¼ 11.2, 6.6 Hz,
1H), 1.83e1.78 (m, 1H), 1.76e1.52 (m, 4H), 1.70 (d, B part of AB,
JAB ¼ 13.9 Hz, 1H), 1.39e1.33 (m, 1H), 1.28 (d, J ¼ 6.6 Hz, 3H),
1.05e0.99 (m, 1H), 1.02 (s, 9H), 0.97 (s, 3H), 0.75 (s, 3H); 13C NMR
CDCl3):
d 175.2, 140.7, 137.0, 130.1 (2C), 129.0 (2C), 128.1 (2C), 127.3
(2C), 126.8, 126.7, 85.4, 79.3, 66.8, 57.7, 54.6, 53.2, 47.6, 47.2, 44.8,
43.2, 37.3, 30.8, 27.6, 27.3 (3C), 20.8, 20.5, 17.1; IR (CHCl3): 3020,
2936, 1717, 1601, 1493, 1456, 1367, 1155, 1094 cmꢀ1; MS (EI,
20 eV) m/z: 491 (Mþ, 0.2), 362 (100), 272 (1), 240 (1), 135 (6), 106
(2), 91 (2); HRMS calcd for C32H45NO3 (Mþ): 491.3399, found
491.3391; Anal. Calcd for C32H45NO3: C, 78.17; H, 9.22; N, 2.85.
(100 MHz, CDCl3):
d 174.9, 140.3, 135.6, 132.6, 131.1 (2C), 128.9 (2C),
128.2 (2C), 127.5 (2C), 126.8, 85.4, 79.5, 65.9, 57.7, 54.5, 53.1, 47.6,
47.1, 44.8, 43.1, 37.3, 30.8, 27.6, 27.4 (3C), 20.8, 20.5, 17.1; IR (CHCl3):
2936, 2881, 2821, 1716, 1593, 1488, 1454, 1367, 1284, 1153,
Please cite this article in press as: Ozeki M, et al., Novel and practical asymmetric synthesis of
addition of chiral amine, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.02.037
b
2,3-amino esters using asymmetric Michael

M. Ozeki et al. / Tetrahedron xxx (2017) 1e8
5
1091 cmꢀ1; MS (EI, 20 eV) m/z: 525 (Mþ, 0.1), 468 (0.2), 424 (0.2),
396 (100), 135 (23), 91 (38); HRMS calcd for C32H44NO3Cl (Mþ):
525.3009, found 525.3012; Anal. Calcd for C32H44NO3Cl: C, 73.05;
H, 8.43; N, 2.66. Found: C, 73.25; H, 8.31; N, 2.77.
(Mþ, 0.1), 464 (0.2), 448 (0.3), 420 (0.2), 392 (100), 148 (30), 106
(38), 91 (45), 56 (7); HRMS calcd for C33H47NO4 (Mþ): 521.3505,
found 521.3499; Anal. Calcd for C33H47NO4: C, 75.97; H, 9.08; N,
2.68. Found: C, 75.46; H, 8.82; N, 2.73.
4.2.3. (2S,3S)-tert-Butyl 3-[(1S,2R)-2-methoxybornyl-10-
benzylamino]-2-methyl-3-(4-(trifluoromethyl)phenyl)propanoate
(3c)
4.2.6. (2S,3S)-tert-Butyl 3-(furan-2-yl) 3-[(1S,2R)-2-
methoxybornyl-10-benzylamino]-2-methylpropanoate (3f)
Colorless oil; [
CDCl3):
a
]
25 ꢀ 135.3 (c ¼ 0.73, CHCl3); 1H NMR (400 MHz,
D
Colorless crystals; mp 175e176 ꢁC (hexane-ethyl acetate);
d
7.39 (br d, J ¼ 7.2 Hz, 3H), 7.32e7.20 (m, 3H), 6.31 (dd,
[
a]
21 ꢀ122.3 (c ¼ 0.84, CHCl3); 1H NMR (400 MHz, CDCl3):
d
7.58 (br
J ¼ 3.2, 1.8 Hz, 1H), 6.15 (br d, J ¼ 3.2 Hz, 1H), 3.82 (d, A part of AB,
JAB ¼ 13.9 Hz, 1H), 3.68 (d, J ¼ 11.4 Hz, 1H), 3.46 (d, B part of AB,
JAB ¼ 13.9 Hz, 1H), 3.43 (dd, J ¼ 7.3, 3.3 Hz, 1H), 3.18 (d, A part of AB,
JAB ¼ 14.2 Hz, 1H), 3.15 (s, 3H), 3.03 (dq, J ¼ 11.4, 6.9 Hz, 1H), 1.93 (d,
B part of AB, JAB ¼ 14.2 Hz,1H),1.82e1.61 (m, 4H),1.56e1.49 (m,1H),
1.39e1.33 (m, 1H), 1.20 (d, J ¼ 6.9 Hz, 3H), 1.17 (s, 9H), 1.05e0.99 (m,
D
d, J ¼ 8.1 Hz, 2H), 7.44 (br d, J ¼ 7.1 Hz, 2H), 7.37e7.31 (m, 4H),
7.29e7.24 (m, 1H), 3.85 (d, A part of AB, JAB ¼ 14.5 Hz, 1H), 3.58 (d,
J ¼ 11.3 Hz, 1H), 3.48 (dd, J ¼ 7.2, 3.2 Hz, 1H), 3.34 (d, B part of AB,
JAB ¼ 14.5 Hz, 1H), 3.27 (d, A part of AB, JAB ¼ 13.7 Hz, 1H), 3.22 (s,
3H), 3.21 (dq, J ¼ 11.3, 6.7 Hz, 1H), 1.86e1.79 (m, 1H), 1.76e1.53 (m,
4H), 1.72 (d, B part of AB, JAB ¼ 13.7 Hz, 1H), 1.39e1.33 (m, 1H), 1.30
1H), 0.96 (s, 3H), 0.77 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 175.0,
(d, J ¼ 6.7 Hz, 3H), 1.06e0.99 (m, 1H), 0.98 (s, 12H), 0.75 (s, 3H); 13
C
154.1, 141.1, 140.5, 129.2 (2C), 128.0 (2C), 126.7, 109.5, 108.2, 85.4,
79.5, 60.6, 58.0, 54.6, 53.2, 48.4, 47.6, 44.9, 42.7, 37.3, 31.0, 27.7 (3C),
27.6, 20.8, 20.5, 16.8; IR (CHCl3): 3043, 3024, 3014, 3004, 2935,
2881, 2821, 1718, 1600, 1494, 1454, 1390, 1367, 1280, 1236, 1153,
1093, 1012 cmꢀ1; MS (EI, 20 eV) m/z: 481 (Mþ, 0.1), 408 (0.3), 390
(2), 352 (100), 272 (2), 152 (4), 106 (30), 91 (4), 56 (9); HRMS calcd
for C30H43NO4 (Mþ): 481.3192, found 481.3189.
