Access to β2-Amino Acids via Enantioselective 1,4-Arylation of β-Nitroacrylates Catalyzed by Chiral Rhodium Catalysts

Article abstract of DOI:10.1021/acs.joc.8b00586

The highly enantioselective conjugate addition of a variety of arylboronic acids to β-nitroacrylates is reported to provide optically active α-aryl β-nitropropionates in up to 70% yields and >99.5% ee's, which are useful building blocks for preparing chiral β²-amino acids. The applicability of this transformation is demonstrated by converting 3aa into the β²-amino acid 5 and transforming 3ap to β-amino ester 7 via reduction and reductive N-alkylation. The latter compound is a precursor for preparing ent-ipatasertib.

Full text of DOI:10.1021/acs.joc.8b00586

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Note
Access to #2-Amino Acids via Enantioselective 1,4-Arylation
of #–Nitroacrylates Catalyzed by Chiral Rhodium Catalysts
Jia-Hong Jian, Chih-Lung Hsu, Jin-Fong Syu, Ting-Shen
Kuo, Ming-Kang Tsai, Ping-Yu Wu, and Hsyueh-Liang Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00586 • Publication Date (Web): 29 Aug 2018
Downloaded from http://pubs.acs.org on August 30, 2018
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The Journal of Organic Chemistry
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Access to
b
2-Amino Acids via Enantioselective 1,4-Arylation of
b
–Ni-
troacrylates Catalyzed by Chiral Rhodium Catalysts
a
a
a
a
a
b
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Jia-Hong Jian, Chih-Lung Hsu, Jin-Fong Syu, Ting-Shen Kuo, Ming-Kang Tsai, Ping-Yu Wu and
a,
Hsyueh-Liang Wu *
aDepartment of Chemistry, National Taiwan Normal University, No. 88, Section 4, Tingzhou Road, Taipei 11677, Taiwan
bOleader Technologies, Co., Ltd., 1F., No. 8, Aly. 29, Ln. 335, Chenggong Rd., Hukou Township 30345, Hsinchu, Taiwan
Supporting Information Placeholder
Rh (I)/L2a
3.0 mol % of Rh)
(
CO
2
R
Ph
CO
2
R
2
O N
H
N
+
ArB(OH)
2
Ph
O
2
N
KOH (10 mol %)
toluene, 60 °C, 24 h
Ar
21 examples
O
36–70% yield
0–>99.5% ee
L2a
9
ABSTRACT: The highly enantioselective conjugate addition of a variety of arylboronic acids to β-nitroacrylates is reported to pro-
vide optically active α-aryl β-nitropropionates in up to 70% yields and >99.5% ee’s, which are useful building blocks for preparing
chiral β -amino acids. The applicability of this transformation is demonstrated by converting 3aa into the β -amino acid 5 and trans-
forming 3ap to β-amino ester 7 via reduction and reductive N-alkylation. The latter compound is a precursor for preparing ent-
ipatasertib.
2
2
4
a,b
The synthesis of chiral β-amino acids and derivatives thereof
has attracted a great deal of interest since they are crucial seg-
ments in numerous naturally occurring compounds of biologi-
cal interest. Amidst chiral β-amino acids, β -amino acids (α-
substituted-β-amino acids) are common building blocks in nat-
ural products and bioactive molecules (Figure 1). For example,
bishyoscyamine (1a), an alkaloid isolated from Anisodus
exhibited inhibitory activity against viral infections and to
have a specific affinity to the human somatostatin receptor 4
1
4c
(hsst4) at the nano-molar level.
2
2
2
While the diastereoselective synthesis of β -amino esters has
been previously reported, these preparations involved the ami-
5
6a
6b
nomethylation of aldehydes and enals, respectively.Further-
more, the Rh-carbenoid induced C–H activation of N-substi-
tuted methylamines and their insertion into aryldiazoesters re-
3
a
acutangulus, has an unusual dimeric tropane structure.
2
6c
sulted in the one pot production of β -amino esters. While the
2
R
*
OH
catalytic asymmetric hydrogenation of β -enamides directly
H2N
OH
2
6d
N
provided optically active β -amino acids, the enantioselective
O
O
N
6e
O
O
hydrogenation of a-phthalimidylmethyl acrylates and a-ami-
O
Me
6
f,g
2
2
nomethyl acrylates readily gave rise to enantio-enriched β -
amino esters. Chiral β -amino esters also can be synthesized by
reducing the nitro group of α-substituted β-nitropropionates,
which can be obtained by asymmetric transfer hydrogenation,
chiral β -amino acid
bishyoscyamine (1a)
2
Cl
N
N
N
6h
N
OH
H
N
6i
1
0
9
H
N
or the hydrogenation of α-substituted β-nitroacrylates.
N
HO2C
O
Since chiral α-substituted β-nitropropionates are crucial build-
ing blocks for the preparation of β -amino acids and also appear
to be cytotoxic, the development of an efficient synthetic route
to α-substituted β-nitropropionates would be highly desirable.
We envisaged that the asymmetric conjugate addition of carbon
nucleophiles to prochiral β-nitroacrylates would offer a conven-
ient and convergent access to α-chiral β-nitropropionates. In
fact, the Cu(I)-catalyzed conjugate addition of dialkylzincs
and trialkylaluminiums to β-nitroacrylates and the Pd(II)-
nakinadine B (1b), C H2–C10H2
nakinadine C (1c), cis C H=C10H
9
ipatasertib (1d)
2
9
7a
2
Figure 1. Compounds containing β -amino acid moieties.
Nakinadines B (1b) and C (1c), which were isolated from the
Okinawa marine sponge, Amphimedon sp. (SS-1059), were re-
ported to show moderate in vitro cytotoxicity toward KB human
epidermoid carcinoma and L1210 murine leukemia cells. Ipa-
tasertib (1d) is an Akt inhibitor that is currently in clinical tri-
7b
3
b
7c
7d
catalyzed enantioselective arylation of β-nitroacrylamides
3
c
2
als. In addition, b-peptides comprised of β -amino acids
gave
2-substituted-3-nitropropion-ates
and
-amides,
1
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2
respectively, that were readily transformed into β -amino acids.
17
NaHCO
3
L2a
L2a
L3
47
42
96
96
8
,9
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
In our recent studies, a chiral Rh(I)/L1 catalyst was found to
have a high catalytic activity and enantioselectivity in the ary-
lation of β-nitroolefins (S/C up to 1000). More recently, the
same catalytic system was used for the enantioselective aryla-
tion of α-substituted β-nitroacrylates to access chiral β -amino
acids. While β-nitroolefins and α-substituted β-nitroacry-
lates were applicable acceptors in the Rh-catalyzed conjugate
addition reactions, the asymmetric arylation of β-nitroacry-
18
K
2
CO
3
8
c
19
20
21
22
23
KOH
KOH
KOH
KOH
KOH
58
–65
–17
N.D.
N.D.
N.D.
L4
20
2
,2
L5
N.R.
N.R.
N.R.
8
g
10
8
g
L6
11
L7
lates resulted in only moderate asymmetric induction when the
diene ligand L1 was used (Table 1, entry 1). At the same time,
we also reported that chiral dienes L2, possessing an extra am-
aSolutions of 1a (0.2 mmol), 2a (0.4 mmol, 2.0 equiv),
RhCl(C (1.5 mol %), L (3.6 mol %) and aq KHF (3.0 M,
.4 mL, 1.2 mmol) were stirred in toluene (1.0 mL) at 60 °C for 24
8g
[
0
2
H
4
)
2
]
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ide group, were effective ligands in achieving the highly selec-
b
h. For other additives: 0.1 M, 0.2 mL, 0.02 mmol. Isolated yield.
9
c
tive arylation of N-DPP (diphenylphosphonyl) imines, as a re-
sult of the hydrogen bond donor ability of the amide group.
Hence, we envisioned that hydrogen bond interactions between
1
N.R. denotes “no reaction” as judged by the H NMR analysis of
c
the crude products. Determined by HPLC analysis. N.D. denotes
d
e
“not determined.” At 40 °C. 10% of 1a was left by analyzing the
1
f
g
h
the NO
2
groups of nitroacrylates and the N−H bond of the chiral
crude H NMR spectrum. At 80 °C for 12 h. At 40 °C in ether. At
40 °C in CH Cl
diene ligand L2 would improve catalytic activity and enhance
2
2
.
the degree of asymmetric induction associated with the conju-
12
Initial investigations involved the conjugate addition of tert-bu-
tyl nitroacrylate 1a with phenylboronic acid (2a) (Table 1).