NMR (100 MHz, CDCl3): d
174.8, 141.3, 140.1, 130.1 (2C), 129.1 (q, 2JC-
¼ 32.0 Hz), 128.9 (2C), 128.3 (2C), 126.9, 124.30 (q, 1JC-F ¼ 272 Hz),
F
3
124.29 (q, JC-F ¼ 3.8 Hz, 2C), 85.4, 79.7, 66.2, 57.8, 54.6, 53.2, 47.7,
47.1, 44.8, 43.0, 37.3, 30.8, 27.6, 27.3 (3C), 20.8, 20.5, 17.1; IR (CHCl3):
2985, 2937, 2881, 2821, 1716, 1618, 1602, 1454, 1367, 1326, 1166,
1130, 1068, 1093, 1018 cmꢀ1; MS (EI, 20 eV) m/z: 559 (Mþ, 0.1), 502
(0.1), 430 (100), 272 (2), 135 (8); HRMS calcd for C33H44NO3F3 (Mþ):
559.3273, found 559.3275; Anal. Calcd for C33H44NO3F3: C, 70.81;
H, 7.92; N, 2.50. Found: C, 71.09; H, 7.88; N, 2.51.
4.2.7. (2S,3S)-tert-Butyl 3-[(1S,2R)-2-methoxybornyl-10-
benzylamino]-2-methyl-3-(thiophen-2-yl)propanoate (3g)
23
Colorless crystals; mp 63e65 ꢁC (hexane); [
a
]
ꢀ 103.5
D
4.2.4. (2S,3S)-tert-Butyl 3-[(1S,2R)-2-methoxybornyl-10-
benzylamino]-2-methyl-3-(p-tolyl)propanoate (3d)
(c ¼ 0.65, CHCl3); 1H NMR (400 MHz, CDCl3):
7.42 (br d, J ¼ 7.1 Hz,
d
2H), 7.32 (br t, J ¼ 7.3 Hz, 2H), 7.26e7.21 (m, 1H), 7.21 (dd, J ¼ 5.1,
1.1 Hz, 1H), 6.99 (dd, J ¼ 5.1, 3.5 Hz, 1H), 6.90 (br dd, J ¼ 3.5, 1.1 Hz,
1H), 3.82 (d, A part of AB, JAB ¼ 14.1 Hz, 1H), 3.81 (d, J ¼ 11.2 Hz, 1H),
3.46 (dd, J ¼ 7.3, 3.3 Hz, 1H), 3.45 (d, B part of AB, JAB ¼ 14.1 Hz, 1H),
3.20 (d, A part of AB, JAB ¼ 14.0 Hz,1H), 3.17 (s, 3H), 3.07 (dq, J ¼ 11.2,
6.7 Hz, 1H), 1.92 (d, B part of AB, JAB ¼ 14.0 Hz, 1H), 1.83e1.63 (m,
4H), 1.57e1.52 (m, 1H), 1.42e1.35 (m, 1H), 1.24 (d, J ¼ 6.7 Hz, 3H),
1.08 (s, 9H), 1.07e1.00 (m, 1H), 0.98 (s, 3H), 0.78 (s, 3H); 13C NMR
Colorless crystals; mp 168e170 ꢁC (hexane-ethyl acetate);
[
a]
22 ꢀ 134.1 (c ¼ 0.55, CHCl3); 1H NMR (400 MHz, CDCl3):
d 7.45 (br
D
d, J ¼ 7.1 Hz, 2H), 7.35e7.31 (m, 2H), 7.26e7.22 (m, 1H), 7.11 (br s,
4H), 3.80 (d, A part of AB, JAB ¼ 14.5 Hz, 1H), 3.47 (d, J ¼ 11.3 Hz, 1H),
3.46 (dd, J ¼ 7.1, 3.3 Hz, 1H), 3.38 (d, B part of AB, JAB ¼ 14.5 Hz, 1H),
3.27 (d, A part of AB, JAB ¼ 13.9 Hz,1H), 3.19 (s, 3H), 3.16 (dq, J ¼ 11.3,
6.6 Hz, 1H), 2.33 (s, 3H), 1.83e1.71 (m, 2H), 1.76 (d, B part of AB,
JAB ¼ 13.9 Hz, 1H), 1.68e1.60 (m, 2H), 1.57e1.52 (m, 1H), 1.39e1.33
(m, 1H), 1.28 (d, J ¼ 6.6 Hz, 3H), 1.05e0.97 (m, 1H), 0.98 (s, 9H), 0.97
(100 MHz, CDCl3):
d 174.8, 140.3, 139.7, 129.2 (2C), 128.0 (2C), 126.8
(2C), 125.9, 123.6, 85.3, 79.4, 62.2, 57.7, 54.5, 53.1, 48.1, 47.7, 45.0,
44.8, 37.3, 30.9, 27.6, 27.4 (3C), 20.8, 20.5, 17.0; IR (CHCl3): 2985,
2935, 2881, 2821, 1718, 1602, 1494, 1454, 1390, 1367, 1282, 1240,
1220, 1195, 1155, 1093 cmꢀ1; MS (EI, 20 eV) m/z: 497 (Mþ, 0.1), 406
(0.8), 368 (100), 168 (8), 124 (13), 106 (33), 56 (5); HRMS calcd for
(s, 3H), 0.75 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 175.2, 140.8,
136.3, 133.8, 130.0 (2C), 129.0 (2C), 128.1 (2C), 128.0 (2C), 126.6,
85.4, 79.2, 77.3, 66.5, 57.7, 54.6, 53.2, 47.6, 47.2, 44.8, 43.3, 37.3, 30.8,
27.6, 27.4 (3C), 21.1, 20.8, 17.1; IR (CHCl3): 3039, 2935, 2881, 2821,
1716, 1602, 1454, 1367, 1213, 1191, 1155, 1093 cmꢀ1; MS (EI,
20 eV) m/z: 505 (Mþ, 0.1), 432 (0.3), 376 (100), 272 (0.8), 132 (5), 56
(5); HRMS calcd for C33H47NO3 (Mþ): 505.3556, found 505.3553;
Anal. Calcd for C33H47NO3: C, 78.37; H, 9.37; N, 2.77. Found: C,
78.67; H, 9.09; N, 2.82.
C
30H43NO3S (Mþ): 497.2963, found 497.2965.
4.2.8. (2S,3S)-tert-Butyl 3-[(1S,2R)-2-methoxybornyl-10-
benzylamino]-2-methyl-3-(1-methyl-1H-indol-3-yl)propanoate
(3h)
26
Colorless crystals; mp 122e123 ꢁC (hexane); [
a
]
ꢀ 109.3
D
4.2.5. (2S,3S)-tert-Butyl 3-[(1S,2R)-2-methoxybornyl-10-
benzylamino]-3-(4-methoxyphenyl)-2-methylpropanoate (3e)
Colorless crystals; mp 146e147 ꢁC (hexane-ethyl acetate);
(c ¼ 0.73, CHCl3); 1H NMR (400 MHz, CDCl3):
7.58 (br d, J ¼ 7.9 Hz,
d
1H), 7.52 (br d, J ¼ 7.3 Hz, 2H), 7.37 (br t, J ¼ 7.4 Hz, 2H), 7.27 (br t,
J ¼ 6.6 Hz, 2H), 7.18 (br t, J ¼ 7.5 Hz, 1H), 7.07 (br d, J ¼ 7.5 Hz, 1H),
6.97 (s, 1H), 3.84 (d, J ¼ 11.2 Hz, 1H), 3.780 (d, A part of AB,
JAB ¼ 14.9 Hz, 1H), 3.777 (s, 3H), 3.53 (dd, J ¼ 6.1, 3.3 Hz, 1H), 3.52 (d,
B part of AB, JAB ¼ 14.9 Hz, 1H), 3.34 (d, A part of AB, JAB ¼ 13.8 Hz,
1H), 3.26e3.19 (m, 1H), 3.23 (s, 3H), 1.94 (d, B part of AB,
JAB ¼ 13.8 Hz, 1H), 1.86e1.72 (m, 2H), 1.67e1.54 (m, 3H), 1.40e1.32
(m, 1H), 1.33 (d, J ¼ 6.6 Hz, 3H), 1.05e0.98 (m, 1H), 1.01 (s, 3H), 0.75
[
a]
21 ꢀ128.6 (c ¼ 3.24, CHCl3); 1H NMR (400 MHz, CDCl3):
d 7.34 (br
D
d, J ¼ 7.1 Hz, 2H), 7.33 (br t, J ¼ 7.7 Hz, 2H), 7.26e7.22 (m, 1H), 7.15
(br d, J ¼ 8.8 Hz, 2H), 6.86 (br d, J ¼ 8.8 Hz, 2H), 3.81 (s, 3H), 3.80 (d,
A part of AB, JAB ¼ 14.5 Hz, 1H), 3.47 (d, J ¼ 11.4 Hz, 1H), 3.46 (dd,
J ¼ 7.1, 3.1 Hz, 1H), 3.36 (d, A part of AB, JAB ¼ 14.5 Hz, 1H), 3.25 (d, A
part of AB, JAB ¼ 14.0 Hz, 1H), 3.19 (s, 3H), 3.13 (dq, J ¼ 11.4, 6.7 Hz,
1H), 1.84e1.71 (m, 2H), 1.74 (d, B part of AB, JAB ¼ 14.0 Hz, 1H),
1.68e1.52 (m, 3H), 1.39e1.33 (m, 1H), 1.28 (d, J ¼ 6.7 Hz, 3H),
1.05e0.99 (m, 1H), 1.00 (s, 9H), 0.98 (s, 3H), 0.76 (s, 3H); 13C NMR
(s, 12H); 13C NMR (100 MHz, CDCl3):
d 175.3, 141.4, 136.2, 130.0,
128.7 (2C), 128.5, 128.0 (2C), 126.5, 121.1, 120.8, 118.7, 110.9, 108.6,
85.5, 78.9, 60.2, 58.3, 54.6, 53.3, 48.4, 47.5, 45.2, 44.9, 37.3, 32.8,