While the desired product was not observed when the reaction
was carried out in the presence of 3 mol % of Rh(I)/L2a under
optimal reaction conditions for α-substituted β-nitroacrylates
gate addition to β-nitroacrylates catalyzed by Rh(I)/L2 cata-
lysts, and we herein report our findings.
a
Table 1. Optimization of Reaction Conditions
(entry 2), the desired product 3aa was obtained in 45% yield
Rh(I)/L (3.0 mol % of Rh)
2
CO tBu
CO
2
tBu
+
PhB(OH)
2
2
O N
O
2
N
and 90% ee when KHF was replaced with KOH (entry 3). Con-
2
additive (10 mol %)
toluene, 60 °C, 24 h
Ph
ducting the reaction at 60 °C gave 3aa in a gratifying 70% yield
and 93% ee (entry 4), whereas the stereoselectivity decreased
with the reaction run at 80 °C (entry 5). A subsequent ligand
study revealed that, while high asymmetric induction was ob-
served using both L2a and L2b, which were derived from (R)-
and (S)-1-phenylethylamine respectively (entries 4 and 6), chi-
ral diene ligands with N-benzyl (L2c), N-1-naphthylmethyl
1
a
2a
3
aa
L2a, R2 = H; R3 = (R)-1-Phenylethyl
L2b, R2 = H; R3 = (S)-1-Phenylethyl
L2c, R2 = H; R3 = C
H CH
6 5 2
Ph
Ar
L2d, R2 = H; R3 = 1-Naphthylmethyl
L2e, R2 = H; R3 = 2-Naphthylmethyl
O
L2f, R2 = H; R3 = tBu
Ar
2
NR R3
L2g, R2 = Et; R3 = Et
L1, Ar = 1-Naphthyl
L2h, R2 = Me; R3 = (R)-1-Phenylethyl
(L2d), N-2-naphthylmethyl (L2e), and N-tBu (L2f) amides
Ph
were found to be less efficient, giving 3aa in 24–50% yield and
85–91% ee (entries 7–10). Conducting the asymmetric reaction
with the N,N-diethyl amide ligand L2g and L2h, which is the
N-Me analogue of L2a, provided compound 3aa in 74% ee and
Ph
H
Ph
O
PPh
PPh
2
L3
S
Ph
N
H
tBu
2
MeO
Me
H
Ph
80% ee, respectively (entries 11 and 12), indicating the signifi-
Ph
L5
L6
L7
iPr
cance of hydrogen bond activation. The ensuing optimization
with respect to solvents and additives resulted in no improve-
ment in both catalytic reactivity and enantioselectivity (entries
13–18). This asymmetric transformation was also tested using
chiral ligands that are known to be efficient in Rh(I)-catalyzed
conjugate addition reactions. While chiral bicyclo[2.2.2]octadi-
L4
yield (%)b
ee (%)c
entry
1
additive
KOH
L
L1
31
N.R.
45
70
68
50
24
45
50
26
73
53
24
36
48
48
83
N.D.
90
93
90
93
86
85
88
91
74
80
96
70
92
96
2d
3d
4e
5f
6
KHF
L2a
L2a
L2a
L2a
L2b
L2c
L2d
L2e
L2f
L2g
L2h
L2a
L2a
L2a
L2a
2
1
3a
13b
ene L3 and L4 gave 3aa in moderate yield and ee (entries
9 and 20), no reaction was observed in the presence of chiral
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
LiOH
NaOH
1
13c
diene L5, which has a bicyclo[3.3.0] framework (entry 21).
Similarly, the use of BINAP (L6, entry 22) and the sulfoxide-
olefin hybrid ligand L7 resulted in no desired product being
13d
13e
produced (entry 23).
7
Table 2 summaries the outcome of asymmetric reactions of as-
sorted arylboronic acids 2 with acceptors 1 under optimal reac-
tion conditions that were presented in Table 1, entry 4. The use
of methoxy-substituted phenylboronic acids (2b–2d) afforded
enantio-enriched adducts 3ab–3ad in 91–98% ee’s and in 44–
56% yields (entries 2–4). Similar results were observed when
tolylboronic acids (2e–2g), 4-tBu-phenylboronic acid (2h) and
4-biphenylboronic acid (2i) were used, producing adducts in
45–65% yields with 90–98% ee (entries 5–9). A single X-ray
crystal analysis of 3ai permitted the absolute configuration of
8
9
1
1
1
0
1
2
1
3g
14h
1
1
5
6
14
newly formed chiral center to be determined as R. 1-Naphthyl-
and 2-naphthyl-boronic acids (2j and 2k) were also applicable
2
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e
in this asymmetric reaction, giving the corresponding adducts
3aj and 3ak in 65% and 45% yields with 93% and 94% ee, re-
spectively (entries 10 and 11). While the steric hindrance of or-
reactions, respectively. An additional 3 mol % of Rh/L2a catalyst
was added after 6 h.
1
2
3
4
5
6
7
8
9
The conversion of 3aa into the corresponding amino acid fur-
ther confirmed the utility of this method (Scheme 1). The hy-
drogenation of 3aa in the presence of Pd/C proceeded
smoothly to give the amino ester 4, which was subsequently hy-
drolyzed in aq HCl to produce the β -amino acid 5 in 67% over
2 steps. This method was also applicable for the preparation of
a known precursor in the synthesis of an enantiomeric isomer
of ipatasertib (Scheme 2).
3
tho-CF substituent caused the chemical yield of compound 3al
to be decreased (entry 12), good chemical yields and high se-
lectivity were found in the cases of its meta- and para-conge-
ners (2m and 2n in entries 13 and 14, respectively). Fluoro-,
chloro- and dichloro-substituted phenylboronic acids are good
reactions partners, providing addition products in 51–63%
yields with 95–98% ee (entries 15–17). The scope of this
method was further extended to acceptors with iPr (1b) and Bn
6h
2
3c,6d
The nitro group of 3ap was re-
15
duced by means of Zn/HOAc to furnish the amine which after
a reductive N-alkylation reaction [acetone / NaBH(OAc) ],
3
gave a 38% yield of the amino ester 7 in a 2-step operation.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(1c) ester groups, which resulted in the formation of the corre-
6d
sponding products in 42–64% yield and 92–97% ee (entries 18–
2
3
21).
Table 2. Substrate Scope in Rh(I)/L2a-Catalyzed Asymmet-
ric Conjugate Addition Reaction
2
Scheme 1. Synthesis of β -amino acid 5
a
CO
2
tBu
CO
2
tBu
2
CO H
O
2
N
H
2
N
2
H N
Rh (I)/L2a
3.0 mol % of Rh)
Pd/C, H2
6 N HCl
(
2
CO R
2
CO R
2
O N
+
ArB(OH)
2
MeOH, rt, 12 h
67% after 2 steps
2
O N
9
3% ee
KOH (10 mol %)
Ar
toluene, 60 °C, 24 h
3aa
3% ee
4
5
1
1
1
a : R = tBu
b : R = iPr
c : R = Bn
2
3
9
Scheme 2. Synthesis of the ent-ipatasertib precursor 7
CO
2
tBu
2
CO tBu
O
2
N
H
2
N
2
CO tBu
NaBH(OAc)
Acetone
3
N
H
Zn dust, HOAc
MeOH, 3 h
ee
(%)
entry
1d
1
Ar (2)
yield (%)b
c
2 2
CH Cl , 12 h
8% after 2 steps
3
Cl
ap
Cl
95% ee
Cl
7
70
3
6
1a
C
6
H
5
(2a)
(52)(55)
93
95% ee
ref 6d
(3aa)
ent-ipatasertib
2e
3
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1c
2-MeO-C
3-MeO-C
4-MeO-C
2-Me-C
3-Me-C
4-Me-C
4-tBu-C
4-Ph-C
H
(2b)
(2c)
(2d)
44 (3ab)
56 (3ac)
48 (3ad)
63 (3ae)
54 (3af)
45 (3ag)
65 (3ah)
57 (3ai)
65 (3aj)
45 (3ak)
36 (3al)
61 (3am)
67 (3an)
63 (3ao)
51 (3ap)
51 (3aq)
64 (3ba)
59 (3bj)
43 (3bn)
42 (3ca)
98
94
91
95
92
90
95
98
93
94
6
4
6
H
4
The stereochemical outcome was illustrated, in Figure 2, by car-
16
4
6
H
4
rying out DFT calculations using Gaussian 16 program using
17,18
19
hybrid B3LYP functional
in conjunction with 6-31G (d,p)
5
6
H
4
(2e)
(2f)
(2g)
(2h)
(2i)
20
for the main group elements and LAN2LDZ basis set for the
Rh atom using toluene and the integral equation formalism var-
6
6 4
H
21
7
8e
6
H
4
iant of the polarizable continuum model (IEFPCM). The re-
sults identified that the observed asymmetric reaction could be
facilitated favorably via complex 8a, in which the tert-butyl ni-
troacrylate 1a was coordinated with the Rh-L2a-phenyl species
via Re-face, by 4.6 kcal lower in energy than the corresponding
Si-faced-coordinated complex 8b. The steric repulsion between
tert-butyl ester group and substituents of ligand backbone and
the nitro group being hydrogen-bonded with the amide substit-
6
H
4
9
6 4
H
1
1
0
1
1-Naphthyl (2j)
2-Naphthyl (2k)
12e
2-CF
-C
-C
-C
H
4
(2l)
(2m)
(2n)
>99.5
98
3
6
12j
1
1
1
1
3
4
5
6
3-CF
3
6
H
4
uent accounted for the observed stereochemistry from Re-face
4-CF
3
6
H
4
98
addition.