30.6, 27.6, 27.1 (3C), 20.9, 20.6, 17.4; IR (CHCl3): 3049, 3028, 3006,
2935, 2881, 1714, 1595, 1454, 1388, 1367, 1290, 1157, 1093,
1045 cmꢀ1; MS (EI, 20 eV) m/z: 544 (Mþ, 0.1), 471 (1), 415 (78), 271
(31), 215 (73), 106 (100), 91 (12), 56 (4); HRMS calcd for C35H48N2O3
(Mþ): 544.3665, found 544.3660; Anal. Calcd for C35H48N2O3: C,
(100 MHz, CDCl3): d 175.2, 158.5, 140.7, 131.0 (2C), 129.2, 129.0 (2C),
128.1 (2C), 126.6, 112.7 (2C), 85.4, 79.2, 66.1, 57.7, 55.2, 54.6, 53.2,
47.6, 47.1, 44.8, 43.4, 37.3, 30.8, 27.6, 27.4 (3C), 20.8, 20.5, 17.1; IR
(CHCl3): 3037, 2956, 2935, 2881, 2837, 1716, 1608, 1583, 1510, 1456,
1367, 1199, 1186, 1155, 1093, 1041 cmꢀ1; MS (EI, 20 eV) m/z: 521
Please cite this article in press as: Ozeki M, et al., Novel and practical asymmetric synthesis of
addition of chiral amine, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.02.037
b
2,3-amino esters using asymmetric Michael

6
M. Ozeki et al. / Tetrahedron xxx (2017) 1e8
77.17; H, 8.88; N, 5.14. Found: C, 77.28; H, 9.12; N, 5.26.
J ¼ 11.6 Hz, 1H), 3.45 (d, A part of AB, JAB ¼ 14.4 Hz, 1H), 3.28 (d, B
part of AB, JAB ¼ 14.4 Hz,1H), 3.03 (d, A part of AB, JAB ¼ 13.8 Hz,1H),
3.01 (dd, J ¼ 7.2, 3.2 Hz, 1H), 2.95 (s, 3H), 2.43 (d, B part of AB,
JAB ¼ 13.8 Hz, 1H), 1.67e1.61 (m, 1H), 1.54e1.52 (m, 1H), 1.42e1.35
4.2.9. (2S,3S)-tert-Butyl 2-ethyl-3-[(1S,2R)-2-methoxybornyl-10-
benzylamino]-3-phenylpropanoate (3i)
Colorless oil; [
CDCl3):
a
]
22 ꢀ 100.2 (c ¼ 7.13, CHCl3); 1H NMR (400 MHz,
(m, 2H),1.00 (s, 9H), 0.91e0.74 (m, 3H), 0.86 (s, 3H), 0.68 (s, 3H); 13
C
D
d
7.44 (br d, J ¼ 7.1 Hz, 2H), 7.35e7.29 (m, 4H), 7.26e7.21 (m,
NMR (100 MHz, CDCl3): d 171.4, 140.9, 140.3, 138.0, 129.5 (2C), 129.2
4H), 3.80 (d, A part of AB, JAB ¼ 14.5 Hz, 1H), 3.62 (d, J ¼ 11.0 Hz, 1H),
3.42 (dd, J ¼ 7.1, 3.1 Hz, 1H), 3.38 (d, B part of AB, JAB ¼ 14.5 Hz, 1H),
3.24 (d, A part of AB, JAB ¼ 14.0 Hz,1H), 3.18 (s, 3H), 2.94 (dt, J ¼ 11.0,
3.8 Hz, 1H), 2.27 (ddq, J ¼ 13.4, 7.6 and 3.8 Hz, 1H), 1.87 (d, B part of
AB, JAB ¼ 14.0 Hz, 1H), 1.83e1.70 (m, 2H), 1.68e1.60 (m, 2H),
1.56e1.51 (m, 1H), 1.46e1.31 (m, 2H), 1.04e0.97 (m, 1H), 0.98 (s,
9H), 0.96 (s, 3H), 0.83 (t, J ¼ 7.6 Hz, 3H), 0.77 (s, 3H); 13C NMR
(2C), 129.1 (2C), 128.2 (2C), 127.70 (2C), 127.65 (2C), 127.2, 126.8,
126.4, 85.4, 80.3, 66.9, 56.1, 54.8, 54.7, 53.0, 47.6, 46.6, 45.1, 37.3,
29.9, 27.3 (3C), 27.1, 20.9, 20.4; IR (CHCl3): 3006, 2933, 2883, 1720,
1494, 1454, 1367, 1145, 1091 cm-1; MS (CI) m/z: 554 (MþþH, 1);
HRMS calcd for C37H48NO3 (MþþH): 554.3634, found 554.3629.