4-F-C
4-Cl-C
3,4-Cl -C
6
H
4
(2o)
(2p)
96
6
H
4
95
17
2
6
H
3
(2q)
(2a)
1-Naphthyl (2j)
4-F-C (2n)
(2a)
98
ꢀ ꢂ
ꢁ
2
CO tBu
H
1
1
2
2
8
9
0
1
C
6
H
5
93
97
−1
−1
8
a (0.0 kcal mol )
8b (+4.6 kcal mol )
6
H
4
96
C
6
H
5
92
Figure 2. DFT-optimized putative transition structures for the
asymmetric reaction to 1a.
aSolutions of 1 (0.2 mmol), 2 (0.4 mmol, 2.0 equiv),
[RhCl(C (1.5 mol %), L2a (3.6 mol %) and aq KOH (0.1 M,
0.2 mL, 0.02 mmol) were stirred in toluene (1.0 mL) at 60 °C for
4 h. Isolated yield. Determined by HPLC analysis. Data in pa-
renthesis was obtained from 2 mmole and 5.8 mmole (1.0 g) scale
2
4 2 2
H ) ]
In summary, a highly enantioselective arylation of β-nitroacry-
lates was realized for the first time in the presence of Rh(I)-
catalyst derived from the chiral diene ligand L2a. This method
tolerated a variety of arylboronic acids as nucleophile donors
and β-nitroacrylates as electrophiles, with addition products
b
c
d
2
3
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The Journal of Organic Chemistry
Page 4 of 9
being produced in up to 70% yield and >99.5% ee. The syn-
thetic application of this asymmetric transformation was
demonstrated by synthesizing β -amino acid 5 and β -amino es-
ter 7, a potential precursor for use in the synthesis of ent-ipa-
tasertib.
mL/min; retention times: 10.51 min [(R)-enantiomer], 12.27
26
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
min [(S)-enantiomer]. 98% ee. [α] +77.1 (c 1.00, CHCl
0
3
). R
.17 (hexanes / ethyl acetate, 20 / 1). H NMR (400 MHz,
CDCl ): δ 7.32–7.26 (m, 1H), 7.15 (dd, J = 7.6, 1.6 Hz, 1H),
f
D
2
2
1
3
6.96–6.86 (m, 2H), 4.97 (dd, J = 14.4, 9.2 Hz, 1H), 4.64 (dd, J
= 9.2, 5.2 Hz, 1H), 4.47 (dd, J = 14.4, 5.2, Hz, 1H), 3.83 (s, 3H),
Experimental section
General information
1
3
1
1
.43 (s, 9H). C NMR (100 MHz, CDCl
29.6, 129.3, 122.8, 120.9, 110.8, 82.0, 74.8, 55.3, 44.9, 27.8.
2979, 2363, 1729, 1556, 1495, 1460, 1370,
251, 1153 cm . HRMS (EI/Magnetic Sector): m/z calcd for
3
): δ 169.9, 156.7,
All commercial chemicals and solvents were reagent grade and
were distilled before use. All reactions were carried out under
an atmosphere of argon or nitrogen gas. Reactions were moni-
tored by TLC using Merck 60 F 254 silica gel plates; zones were
detected visually under ultraviolet irradiation (254 nm) or by
FT-IR (KBr, neat): ν
̃
−1
1
C
+
+
14
H19NO
5
[M] 281.1263, found 281.1265.
2-(3-methoxyphenyl)-3-nitropropanoate
3ac). Isolated as a colorless oil: 31.6 mg, 56% yield. The ee
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(R)-tert-butyl
(
4
spraying with KMnO solution followed by heating with a heat
was determined on a Daicel Chiralpak IB column (250 mm);
detected at 220 nm; hexanes / 2-propanol, 90 / 10; flow = 1.0
gun or on a hot plate. Column chromatography was conducted
over silica gel. NMR spectra were recorded at room temperature
in deuterated solvents on Bruker spectrometers. Chemical shifts
δ were recorded in parts per million (ppm) and were reported
mL/min; retention times: 7.31 min [(R)-enantiomer], 20.93 min
26
[
(S)-enantiomer]. 94% ee. [α] +55.6 (c 1.00, CHCl
3
). R
f
0.17
D
1
1
3
(hexanes / ethyl acetate, 20 / 1). H NMR (400 MHz, CDCl ): δ
3
relative to the deuterated solvent signal for C NMR spectros-
1
1
7.27 (dd, J = 8.0, 7.6 Hz, 1H), 6.89–6.77 (m, 3H), 5.02 (dd, J =
copy, the residual H-solvent signal for H NMR spectroscopy.
First order spin multiplicities are abbreviated as singlet (s), dou-
blet (d), doublet of doublets (dd), septet (sep), and mutiplets are
abbreviated as (m). High-resolution mass spectra were obtained
using EI, ESI and FAB ionization methods. Optical rotations
were measured on a Jasco P-2000 polarimeter. Enantiomeric
excess was determined by HPLC analysis on a Chiralcel OD-H,
or OJ-H and Chiralpak AD-H, or IB columns (Daicel Chemical
Industries, Ltd). Substrates 1 were prepared according to the lit-
1
4.4, 10.4 Hz, 1H), 4.47 (dd, J = 14.4, 4.8 Hz, 1H), 4.29 (dd, J
1
3
= 10.4, 4.8 Hz, 1H), 3.80 (s, 3H), 1.42 (s, 9H). C NMR (100
MHz, CDCl ): δ 169.4, 160.0, 135.2, 130.2, 119.9, 113.7, 113.6,
82.5, 75.9, 55.2, 49.6, 27.8. FT-IR (KBr, neat): ν 2982, 1727,
3
̃
−1
1
601, 1586, 1556, 1492, 1371, 1258, 1219 cm . HRMS
+
+
(EI/Magnetic Sector): m/z calcd for C14
H
19NO
5
[M] 281.1263,
found 281.1263.
(R)-tert-butyl
2-(4-methoxyphenyl)-3-nitropropanoate
2
2
erature. Boronic acids 2 that were commercially available
(3ad). Isolated as a colorless oil: 27.0 mg, 48% yield. The ee
was determined on a Daicel Chiralpak IB column (250 mm);
detected at 220 nm; hexanes / 2-propanol, 90 / 10; flow = 1.0
were used as supplied and/or were prepared using methods re-
2
3
ported in the literature. Chiral diene ligands L2 were prepared
8
a
according to the reported procedure.
The following procedures were followed for the Rh-catalyzed
asymmetric reactions: Under N atmosphere, to a mixture of
RhCl(C (1.2 mg, 3.1 µmol, 3.0 mol % of Rh), chiral lig-
and L2d (2.58 mg, 7.2 µmol, 3.6 mol %), (E)-nitroacrylate 1
0.2 mmol, 1.0 equiv) and arylboronic acid 2 (0.4 mmol, 3.0
equiv) were added toluene (1.0 mL) and aqueous KOH (0.1 M,
.2 mL, 0.02 mmol, 0.1 equiv). The resulting mixture was
mL/min; retention times: 9.17 min [(R)-enantiomer], 14.32 min
26
[(S)-enantiomer]. 91% ee. [α]
(hexanes / ethyl acetate, 20 / 1). H NMR (400 MHz, CDCl
3 f
+55.7 (c 1.00, CHCl ). R
0.17
): δ
D
1
2
3
[
2
H
4
)
2
]
2
7.18 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 4.99 (dd, J =
14.4, 10.0 Hz, 1H), 4.46 (dd, J = 14.4, 5.2 Hz, 1H), 4.26 (dd, J
13
(
= 10.0, 5.2 Hz, 1H), 3.80 (s, 3H), 1.41 (s, 9H). C NMR (100
MHz, CDCl
55.3, 48.9, 27.8. FT-IR (KBr, neat): ν
3
): δ 169.8, 159.6, 128.9, 125.8, 114.6, 82.4, 76.1,
2979, 1725, 1610, 1556,
1513, 1369, 1303, 1252, 1152 cm . HRMS (EI/Magnetic Sec-
0
̃
−
1
heated to 60 °C for 24 h and the product mixture was concen-
trated in vacuo and the residue was purified by column chroma-
tography over silica gel (hexanes / ethyl acetate = 20 / 1) to af-
ford the desired products 3.
+
+
tor): m/z calcd for C14
5
H19NO [M] 281.1263, found 281.1265.
(R)-tert-butyl 3-nitro-2-(o-tolyl)propanoate (3ae). Isolated as
a colorless oil: 33.5 mg, 63% yield. The ee was determined on
a Daicel Chiralpak IB column (250 mm); detected at 220 nm;
hexanes / 2-propanol, 90 / 10; flow = 1.0 mL/min; retention
times: 6.85 min [(R)-enantiomer], 17.57 min [(S)-enantiomer].
(R)-tert-butyl 3-nitro-2-phenylpropanoate (3aa). Isolated as
a colorless oil: 35.2 mg (0.2 mmol scale), 70% yield; 137 mg
(1.0 mmol), 52% yield. The ee was determined on a Daicel Chi-
2
6
ralpak IB column (250 mm) with hexanes / 2-propanol = 90 /
95% ee. [α] +75.9 (c 1.00, CHCl ). R 0.3 (hexanes / ethyl ac-
D
3
f
1
1
6
0, flow = 1.0 mL/min, wavelength = 220 nm. Retention times:
etate, 20 / 1). H NMR (400 MHz, CDCl
3
): δ 7.24–7.12 (m, 4H),
.61 min [(R)-enantiomer], 9.47 min [(S)-enantiomer]. 93% ee.
5
.03 (dd, J = 14.4, 10.0 Hz, 1H), 4.62 (dd, J = 10.0, 4.8 Hz, 1H),
28
13
[
α] +131.9 (c 1.00, CHCl
0 / 1). H NMR (400 MHz, CDCl
.24 (m, 2H), 5.03 (dd, J = 14.8, 10.0 Hz, 1H), 4.49 (dd, J =
4.8, 5.2 Hz, 1H), 4.32 (dd, J = 10.0, 5.2 Hz, 1H), 1.41 (s, 9H).
C NMR (100 MHz, CDCl
3
). R
f
0.22 (hexanes / ethyl acetate,
): δ 7.39–7.29 (m, 3H), 7.28–
4.42 (dd, J = 14.4, 4.8 Hz, 1H), 2.44 (s, 3H), 1.40 (s, 9H).
NMR (100 MHz, CDCl ): δ 169.9, 136.4, 132.4, 131.2, 128.2,
126.7, 126.4, 82.4, 75.2, 45.4, 27.8, 19.6. FT-IR (KBr, neat): ν
2979, 1727, 1556, 1370, 1253, 1152 cm . HRMS (EI/Magnetic
Sector): m/z calcd for C14
C
D
1
2
7
1
3
3
̃
−1
13
+
+
): δ 169.5, 133.9, 129.2, 128.4,
2980, 1726,
1556, 1370, 1254, 1210, 1152 cm . HRMS (FAB/Magnetic
H
19NO
4
[M] 265.1314, found
3
1
27.6, 82.5, 75.9, 49.7, 27.8. FT-IR (KBr, neat): ν
̃
265.1313.
−1
(R)-tert-butyl 3-nitro-2-(m-tolyl)propanoate (3af). Isolated
+
+
4
Sector): m/z calcd for C13H18NO [M + H] 252.1236, found
as a colorless oil: 28.7 mg, 54% yield. The ee was determined
on a Daicel Chiralpak IB column (250 mm); detected at 220 nm;
hexanes / 2-propanol, 90 / 10; flow = 1.0 mL/min; retention
times: 5.36 min [(R)-enantiomer], 7.52 min [(S)-enantiomer].
252.1235.
(R)-tert-butyl
2-(2-methoxyphenyl)-3-nitropropanoate
(3ab). Isolated as a colorless oil: 24.8 mg, 44% yield. The ee
was determined on a Daicel Chiralcel OJ-H column (250 mm);
detected at 220 nm; hexanes / 2-propanol, 90 / 10; flow = 1.0
2
6
92% ee. [α] +59.0 (c 1.00, CHCl ). R 0.3 (hexanes / ethyl ac-
3
f
D
1
3
etate, 20 / 1). H NMR (400 MHz, CDCl ): δ 7.25–7.21 (m, 1H),
4
ACS Paragon Plus Environment

Page 5 of 9
The Journal of Organic Chemistry
7
.13 (d, J = 7.6 Hz, 1H), 7.06–7.03 (m, 2H), 5.02 (dd, J = 14.4,
126.2, 125.4, 125.3, 122.4, 82.7, 75.5, 45.4, 27.8. FT-IR (KBr,
−1
1
2
3
4
5
6
7
8
9
10.0 Hz, 1H), 4.46 (dd, J = 14.4, 4.8 Hz, 1H), 4.28 (dd, J = 10.0,
neat): ν̃ 2978, 1726, 1556, 1513, 1370, 1254, 1153 cm . HRMS
1
3
+
+
4.8 Hz, 1H), 2.35 (s, 3H), 1.42 (s, 9H). C NMR (100 MHz,
CDCl ): δ 169.6, 139.0, 133.7, 129.15, 129.05, 128.5, 124.7,
2.4, 76.0, 49.6, 27.8, 21.3. FT-IR (KBr, neat): ν 2981, 1726,
556, 1370, 1252, 1150 cm . HRMS (EI/Magnetic Sector): m/z
4
(EI/Magnetic Sector): m/z calcd for C17H19NO [M] 301.1314,
3
found 301.1315.
8
1
̃
(R)-tert-butyl 2-(naphthalen-2-yl)-3-nitropropanoate (3ak).
Isolated as an off-white solid: 27.2 mg, 45% yield. The ee was
determined on a Daicel Chiralpak AD-H column (250 mm); de-
tected at 220 nm; hexanes / 2-propanol, 90 / 10; flow = 1.0
mL/min; retention times: 9.36 min [(S)-enantiomer], 10.16 min
−1
+
+
4
calcd for C14H19NO [M] 265.1314, found 265.1316.
(R)-tert-butyl 3-nitro-2-(p-tolyl)propanoate (3ag). Isolated as
a colorless oil: 23.9 mg, 45% yield. The ee was determined on
a Daicel Chiralpak IB column (250 mm); detected at 220 nm;
hexanes / 2-propanol, 90 / 10; flow = 1.0 mL/min; retention
2
6
[
9
(R)-enantiomer]. 94% ee. [α] +66.0 (c 1.00, CHCl
0 ºC. R
f
3
). M.p. 88–
0.35 (hexanes / ethyl acetate, 20 / 1). H NMR (400
): δ 7.89–7.79 (m, 3H), 7.74–7.72 (m, 1H), 7.55–
D
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
times: 6.51 min [(R)-enantiomer], 10.64 min [(S)-enantiomer].