4.3. Typical procedure for the conversion of Michael adducts 3 into
(100 MHz, CDCl3):
d
174.0, 140.9, 136.9, 130.3 (2C), 129.0 (2C), 128.1
b
2,3-amino ester derivatives 4 by treatment with NIS
(2C), 127.3 (2C), 126.8, 126.6, 85.4, 79.4, 66.7, 57.4, 54.6, 53.2, 50.6,
47.7 (2C), 44.9, 37.4, 31.0, 27.6, 27.4 (3C), 24.2, 20.9, 20.5, 11.7; IR
(CHCl3): 2958, 2935, 2877, 2821, 1716, 1602, 1525, 1454, 1367, 1311,
1155, 1091 cmꢀ1; MS (EI, 20 eV) m/z: 505 (Mþ, 0.2), 414 (0.1), 362
(100), 132 (7), 106 (9), 91 (4), 56 (7); HRMS calcd for C33H47NO3
(Mþ): 505.3556, found 505.3550.
A typical procedure for the conversion into
derivatives 4 is shown in the reaction of 4a. Here, single major
isomer 3 was employed in all reactions.
b
2,3-amino ester
4.3.1. (2S,3S)-tert-Butyl 3-amino-2-methyl-3-phenylpropanoate
(4a)
4.2.10. (2S,3S)-tert-Butyl 2-benzyl-3-[(1S,2R)-2-methoxybornyl-
N-Iodosuccinimide (126.7 mg, 0.563 mmol) was added drop-
wise to a solution of Michael adduct 3a (55.4 mg, 0.113 mmol) in
dichloromethane (1.5 mL) at room temperature under an argon
atmosphere, and the reaction mixture was stirred for 19 h. the re-
action mixture was poured into a saturated aqueous solution of
sodium hydrogen carbonate and extracted with chloroform. The
organic layer was washed with a saturated aqueous solution of
sodium thiosulfate followed by brine, dried over anhydrous sodium
sulfate, and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel (chloroform-
methanol, 30:1). Further purification by column chromatography
on NH-silica gel (hexane-ethyl acetate, 2:1) afforded 4a (21.2 mg,
10-benzylamino]-3-phenylpropanoate (3j)
Colorless oil; [
CDCl3):
a
]
25 ꢀ 95.5 (c ¼ 0.23, CHCl3); 1H NMR (400 MHz,
D
d
7.49 (br d, J ¼ 7.1 Hz, 2H), 7.39e7.09 (m, 13H), 3.91 (d, A
part of AB, JAB ¼ 14.5 Hz, 1H), 3.86 (d, J ¼ 11.5 Hz, 1H), 3.82 (dd, A
part of AB, JAB ¼ 13.5 Hz, J ¼ 3.8 Hz, 1H), 3.44 (dd, J ¼ 7.1, 3.1 Hz, 1H),
3.38 (d, B part of AB, JAB ¼ 14.5 Hz, 1H), 3.26 (dt, J ¼ 11.5, 3.8 Hz, 1H),
3.23 (d, A part of AB, JAB ¼ 13.6 Hz, 1H), 3.04 (s, 3H), 2.61 (dd, B part
of AB, JAB ¼ 13.5 Hz, J ¼ 11.5 Hz, 1H), 2.20 (d, B part of AB,
JAB ¼ 13.6 Hz, 1H), 1.82e1.74 (m, 2H), 1.72e1.63 (m, 2H), 1.56e1.51
(m, 1H), 1.45e1.39 (m, 1H), 1.06e1.00 (m, 1H), 1.04 (s, 3H), 0.84 (s,
3H), 0.77 (s, 9H); 13C NMR (100 MHz, CDCl3):
d 173.2, 140.9, 140.4,
24
25
135.9, 130.4 (2C), 129.1 (2C), 129.0 (2C), 128.3 (2C), 127.9 (2C), 127.3
(2C), 127.1, 126.7, 125.8, 85.4, 79.6, 68.1, 56.4, 54.7, 53.1, 51.0, 49.1,
48.1, 44.9, 37.5, 37.1, 32.2, 27.7, 27.2 (3C), 21.0, 20.6; IR (CHCl3): 3003,
2933, 2881, 2821, 1716, 1602, 1517, 1494, 1454, 1390, 1369, 1199,
1155, 1091 cmꢀ1; MS (EI, 20 eV) m/z: 567 (Mþ, 0.2), 494 (0.2), 476
(0.1), 362 (100), 272 (6), 194 (4), 106 (2), 91 (2), 56 (2); HRMS calcd
for C38H49NO3 (Mþ): 567.3712, found 567.3716.
80%). Colorless oil; [
a
]
þ19.8 (c ¼ 1.37, CHCl3) (lit. [
a
]
þ19.3,
D
D
c ¼ 2.37 in CHCl3)4c
; d 7.36e7.28 (m,
1H NMR (400 MHz, CDCl3):
4H), 7.25e7.23 (m, 1H), 4.15 (d, J ¼ 6.9 Hz, 1H), 2.64 (quint,
J ¼ 6.9 Hz,1H), 1.61 (br s, 2H), 1.28 (s, 9H), 1.17 (d, J ¼ 6.9 Hz, 3H); 13
C
NMR (100 MHz, CDCl3):
d 174.3, 143.9, 128.2 (2C), 127.1, 126.9 (2C),
80.2, 57.9, 48.2, 27.8 (3C), 12.7; IR (CHCl3): 3381, 2981, 2935, 2877,
1716, 1602, 1492, 1477, 1454, 1369, 1350, 1286, 1257, 1153 cmꢀ1; MS
(CI) m/z: 491 (MþþH, 100); HRMS calcd for C14H22NO2 (MþþH):
236.1650, found 236.1647.