MHz, CDCl
3
26
9
0% ee. [α] +54.0 (c 1.00, CHCl
3
). R
f
0.3 (hexanes / ethyl ac-
): δ 7.17 (d, J = 8.6
7.48 (m, 2H), 7.37 (dd, J = 8.4, 2.0 Hz, 1H), 5.14 (dd, J = 14.8,
D
1
etate, 20 / 1). H NMR (400 MHz, CDCl
Hz, 2H), 7.14 (d, J = 8.6 Hz, 2H), 5.01 (dd, J = 14.4, 10.0 Hz,
3
10.0 Hz, 1H), 4.58 (dd, J = 14.8, 5.2 Hz, 1H), 4.50 (dd, J = 10.0,
13
3
5.2 Hz, 1H), 1.42 (s, 9H). C NMR (100 MHz, CDCl ): δ 169.6,
1
1
1
H), 4.46 (dd, J = 14.4, 5.2 Hz, 1H), 4.28 (dd, J = 10.0, 5.2 Hz,
133.4, 133.0, 131.2, 129.1, 127.9, 127.7, 127.2, 126.7, 126.6,
125.1, 82.6, 76.0, 49.8, 27.8. FT-IR (KBr, neat): ν 2979, 1726,
1555, 1370, 1252, 1218, 1151 cm . HRMS (EI/Magnetic Sec-
13
H), 2.33 (s, 3H), 1.41 (s, 9H). C NMR (100 MHz, CDCl
69.7, 138.3, 130.8, 129.9, 127.6, 82.4, 76.1, 49.3, 27.8, 21.1.
2980, 1727, 1514, 1416, 1371, 1253, 1210,
1153 cm . HRMS (EI/Magnetic Sector): m/z calcd for
3
): δ
̃
−1
+
+
FT-IR (KBr, neat): ν
̃
tor): m/z calcd for C17
4
H19NO [M] 301.1314, found 301.1314.
−1
(R)-tert-butyl 3-nitro-2-(2-(trifluoromethyl)phenyl)pro-
+
+
C
14
H19NO
4
[M] 265.1314, found 265.1314.
panoate (3al). Isolated as a colorless oil: 23.0 mg, 36% yield.
The ee was determined on a Daicel Chiralpak IB column (250
mm); detected at 220 nm; hexanes / 2-propanol, 90 / 10; flow =
1.0 mL/min; retention times: 5.84 min [(R)-enantiomer], 6.19
(R)-tert-butyl 2-(4-(tert-butyl)phenyl)-3-nitropropanoate
(3ah). Isolated as a colorless oil: 40.0 mg, 65% yield. The ee
was determined on a Daicel Chiralpak IB column (250 mm);
detected at 220 nm; hexanes / 2-propanol, 90 / 10; flow = 1.0
mL/min; retention times: 4.96 min [(R)-enantiomer], 14.72 min
2
6
3 f
min [(S)-enantiomer]. 99.5% ee. [α] +75.9 (c 1.00, CHCl ). R
D
1
0.25 (hexanes / ethyl acetate, 20 / 1). H NMR (400 MHz,
2
6
[(S)-enantiomer]. 95% ee. [α] +48.7 (c 1.00, CHCl
3
). R
f
0.37
): δ
CDCl ): δ 7.74 (d, J = 8.0 Hz, 1H), 7.56 (dd, J = 8.0, 7.2 Hz,
D
3
1
(hexanes / ethyl acetate, 20 / 1). H NMR (400 MHz, CDCl
3
1H), 7.50–7.41 (m, 2H), 4.98 (dd, J = 14.8, 10.4 Hz, 1H), 4.79
(dd, J = 10.4, 4.0, Hz, 1H), 4.41 (dd, J = 14.8, 4.0 Hz, 1H), 1.40
7
1
=
.37 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 8.6 Hz, 2H), 5.01 (dd, J =
4.8, 10.4 Hz, 1H), 4.46 (dd, J = 14.8, 4.8 Hz, 1H), 4.29 (dd, J
1
3
(s, 9H). C NMR (100 MHz, CDCl
J = 30.0 Hz), 128.61, 128.55, 127.0 (q, J = 6.0 Hz), 124.0 (q, J
= 272.0 Hz), 83.0, 75.3, 45.3, 27.7. FT-IR (KBr, neat): ν 2980,
1730, 1561, 1376, 1314, 1255, 1156 cm . HRMS
3
): δ 169.1, 132.5, 129.2 (q,
13
10.4, 4.8 Hz, 1H), 1.43 (s, 9H) 1.31 (s, 9H). C NMR (100
): δ 169.7, 151.4, 130.7, 127.4, 126.1, 82.4, 76.1,
9.3, 34.6, 31.2, 27.8. FT-IR (KBr, neat): ν 2966, 1727, 1555,
MHz, CDCl
4
1
3
̃
−1
̃
−1
+
+
369, 1252, 1152 cm . HRMS (EI/Magnetic Sector): m/z calcd
17 3 4
(FAB/Magnetic Sector): m/z calcd for C14H F NO [M + H]
+
+
for C17
H
25NO
4
[M] 307.1784, found 307.1782.
320.1110, found 320.1108.
(R)-tert-butyl
2-([1,1'-biphenyl]-4-yl)-3-nitropropanoate
(R)-tert-butyl
3-nitro-2-(3-(trifluoromethyl)phenyl)pro-
(3ai). Isolated as an off-white solid: 37.3 mg, 57% yield. The ee
panoate (3am). Isolated as a colorless oil: 39.1 mg, 61% yield.
The ee was determined on a Daicel Chiralpak IB column (250
mm); detected at 220 nm; hexanes / 2-propanol, 90 / 10; flow =
was determined on a Daicel Chiralpak IB column (250 mm);
detected at 220 nm; hexanes / 2-propanol, 90 / 10; flow = 1.0
mL/min; retention times: 11.28 min [(R)-enantiomer], 11.87
1.0 mL/min; retention times: 6.43 min [(R)-enantiomer], 7.65
2
6
26
min [(S)-enantiomer]. 98% ee. [α] +67.0 (c 1.00, CHCl
84–86 ºC. R
MHz, CDCl
3
). M.p.
0.17 (hexanes / ethyl acetate, 20 / 1). H NMR (400
): δ 7.61–7.55 (m, 4H), 7.48–7.42 (m, 2H), 7.40–
.31 (m, 3H), 5.07 (dd, J = 14.4, 10.4 Hz, 1H), 4.53 (dd, J =
4.4, 5.2 Hz, 1H), 4.37 (dd, J = 10.4, 5.2 Hz, 1H), 1.44 (s, 9H).
min [(S)-enantiomer]. 98% ee. [α] +62.0 (c 1.00, CHCl
3
). R
0.25 (hexanes / ethyl acetate, 20 / 1). H NMR (400 MHz,
CDCl ): δ 7.61 (d, J = 7.2 Hz, 1H), 7.56–7.42 (m, 3H), 5.05 (dd,
J = 14.4, 9.6 Hz, 1H), 4.53 (dd, J = 14.4, 5.6 Hz, 1H), 4.40 (dd,
f
D
D
1
1
f
3
3
7
1
1
3
3
J = 9.6, 5.6 Hz, 1H), 1.41 (s, 9H). C NMR (100 MHz, CDCl ):
1
3
C NMR (100 MHz, CDCl
28.8, 128.2, 127.9, 127.6, 127.0, 82.6, 75.9, 49.4, 27.8. FT-IR
2978, 1727, 1556, 1487, 1413, 1370, 1253, 1152
3
): δ 169.5, 141.4, 140.2, 132.8,
δ 168.8, 135.0, 131.7 (q, J = 32.0 Hz), 131.2, 129.8, 125.4 (q, J
= 3.0 Hz), 124.8 (q, J = 3.0 Hz), 123.7 (q, J = 271.0 Hz), 83.2,
1
(KBr, neat): ν
̃
75.6, 49.4, 27.7. FT-IR (KBr, neat): ν
̃
2980, 1729, 1562, 1372,
−1
+
−1
cm . HRMS (EI/Magnetic Sector): m/z calcd for C19H21NO
4
1330, 1256, 1154 cm . HRMS (FAB/Magnetic Sector): m/z
+
+
+
[M] 327.1471, found 327.1472.
calcd for C14
H
17
3
F NO
4
[M + H] 320.1110, found 320.1110.
(R)-tert-butyl 2-(naphthalen-1-yl)-3-nitropropanoate (3aj).
(R)-tert-butyl
3-nitro-2-(4-(trifluoromethyl)phenyl)pro-
Isolated as a colorless oil: 39.2 mg, 65% yield. The ee was de-
termined on a Daicel Chiralpak IB column (250 mm); detected
at 220 nm; hexanes / 2-propanol, 90 / 10; flow = 1.0 mL/min;
retention times: 11.01 min [(R)-enantiomer], 28.53 min [(S)-en-
panoate (3an). Isolated as a colorless oil: 42.8 mg, 67% yield.
The ee was determined on a Daicel Chiralpak IB column (250
mm); detected at 220 nm; hexanes / 2-propanol, 90 / 10; flow =
1.0 mL/min; retention times: 7.01 min [(R)-enantiomer], 9.25
2
6
26
antiomer]. 93% ee. [α] +124.5 (c 1.00, CHCl
anes / ethyl acetate, 20 / 1). H NMR (400 MHz, CDCl
(d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.0
Hz, 1H), 7.64–7.52 (m, 2H), 7.49–7.37 (m, 2H), 5.23–5.12 (m,
3
). R
f
0.35 (hex-
): δ 8.09
min [(S)-enantiomer]. 98% ee. [α] +62.4 (c 1.00, CHCl
3
). R
0.25 (hexanes / ethyl acetate, 20 / 1). H NMR (400 MHz,
CDCl ): δ 7.64 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.0 Hz, 2H),
f
D
D
1
1
3
3
5.04 (dd, J = 14.8, 9.6 Hz, 1H), 4.52 (dd, J = 14.8, 5.6 Hz, 1H),
13
13
2
H) 4.55 (d, J = 10.8 Hz, 1H), 1.42 (s, 9H). C NMR (100 MHz,
4.40 (dd, J = 9.6, 5.6 Hz, 1H), 1.42 (s, 9H). C NMR (100 MHz,
CDCl ): δ 170.1, 134.2, 130.9, 130.1, 129.2, 129.1, 127.1,
3
3
CDCl ): δ 168.8, 137.9, 130.9 (q, J = 33.0 Hz), 128.3, 126.2 (q,
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J = 4.0 Hz), 123.8 (q, J = 270.0 Hz), 83.2, 75.6, 49.5, 27.7. FT-
IR (KBr, neat): ν 2982, 1729, 1561, 1421, 1372, 1326, 1256,
1154 cm . HRMS (FAB/Magnetic Sector): m/z calcd for
(R)-isopropyl 2-(naphthalen-1-yl)-3-nitropropanoate (3bj).
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
̃
Isolated as a colorless oil: 33.9 mg, 59% yield. The ee was de-
termined on a Daicel Chiralcel OJ-H column (250 mm); de-
tected at 220 nm; hexanes / 2-propanol, 90 / 10; flow = 1.0
mL/min; retention times: 23.04 min [(R)-enantiomer], 28.56
−1
+
+
14 17 3 4
C H F NO [M + H] 320.1110, found 320.1110.
(R)-tert-butyl 2-(4-fluorophenyl)-3-nitropropanoate (3ao).
Isolated as a colorless oil: 33.9 mg, 63% yield. The ee was de-
termined on a Daicel Chiralcel OD-H column (250 mm); de-
tected at 220 nm; hexanes / 2-propanol, 90 / 10; flow = 1.0
mL/min; retention times: 10.27 min [(S)-enantiomer], 10.91
2
6
min [(S)-enantiomer]. 96% ee. [α]
0.2 (hexanes / ethyl acetate, 20 / 1). H NMR (400 MHz,
CDCl ): δ 8.08 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H),
7.84 (d, J = 8.0 Hz, 1H), 7.64–7.51 (m, 2H), 7.47–7.41 (m, 1H),
.39–7.35 (m, 1H), 5.28–5.16 (m, 2H), 5.11 (sep, J = 6.4 Hz,
1H), 4.64–4.51 (m, 1H), 1.27 (d, J = 6.4 Hz, 3H), 1.09 (d, J =
3 f
+210.5 (c 1.00, CHCl ). R
D
1
3
2
6
7
min [(R)-enantiomer]. 96% ee. [α] +64.8 (c 1.00, CHCl
3
). R
f
D
1
0.22 (hexanes / ethyl acetate, 20 / 1). H NMR (400 MHz,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
6
.4 Hz, 3H). C NMR (100 MHz, CDCl
3
): δ 170.6, 134.2,
3
CDCl ): δ 7.25–7.21 (m, 2H), 7.09–7.02 (m, 2H), 5.00 (dd, J =
130.9, 129.7, 129.3, 129.2, 127.2, 126.2, 125.5, 125.4, 122.3,
1
=
4.4, 10.0 Hz, 1H), 4.48 (dd, J = 14.4, 5.2, Hz 1H), 4.31 (dd, J
1
3
75.4, 69.8, 44.8, 21.6, 21.2. FT-IR (KBr, neat): ν
̃
2983, 1728,
10.0, 5.2 Hz, 1H), 1.41 (s, 9H). C NMR (100 MHz, CDCl
3
):
−1
1645, 1557, 1522, 1418, 1376, 1319, 1253, 1203, 1144 cm .
δ 169.4, 165.1 (d, J = 246.0 Hz), 129.7, 129.5 (d, J = 8.0 Hz),
+
+
HRMS (EI/Magnetic Sector): m/z calcd for C16
H
17NO
4
[M]
1
16.2 (d, J = 22.0 Hz), 82.7, 75.9, 48.9, 27.7. FT-IR (KBr, neat):
−1
287.1158, found 287.1159.
ν
̃
2983, 1728, 1605, 1157, 1510, 1418, 1372, 1228, 1152 cm .
+
+
HRMS (EI/Magnetic Sector): m/z calcd for C13
H16FNO
4
[M]
(R)-isopropyl
3-nitro-2-(4-(trifluoromethyl)phenyl)pro-
269.1063, found 269.1062.
panoate (3bn). Isolated as a colorless oil: 22.0 mg, 43% yield.
The ee was determined on a Daicel Chiralpak IB column (250
mm); detected at 220 nm; hexanes / 2-propanol, 90 / 10; flow =
(R)-butyl 2-(4-chlorophenyl)-3-nitropropanoate (3ap). Iso-
lated as an off-white solid: 29.3 mg, 51% yield. The ee was de-
termined on a Daicel Chiralpak IB column (250 mm); detected
at 220 nm; hexanes / 2-propanol, 90 / 10; flow = 1.0 mL/min;
retention times: 7.47 min [(R)-enantiomer], 10.11 min [(S)-en-
1
.0 mL/min; retention times: 7.17 min [(R)-enantiomer], 11.15
26
min [(S)-enantiomer]. 96% ee. [α]
0.17 (hexanes / ethyl acetate, 20 / 1). H NMR (400 MHz,
CDCl ): δ 7.29–7.22 (m, 2H), 7.10–7.02 (m, 2H), 5.10–5.01 (m,
2H), 4.53 (dd, J = 14.4, 5.2 Hz, 1H), 4.37 (dd, J = 10.0, 5.2 Hz,
3 f
+117.6 (c 1.00, CHCl ). R
D
1
2
6
antiomer]. 95% ee. [α] +67.5 (c 1.00, CHCl
3
). M.p. 60–62 ºC.
0.27 (hexanes / ethyl acetate, 20 / 1). H NMR (400 MHz,
CDCl ): δ 7.34 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H),
.00 (dd, J = 14.4, 10.0 Hz, 1H), 4.48 (dd, J = 14.4, 5.4 Hz, 1H),
3
D
1
R
f
13
1
(
H), 1.27 (d, J = 6.4 Hz, 3H), 1.13 (d, J = 6.4 Hz, 3H). C NMR
100 MHz, CDCl ): δ 169.8, 162.7 (d, J = 247.0 Hz), 129.6 (d,
J = 8.0 Hz), 129.3 (d, J = 3.0 Hz), 116.3 (d, J = 22.0 Hz), 75.8,
3
3
5
4
13
.30 (dd, J = 10.0, 5.4 Hz, 1H), 1.41 (s, 9H). C NMR (100
): δ 169.1, 134.5, 132.4, 129.5, 129.2, 82.9, 75.7,
9.1, 27.8. FT-IR (KBr, neat): ν 2980, 1726, 1556, 1492, 1370,
6
1
9.8, 48.3, 21.6, 21.3. FT-IR (KBr, neat): ν
̃
2989, 1731, 1621,
MHz, CDCl
4
3
−1
560, 1421, 1377, 1326, 1254, 1205 cm . HRMS (EI/Magnetic
̃
+
+
−1
12 14 4
Sector): m/z calcd for C H FNO [M] 255.0907, found
1254, 1152 cm . HRMS (EI/Magnetic Sector): m/z calcd for
+
+
255.0908.