4.2.11. (2S,3S)-tert-Butyl 2-isopropyl-3-[(1S,2R)-2-methoxybornyl-
10-benzylamino]-3-phenylpropanoate (3k)
Colorless oil; [
CDCl3):
a
]
20 ꢀ 88.5 (c ¼ 1.64, CHCl3); 1H NMR (400 MHz,
4.3.2. (2S,3S)-tert-Butyl 3-amino-3-(4-chlorophenyl)-2-
D
d
7.45 (br d, J ¼ 7.2 Hz, 2H), 7.35e7.30 (m, 4H), 7.26e7.22 (m,
methylpropanoate (4b)
26
4H), 3.78 (d, J ¼ 12.0 Hz,1H), 3.73 (d, A part of AB, JAB ¼ 14.8 Hz, 1H),
3.42 (d, B part of AB, JAB ¼ 14.8 Hz, 1H), 3.41 (dd, J ¼ 7.2, 2.8 Hz, 1H),
3.26 (d, A part of AB, JAB ¼ 14.0 Hz, 1H), 3.18 (s, 3H), 2.94 (dd,
J ¼ 12.0, 3.2 Hz, 1H), 2.60 (d of septet, J ¼ 7.2, 3.2 Hz, 1H), 1.92 (d, B
part of AB, JAB ¼ 14.0 Hz, 1H), 1.83e1.72 (m, 2H), 1.70e1.52 (m, 3H),
1.40e1.33 (m, 1H), 1.06e1.00 (m, 1H), 0.98 (s, 9H), 0.96 (s, 3H), 0.95
(d, J ¼ 7.2 Hz, 3H), 0.78 (s, 3H), 0.60 (d, J ¼ 7.2 Hz, 3H); 13C NMR
Colorless oil; [
CDCl3):
a
]
þ12.5 (c ¼ 0.75, CHCl3); 1H NMR (400 MHz,
D
d
7.28 (br s, 4H), 4.15 (d, J ¼ 6.8 Hz, 1H), 2.59 (quint,
J ¼ 6.8 Hz,1H), 1.58 (br s, 2H), 1.31 (s, 9H), 1.15 (d, J ¼ 6.8 Hz, 3H); 13
C
NMR (100 MHz, CDCl3):
d 174.1, 142.4, 132.8, 128.3 (4C), 80.4, 57.2,
48.1, 27.9 (3C), 12.6; IR (CHCl3): 3380, 2979, 2931, 2854, 1716, 1600,
1490, 1456, 1369, 1282, 1153, 1091, 1014 cmꢀ1; MS (CI) m/z: 270
(MþþH, 7); HRMS calcd for C14H21NO2Cl (MþþH): 270.1261, found
270.1266.
(150 MHz, CDCl3):
d 171.8, 141.0, 137.6, 130.0 (2C), 129.2 (2C), 128.1
(2C), 127.4 (2C), 126.7 (2C), 85.4, 79.4, 64.0, 57.0, 54.6, 53.9, 53.2,
48.4, 47.9, 44.9, 37.9, 31.2, 27.6, 27.5 (3C), 25.8, 22.5, 20.9, 20.4, 17.1;
IR (CHCl3): 3028, 2935, 2877, 2821, 1714, 1494, 1452, 1390, 1367,
1245, 1151, 1091 cmꢀ1; MS (EI, 70 eV) m/z: 519 (Mþ, 0.1), 462 (0.3),
446 (0.4), 418 (0.2), 362 (100), 272 (4), 91 (21), 57 (7); HRMS calcd
for C34H49NO3 (Mþ): 519.3713, found 519.3706.
4.3.3. (2S,3S)-tert-Butyl 3-amino-2-methyl-3-(4-(trifluoromethyl)
phenyl)propanoate (4c)
27
Colorless oil; [
CDCl3):
a
]
þ15.0 (c ¼ 0.39, CHCl3); 1H NMR (400 MHz,
D
d
7.58 (d, J ¼ 8.1 Hz, 2H), 7.47 (d, J ¼ 8.1 Hz, 2H), 4.25 (d,
J ¼ 6.8 Hz, 1H), 2.63 (quint, J ¼ 6.8 Hz, 1H), 1.58 (br s, 2H), 1.30 (s,
9H), 1.16 (d, J ¼ 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 174.0,
2
3
4.2.12. (2S,3S)-tert-Butyl 2,3-diphenyl-3-[(1S,2R)-2-
148.0, 129.4 (q, JC-F ¼ 32.4 Hz), 127.3 (2C), 125.1 (q, JC-F ¼ 3.8 Hz,
1
methoxybornyl-10-benzylamino]propanoate (3l)
2C), 124.1 (q, JC-F ¼ 272 Hz), 80.6, 57.4, 48.0, 27.8 (3C), 12.4; IR
Colorless oil; [
a
]
24 ꢀ 69.0 (c ¼ 1.08, CHCl3); 1H NMR (400 MHz,
(CHCl3): 3687, 3055, 1716, 1600, 1517, 1369, 1326, 1166, 1128,
D
CDCl3):
d
7.50 (br d, J ¼ 7.6 Hz, 2H), 7.39e7.28 (m, 7H), 7.26e7.18 (m,
1068 cmꢀ1; MS (CI) m/z: 304 (MþþH, 9); HRMS calcd for
4H), 7.02 (br d, J ¼ 7.6 Hz, 2H), 4.45 (d, J ¼ 11.6 Hz, 1H), 4.34 (d,
C
15H21NO2F3 (MþþH): 304.1524, found 304.1530.