C
13
H
16ClNO
4
[M] 285.0768, found 285.0768.
(R)-benzyl 3-nitro-2-phenylpropanoate (3ca). Isolated as an
(R)-tert-butyl
2-(3,4-dichlorophenyl)-3-nitropropanoate
off-white solid: 24.0 mg, 42% yield. The ee was determined on
a Daicel Chiralpak IB column (250 mm); detected at 220 nm;
hexanes / 2-propanol, 90 / 10; flow = 1.0 mL/min; retention
times: 13.89 min [(R)-enantiomer], 26.77 min [(S)-enantiomer].
(3aq). Isolated as a colorless oil: 32.7 mg, 51% yield. The ee
was determined on a Daicel Chiralpak IB column (250 mm);
detected at 220 nm; hexanes / 2-propanol, 90 / 10; flow = 1.0
mL/min; retention times: 8.03 min [(R)-enantiomer], 15.57 min
2
8
2
6
92% ee. [α] +98.2 (c 1.00, CHCl
anes / ethyl acetate, 20 / 1). H NMR (400 MHz, CDCl ): δ
3
). M.p. 50–52 ºC. R
f
0.2 (hex-
[
(S)-enantiomer]. 98% ee. [α] +61.8 (c 1.00, CHCl
3
). R
f
0.25
): δ
D
D
1
1
3
(hexanes / ethyl acetate, 20 / 1). H NMR (400 MHz, CDCl
3
7.37–7.18 (m, 10H), 5.22 (d, J = 12.4 Hz, 1H), 5.12 (d, J = 12.4
7.44 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.12 (dd, J =
8.4, 2.4 Hz, 1H), 4.99 (dd, J = 14.8, 9.6 Hz, 1H), 4.49 (dd, J =
Hz, 1H), 5.11 (dd, J = 14.4, 10.0 Hz, 1H), 4.56 (dd, J = 14.8,
1
3
5
.2 Hz, 1H), 4.48 (dd, J = 10.0, 5.2 Hz, 1H). C NMR (100
MHz, CDCl ): δ 170.4, 135.1, 133.1, 129.4, 128.7, 128.6, 128.4,
28.01, 127.96, 75.7, 67.5, 48.8. FT-IR (KBr, neat): ν 3036,
1737, 1557, 1498, 1455, 1416, 1377, 1247, 1195 cm . HRMS
1
4.8, 5.6 Hz, 1H), 4.28 (dd, J = 9.6, 5.6 Hz, 1H), 1.42 (s, 9H).
1
3
3
3
C NMR (100 MHz, CDCl ): δ 168.6, 134.0, 133.4, 132.9,
1
̃
1
31.2, 129.9, 127.1, 83.3, 75.5, 48.8, 27.8. FT-IR (KBr, neat):
−1
−1
ν̃ 2981, 1729, 1556, 1472, 1371, 1253, 1153 cm . HRMS
+
+
+
+
16 15 4
(EI/Magnetic Sector): m/z calcd for C H NO [M] 285.1001,
(
3
EI/Magnetic Sector): m/z calcd for C13
19.0378, found 319.0380.
R)-isopropyl 3-nitro-2-phenylpropanoate (3ba). Isolated as
H
15Cl
2
NO
4
[M]
found 285.1001.
2
(
General procedures for the synthesis of
ids
b
-amino ac-
a colorless oil: 30.4 mg, 64% yield. The ee was determined on
a Daicel Chiralpak IB column (250 mm); detected at 220 nm;
hexanes / 2-propanol, 90 / 10; flow = 1.0 mL/min; retention
A 10 mL round bottle flask charged with 3aa (50.3 mg, 0.2
mmol), and Pd/C (20 mg, 5wt%, 10%, 0.01 mmol) was evacu-
ated and backed filled with H . MeOH (2 mL) was then added.
2
2
8
times: 9.04 min (R), 17.65 min (S). 93% ee. [α] +118.1 (c 1.00,
D
1
CHCl
MHz, CDCl
dd, J = 14.8, 5.2 Hz, 1H), 4.38 (dd, J = 10.0, 5.2 Hz, 1H), 1.27
3
). R
f
0.3 (hexanes / ethyl acetate, 20 / 1). H NMR (400
After being stirred at rt for 12 h, the mixture was filtered
3
): δ 7.40–7.24 (m, 5H), 5.13–5.00 (m, 2H), 4.53
®
through a pad of Celite and the volatile was removed at re-
(
duced pressure, followed by the addition of 6 N HCl (10 mL).
The mixture was heated to reflux, and it was cooled to rt after
1
3
(d, J = 6.2 Hz, 3H), 1.13 (d, J = 6.2 Hz, 3H). C NMR (100
MHz, CDCl ): δ 170.0, 133.5, 129.3, 128.5, 127.8, 75.8, 69.6,
49.0, 21.6, 21.3. FT-IR (KBr, neat): ν 2987, 2360, 1729, 1697,
557, 1376, 1251, 1203, 1178 cm . HRMS (EI/Magnetic Sec-
3
12 h. The aqueous layer was extracted with ether (20 mLx3),
̃
and the aqueous layer was concentrated to give ammonium salt
of compound 5 as a white solid. The solid was purified and neu-
tralized by column chromatography on silica gel (eluting with
−1
1
+
+
4
tor): m/z calcd for C12H15NO [M] 237.1001, found 237.1000.
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The Journal of Organic Chemistry
OH, 5/2/1) to give 5 (22.1 mg, 67%) as a white
REFERENCES
IPA/MeOH/NH
solid.
4
1
2
3
4
5
6
7
8
9
(
1) (a) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. β-Peptides:ꢀ
25
2
5
From Structure to Function. Chem. Rev. 2001, 101, 3219–3213. (b) Liu,
M.; Sibi, M. P. Recent Advances in the Stereoselective Synthesis of β-
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(
R)-3-amino-2-phenylpropanoic acid (5). [α] D +80.7 (c
.22, H O) M.p. 204–206 ºC. H NMR (400 MHz, D O): δ
2 2
.48–7.32 (m, 5H), 3.80 (dd, J = 7.6, 7.6 Hz, 1H), 3.47 (dd, J =
2.8, 7.6 Hz, 1H), 3.29 (dd, J = 12.8, 7.6 Hz, 1H). C NMR
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0
7
1
2
bach, D. β -Amino Acids—Syntheses, Occurrence in Natural Products,
13
and Components of β-Peptides. Biopolymers 2004, 76, 206–243. (d)
Davies, S. G.; Smith, A. D.; Price, P. D. The Conjugate Addition of
Enantiomerically Pure Lithium Amides as Homochiral Ammonia
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dron: Asymmetry 2005, 16, 2833–2891. (e) Juaristi, E.; Soloshonok, V.
A. Eds. Enantioselective Synthesis of β-Amino Acids, 2nd ed., Wiley-
VCH: Weinheim, 2005. (f) Liljeblad, A.; Kanerva, L. T. Biocatalysis
as a Profound Tool in the Preparation of Highly Enantiopure β-Amino
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velopments in the Synthesis of Amino Acids and Analogues for Folda-
mers Study. Curr. Org. Synth. 2008, 5, 61–80.
(100 MHz, D
42.3. HRMS (ESI/Q-TOF): m/z calcd for C
164.0717, found 164.0711.
2
O): δ 178.3, 137.2, 129.3, 128.2, 128.0, 51.4,
−
−
9
H
10NO
2
[M]
To a 15 mL round bottle flask were added 3ap (108.6 mg, 0.38
mmol), Zn dust (99.2 mg, 1.52 mmol), and MeOH (4 mL). At 0
°C, AcOH (4 mL) was added and the mixture was stirred for
additional 3 h. Ethyl acetate (10 mL) was added after the mix-
ture was warmed to rt. The whole mixture was neutralized with
NaHCO3(aq), and the aqueous layer was separated, and extracted
with ethyl acetate (10 mLx3). The combined organic layer was
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
2) Kudo, F.; Miyanaga, A.; Eguchi, T. Nat. Prod. Rep. 2014, 31,
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(3) (a) Geng, C.-A.; Ma, Y.-B.; Chen, J.-J. Bishyoscyamine, One
1
washed with brine, dried over anhydrous Na
concentrated at reduced pressure to give the crude mixture. To
this mixture were added NaBH(OAc) , and CH Cl (2 mL) un-
der Ar atmosphere. The mixture was added anhydrous acetone
22 µL, 0.3 mmol), and after being stirred for overnight, the
mixture was neutralized with 5 % NaOH(aq). The organic layer
4
was separated, washed with brine, dried over anhydrous Na SO ,
filtered and concentrated at reduced pressure to give the crude
mixture, which was purified by column chromatography on sil-
ica gel (eluting with ethyl acetate/hexanes, 3/7) to give 7 (47.3
mg, 38%) as a white solid.
2 4
SO , filtered and
Unusual Dimeric Tropane Alkaloid from Anisodus Acutangulus. Chin.
Chem. Lett. 2013, 24, 236–238. (b) Nishi, T.; Kubota, T.; Fromont, J.;
Sasaki, T.; Kobayashi, J. Nakinadines B–F: New Pyridine Alkaloids
with a β-Amino Acid Moiety from Sponge Amphimedon sp. Tetrahe-
dron, 2008, 64, 3127–3132. (c) Blake, J. F.; Xu, R.; Bencsik, J. R.;
Xiao, D.; Kallan, N. C.; Schlachter, S.; Mitchell, I. S.; Spencer, K. L.;
Banka, A. L.; Wallace, E. M.; Gloor, S. L.; Martinson, M.; Woessner,
R. D.; Vigers, G. P. A.; Brandhuber, B. J.; Liang, J.; Safina, B. S.; Li,
J.; Zhang, B.; Chabot, C.; Do, S.; Lee, L.; Oeh, J.; Sampath, D.; Lee,
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Pharmacology of a Selective ATP-Competitive Akt Inhibitor (GDC-
0068) for the Treatment of Human Tumors. J. Med. Chem. 2012, 55,
8110–8127.
3
2
2
(
2
tert-butyl (R)-2-(4-chlorophenyl)-3-(isopropylamino)pro-
panoate (7). The ee was determined on a Daicel Chiralpak OJ-
H column (250 mm); detected at 220 nm; hexanes / 2-propanol,
(
4) (a) Stephens, O. M.; Kim, S.; Welch, B. D.; Hodsdon, M. E.; Kay,
M. S.; Schepartz, A. Inhibiting HIV Fusion with a β-Peptide Foldamer.
J. Am. Chem. Soc. 2005, 127, 13126–13127. (b) English, E. P.; Chu-
manov, R. S.; Gellman, S. H.; Compton, T. Rational Development of
β-Peptide Inhibitors of Human Cytomegalovirus Entry. J. Biol. Chem.
2006, 281, 2661–2667. (c) Gademann, K.; Kimmerlin, T.; Hoyer, D.;
Seebach, D. Peptide Folding Induces High and Selective Affinity of a
Linear and Small β-Peptide to the Human Somatostatin Receptor 4. J.
Med. Chem. 2001, 44, 2460–2468.
9
0 / 10; flow = 1.0 mL/min; retention times: 3.46 min [(R)-en-
29
antiomer], 4.88 min [(S)-enantiomer]. 95% ee. [α] +15.2 (c
D
1
3
7
.00, CHCl
3
). M.p. 61–63 ºC. R
/ 1). H NMR (400 MHz, CDCl
.22 (d, J = 8.4 Hz, 2H), 3.64 (dd, J = 8.4, 6.8 Hz, 1H), 3.17
f
0.37 (hexanes / ethyl acetate,
1
3
): δ 7.29 (d, J = 8.4 Hz, 2H),
(dd, J = 12.0, 8.4 Hz, 1H), 2.84–2.73 (m, 2H), 1.39 (s, 9H),
1
3
.37–1.25 (m, 1H), 1.03 (d, J = 6.4 Hz, 3H), 1.01 (d, J = 6.4 Hz,
13
(5) (a) Evans, D. A.; Urpi, F.; Somers, T. C.; Clark, J. S.; Bilodeau,
M. T. New Procedure for the Direct Generation of Titanium Enolates.
Diastereoselective Bond Constructions with Representative Electro-
philes. J. Am. Chem. Soc. 1990, 112, 8215–8216. (b) Hintermann, T.;
Seebach, D. Synthesis of a β-Hexapeptide from (R)-2-Aminomethyl-
alkanoic Acids and Structural Investigations. Synlett 1997, 437–438. (c)
Beddow, J. E.; Davies, S. G.; Smith, A. D.; Russell, A. J. Asymmetric
3
H). C NMR (100 MHz, CDCl ): δ 172.1, 136.5, 133.1, 129.3,
128.8, 81.1, 52.6, 50.2, 48.3, 27.9, 22.9, 22.8. FT-IR (KBr,
neat): ν 2968, 2931, 2869, 1724, 1506, 1491, 1367, 1257, 1147
cm . HRMS (ESI/Q-TOF): m/z calcd for C16H25NO Cl
2
̃
−1
+
+
[M+H] 298.1574, found 298.1577.
2
ASSOCIATED CONTENT
Supporting Information
Synthesis of 2-Alkyl- and 2-aryl-3-aminopropionic acids (β -Amino
Acids) from (S)-N-Acryloyl-5,5-dimethyloxazolidin-2-one SuperQuat
Derivatives. Chem. Commun. 2004, 2778–2779. (d) Tessier, A.; Lah-
mar, N.; Pytkowicz, J.; Brigaud, T. Highly Diastereoselective Synthetic
The Supporting Information containing HPLC chromatograms, and
NMR spectra of addition products is available free of charge on the
ACS Publications website.
2
Route to Enantiopure β -Amino Acids and γ-Amino Alcohols Using a
Fluorinated Oxazolidine (Fox) as Chiral Auxiliary. J. Org. Chem. 2008,
7
3, 3970–3973.
6) (a) Chi, Y.; Gellman, S. H. Enantioselective Organocatalytic
(
AUTHOR INFORMATION
Corresponding Author
Aminomethylation of Aldehydes:ꢀ A Role for Ionic Interactions and Ef-
2
ficient Access to β -Amino Acids. J. Am. Chem. Soc. 2006, 128, 6804–
6
805. (b) Xu, J.; Chen, X.; Wang, M.; Zheng, P.; Song, B.-A.; Chi, Y.
* E-mail:hlw@ntnu.edu.tw.
Notes
The authors declare no competing financial interest.
R. Aminomethylation of Enals through Carbene and Acid Cooperative
2
Catalysis: Concise Access to β -Amino Acids. Angew. Chem. Int. Ed.
2015, 54, 5161–5165. (c) Davies, H. M. L.; Venkataramani, C. Cata-
2
lytic Enantioselective Synthesis of β -Amino Acids. Angew. Chem. Int.
ACKNOWLEDGMENT
Ed. 2002, 41, 2197–2199. (d) Remarchuk, T.; Babu, S.; Stults, J.; Za-
notti-Gerosa, A.; Roseblade, S.; Yang, S.; Huang, P.; Sha, C.; Wang,
Y. An Efficient Catalytic Asymmetric Synthesis of a β -Amino Acid
on Multikilogram Scale. Org. Process Res. Dev. 2014, 18, 135–141. (e)
Huang, H.; Liu, X.; Deng, J.; Qiu, M.; Zheng, Z. Rhodium-Catalyzed
Enantioselective Hydrogenation of β-Phthalimide Acrylates to
Financial support from the Ministry of Science and Technology of
Republic of China (102-2113-M-003-006-MY2 and 104-2628-M-
2
0
2
03-001-MY3) and National Taiwan Normal University (NTNU
016 Subsidy Policy for International Collaboration and Research
Projects) is gratefully acknowledged.
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2
Synthesis of β -Amino Acids. Org. Lett. 2006, 8, 3359–3362. (f) Qiu,
L.; Prashad, M.; Hu, B.; Prashad, K.; Repic, O.; Blacklock, T. J.;
Kwong, F. Y.; Kok, S. H. L.; Lee, H. W.; Chan, A. S. C. Enantioselec-
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