Please cite this article in press as: Ozeki M, et al., Novel and practical asymmetric synthesis of
addition of chiral amine, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.02.037
b
2,3-amino esters using asymmetric Michael

M. Ozeki et al. / Tetrahedron xxx (2017) 1e8
7
4.3.4. (2S,3S)-tert-Butyl 3-amino-2-methyl-3-(p-tolyl)propanoate
1369, 1251, 1151 cmꢀ1; MS (EI, 20 eV) m/z: 311 (Mþ, 4), 254 (13), 238
(4d)
(4), 205 (1), 193 (7), 164 (10), 106 (100), 91 (0.3); HRMS calcd for
C
C
25
Colorless oil; [
CDCl3):
a
]
þ13.4 (c ¼ 1.15, CHCl3); 1H NMR (400 MHz,
20H25NO2 (Mþ): 491.3399, found 491.3391; Anal. Calcd for
20H25NO2: C, 77.14; H, 8.09; N, 4.50. Found: C, 77.00; H, 7.97; N,
D
d
7.21 (d, J ¼ 8.0 Hz, 2H), 7.12 (d, J ¼ 8.0 Hz, 2H), 4.13 (d,
J ¼ 6.9 Hz, 1H), 2.62 (quint, J ¼ 6.9 Hz, 1H), 2.32 (s, 3H), 1.60 (br s,
4.68.
2H), 1.30 (s, 9H), 1.15 (d, J ¼ 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
174.4, 140.9, 136.6, 128.9 (2C), 126.7 (2C), 80.2, 57.5, 48.1, 27.8 (3C),
4.3.10. (2S,3S)-tert-Butyl 3-amino-2-isopropyl-3-
phenylpropanoate (4k)
21.0, 12.6; IR (CHCl3): 3016, 1718, 1460, 1369, 1276, 1215, 1153 cmꢀ1
;
MS (CI) m/z: 250 (MþþH, 22); HRMS calcd for C15H24NO2 (MþþH):
Colorless crystals (hexane-ethyl acetate); mp 78e79 ꢁC (hex-
ane-ethyl acetate); [
CDCl3):
a
]
26 þ2.63 (c ¼ 1.68, CHCl3); 1H NMR (400 MHz,
250.1807, found 250.1811.
D
d
7.35e7.26 (m, 4H), 7.24e7.19 (m, 1H), 4.09 (d, J ¼ 10.2 Hz,
4.3.5. (2S,3S)-tert-Butyl 3-amino-3-(4-methoxyphenyl)-2-
methylpropanoate (4e)
Colorless oil; [
CDCl3):
1H), 2.54 (dd, J ¼ 10.2, 4.4 Hz, 1H), 2.26 (d of septet, J ¼ 6.8, 4.4 Hz,
1H), 1.49 (br s, 2H), 1.13 (s, 9H), 1.09 (d, J ¼ 6.8 Hz, 3H), 1.05 (d,
25
a
]
þ9.4 (c ¼ 0.59, CHCl3); 1H NMR (400 MHz,
J ¼ 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
171.8, 144.6, 128.2
D
d
7.25 (br d, J ¼ 8.6 Hz, 2H), 6.85 (br d, J ¼ 8.6 Hz, 2H), 4.10
(2C), 127.3 (2C), 127.2, 79.9, 59.7, 55.6, 27.7 (3C), 27.1, 21.8, 17.0; IR
(CHCl3): 3030, 2966, 2933, 2875, 1714, 1580, 1492, 1456, 1392, 1367,
1290, 1247, 1151, 1087 cmꢀ1; MS (EI, 20 eV) m/z: 263 (Mþ, 2), 206
(23), 190 (1.2), 164 (4), 146 (0.6), 106 (100); HRMS calcd for
(d, J ¼ 7.0 Hz, 1H), 3.80 (s, 3H), 2.60 (quint, J ¼ 7.0 Hz, 1H), 1.58 (br s,
2H), 1.29 (s, 9H), 1.16 (d, J ¼ 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d
174.4, 158.7, 136.1, 127.9 (2C), 113.5 (2C), 80.1, 57.3, 55.3, 48.3, 27.9
C
C
16H25NO2 (Mþ): 263.1885, found 263.1887; Anal. Calcd for
16H25NO2: C, 72.96; H, 9.57; N, 5.32. Found: C, 72.85; H, 9.78; N,
(3C), 12.8; IR (CHCl3): 3037, 3014, 1716, 1600, 1514, 1238, 1224,1209,
1195, 1153 cmꢀ1; MS (CI) m/z: 266 (MþþH, 7); HRMS calcd for
C
15H24NO3 (MþþH): 266.1756, found 266.1752.
5.31.
4.3.6. (2S,3S)-tert-Butyl 3-amino-3-(furan-2-yl)-2-
4.3.11. (2S,3S)-tert-Butyl 3-amino-2,3-diphenylpropanoate (4l)
Pale yellow crystals (hexane-ethyl acetate); mp 86e87 ꢁC
methylpropanoate (4f)
25
þ10.8 (c ¼ 0.48, CHCl3); 1H NMR (400 MHz,
22
(hexane-ethyl acetate); [
(400 MHz, CDCl3):
a
]
D
- 9.51 (c ¼ 1.40, CHCl3); 1H NMR
Colorless oil; [
CDCl3):
a
]
D
d
7.25 (dd, J ¼ 1.8, 0.8 Hz, 1H), 6.30 (dd, J ¼ 3.2, 1.8 Hz, 1H),
d
7.51 (br d, J ¼ 7.6 Hz, 2H), 7.45 (br d, J ¼ 7.6 Hz,
6.17 (dt, J ¼ 3.2, 0.8 Hz, 1H), 4.25 (d, J ¼ 5.7 Hz, 1H), 2.79 (dq, J ¼ 7.1,
2H), 7.39e7.25 (m, 6H), 4.47 (d, J ¼ 10.0 Hz, 1H), 3.70 (d, J ¼ 10.0 Hz,
5.7 Hz, 1H), 1.62 (br s, 2H), 1.41 (s, 9H), 1.14 (d, J ¼ 7.1 Hz, 3H); 13C
1H), 1.49 (br s, 2H), 1.13 (s, 9H); 13C NMR (100 MHz, CDCl3):
d
171.1,
NMR (100 MHz, CDCl3):
d 174.0, 156.8, 141.3, 110.0, 105.4, 80.5, 51.9,
142.9, 136.8, 128.74 (2C), 128.70 (2C), 128.3 (2C), 127.7, 127.6 (3C),
80.7, 61.5, 59.2, 27.6 (3C); IR (CHCl3): 3031, 2981, 2931, 1718, 1585,
1494, 1454, 1369, 1288, 1255, 1147 cmꢀ1; MS (EI, 70 eV) m/z: 297
(Mþ, 0.1), 240 (3), 196 (1), 106 (100), 91 (2), 77 (2); HRMS calcd for
45.4, 27.9 (3C), 12.1; IR (CHCl3): 2983, 2962, 2933, 2862, 1720, 1602,
1506, 1456, 1369, 1288, 1153, 1074, 1010 cmꢀ1; MS (CI) m/z: 226
(MþþH, 38); HRMS calcd for C12H20NO3 (MþþH): 226.1443, found
226.1448.
C
C
19H23NO2 (Mþ): 297.1729, found 297.1724; Anal. Calcd for
19H23NO2: C, 76.73; H, 7.80; N, 4.71. Found: C, 76.52; H, 7.69; N,
4.3.7. (2S,3S)-tert-Butyl 3-amino-2-methyl-3-(thiophen-2-yl)
4.73.
propanoate (4g)
Colorless oil; [
CDCl3):
23
a]
þ19.3 (c ¼ 1.11, CHCl3); 1H NMR (400 MHz,
Acknowledgment
D
d
7.19 (dd, J ¼ 4.8, 1.5 Hz, 1H), 6.95e6.92 (m, 2H), 4.50 (d,
J ¼ 5.9 Hz, 1H), 2.71 (dq, J ¼ 7.0, 5.9 Hz, 1H), 1.70 (br s, 2H), 1.38 (s,
This research was financially supported in part by the MEXT-
Supported Program for the Strategic Research Foundation at Pri-
vate Universities, JSPS KAKENHI Grant Number JP22590024 and a
Strategic Research Foundation Grant-in-Aided Project for Private
Universities from the Ministry of Education, Culture, Sports, Sci-
ence, and Technology of Japan (MEXT) Grant Number S1511024L.
9H), 1.19 (d, J ¼ 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 174.2,
148.7, 126.7, 124.0, 123.8, 80.7, 53.9, 48.6, 28.1 (3C), 12.5; IR (CHCl3):
3687, 2972, 2935, 1718, 1600, 1519, 1456, 1369, 1353, 1255, 1217,
1155 cmꢀ1; MS (CI) m/z: 242 (MþþH, 30); HRMS calcd for
C
12H20NO2S(MþþH): 242.1215, found 242.1208.
4.3.8. (2S,3S)-tert-Butyl 3-amino-2-ethyl-3-phenylpropanoate (4i)
Appendix A. Supplementary data
þ10.8 (c ¼ 1.05, CHCl3); 1H NMR (400 MHz,
25
Colorless oil; [
CDCl3):
a
]
D
d
7.34e7.21 (m, 5H), 4.01 (d, J ¼ 8.4 Hz, 1H), 2.46 (ddd,
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2017.02.037.
J ¼ 10.8, 8.4 and 3.7 Hz, 1H), 1.83e1.62 (m, 2H), 1.58 (br s, 2H), 1.20
(s, 9H), 0.94 (t, J ¼ 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d 173.5,
144.1, 128.2 (2C), 127.2, 127.1 (2C), 80.1, 58.0, 56.4, 27.7 (3C), 22.2,
11.9; IR (CHCl3): 3689, 3045, 3018, 2968, 2877, 1716, 1602, 1525,
1456, 1367, 1251, 1153, 1047 cmꢀ1; MS (CI) m/z: 250 (MþþH, 45);
HRMS calcd for C15H24NO2 (MþþH): 250.1807, found 250.1803.
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18 ꢀ 30.3 (c ¼ 0.68, CHCl3) (lit. [
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]
25 - 28.5, c ¼ 1.12
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]
D
D
in CHCl3)4c
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7.38e7.29 (m, 4H),
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(dd, J ¼ 13.0, 3.5 Hz, 1H), 2.96e2.82 (m, 2H), 1.66 (br s, 2H), 1.01 (s,
9H); 13C NMR (100 MHz, CDCl3):
d 172.8, 143.7, 139.4, 129.0 (2C),
128.3 (2C), 128.1 (2C), 127.3, 127.1 (2C), 126.1, 80.2, 58.2, 56.3, 35.1,
27.5 (3C); IR (CHCl3): 3030, 2978, 2931, 1714, 1602, 1494, 1454, 1392,
Please cite this article in press as: Ozeki M, et al., Novel and practical asymmetric synthesis of
addition of chiral amine, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.02.037
b
2,3-amino esters using asymmetric Michael

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addition of chiral amine, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.02.037
b
2,3-amino esters using asymmetric Michael