Synthesis of Quaternary-Carbon-Containing β2,2-Amino Acids by the RhI-Catalyzed Enantioselective Arylation of α-Substituted β-Nitroacrylates

Article abstract of DOI:10.1002/chem.201604120

An enantioselective Rh^I-catalyzed conjugate addition reaction of α-substituted β-nitroacrylates with various arylboronic acids by using chiral Rh^Idiene catalysts is described for the first time. The addition reaction proceeds under mild conditions in a range of common organic solvents and additives, and it affords the corresponding quaternary-carbon-containing α,α-disubstituted β-nitropropionate products in up to 63 % yield and 99 % ee. Reaction of either (E)- or (Z)-β-nitroacrylates provided the same enantiomer of the product, and a range of esters and aryl groups were tolerated. To demonstrate the utility of the method, ethyl (R)-1,1-methyl-1-phenyl-3-nitropropionate, prepared herein, was converted to the non-proteinogenic β^2,2-amino acid, (R)-2-(aminomethyl)-2-phenylpropanoic acid, and to the β^2,2-lactam, (R)-3-methyl-3-phenylazetidin-2-one. In addition, a tripeptide, which comprised l-phenylalanine, l-alanine, and β^2,2-amino acid 7, was also synthesized.

Full text of DOI:10.1002/chem.201604120

A Journal of
Accepted Article
Title: Synthesis of Quaternary Carbon-containing β2,2-Amino Acids
via Rh(I)-Catalyzed Enantioselective Arylation of α-Substituted β-
Nitroacrylates
Authors: Jo-Hsuan Fang, Jia-Hong Jian, Hao-Ching Chang, Ting-Shen
Kuo, Way-Zen Lee, and Hsyueh-Liang Wu
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201604120
Link to VoR: http://dx.doi.org/10.1002/chem.201604120
Supported by

10.1002/chem.201604120
Chemistry - A European Journal
FULL PAPER
Synthesis of Quaternary Carbon-containing β2,2-Amino Acids via
Rh(I)-Catalyzed Enantioselective Arylation of α-Substituted β-
Nitroacrylates
Jo-Hsuan Fang, Jia-Hong Jian, Hao-Ching Chang, Ting-Shen Kuo, Way-Zen Lee, Ping-Yu Wu and
Hsyueh-Liang Wu*[a]
Dedication ((optional))
Abstract: An enantioselective Rh(I)-catalyzed conjugate addition
reaction of α-substituted β-nitroacrylates with various arylboronic
acids using Rh(I)-chiral diene catalysts is described for the first time.
The addition reaction proceeds under mild conditions in a range of
common organic solvents and additives offers the corresponding
quaternary carbon-containing α,α-disubstituted β-nitropropionate
products in up to 63% yield with up to 99% ee. Reaction of (E)- or
(Z)-β-nitroacrylates both provide the same enantiomer, and a range
of esters and aryl groups are tolerated. To demonstrate the utility of
the Pd(II)-catalyzed arylation of β-nitroacrylamides4h using
arylboronic acids (Scheme 1c). In addition, enzymatic4d and
organocatalytic4g transfer hydrogenation of α-substituted β-
nitroacrylates (Scheme 1d) have been used to generate optically
active β2-amino acids with ees of up to 96%. More interestingly
and of relevance to our own work, however, the asymmetric
addition of nucleophiles to α-substituted β-nitroacrylates has
enabled the synthesis of enantioenriched β2,2-amino acids that
harbor chiral quaternary carbon centers (Scheme 1e).5
the
prepared herein, was converted to the non-proteinogenic β2,2-amino
acid, (R)-2-(aminomethyl)-2-phenylpropanoic acid, and to the β2,2
method
ethyl
(R)-1,1-methyl-1-phenyl-3-nitropropionate,
Scheme 1.
(a) Synthesis of β3-amino acids using the Arndt-Eistert reaction of α-amino
-
acids
lactam, (R)-3-methyl-3-phenylazetidin-2-one. In addition, a tripeptide
comprising L-phenylalanine, L-alanine, and β2,2-amino acid 7 was
also synthesized.
R
Arndt-Eistert
reaction
R
R
Pg
Pg
CO2H
CO2H
N
CO2H
N
H2N
β3-amino acids
(b) Cu(I)-catalyzed addition of diorganozincs and Me3Al to β-nitroacrylates
H
H
α-amino acids
R'
R'
cat. Cu(I) / L*
Introduction
O2N
H2N
CO2R
O2N
*
*
CO2H
CO2R
R'2Zn or Me3Al
R' = Me, Et, iBu
β2-amino acids
β-Amino acids and their derivatives have attracted
considerable synthetic interest owing to their ubiquity in natural
products1 and pharmaceuticals as well as their importance as
structural motifs in β-peptides2a,b and β-lactams.2c,d While one
carbon homologation of natural amino acids via the Arndt–
Eistert reaction provides facile access to β3-amino acids (β-
substituted-β-amino acids; Scheme 1a),3 asymmetric synthesis
of their β2-congeners (α-substituted β-amino acids) is
comparably challenging, prompting considerable synthetic
endeavors toward their preparation.3,4 The catalytic asymmetric
addition reaction of nucleophiles to β-nitroacrylates followed by
reduction of the nascent α-substituted β-nitroacrylates and
hydrolysis provides convenient access to β2-amino acids.
Examples of this include the Cu(I)-catalyzed conjugate addition
of Et2Zn4a,b and Me3Al4c,e to β-nitroacrylates (Scheme 1b) and
up to 93% ee
(c) Pd(II)-catalyzed addition of arylboronic acids to β-nitroacrylamide
Ar
*
Ar
*
cat. Pd(II) / L*
O2N
H2N
CONH2
O2N
CO2H
CONH2
ArB(OH)2
β2-amino acids
up to 89% ee
(d) Asymmetric reduction of α-substituted β-nitroacrylates
R'
Jacobsen-type thiourea
R'
R'
Hantzsch ester
O2N
H2N
CO2R
O2N
*
*
CO2H
or enzyme, NADPH
CO2R
β2-amino acids
up to 96% ee
(e) Asymmetric addition of α-substituted β-nitroacrylates
R'
R' Nu
R' Nu
H2N
organocatalysts
+
NuH
O2N
O2N
*
*
CO2H
CO2R
CO2R
or cat. Ni(II)/L*
β
2,2-amino acids
up to 98% ee
[a]
J.-H. Fang, J.-H. Jian, Dr. H.-C. Chang, T.-S. Kuo, Prof. Dr. W.-Z.
Lee, Dr. P.-Y. Wu, Prof. Dr. H.-L. Wu
In recent years, Rh(I)-catalyzed conjugate addition reactions
have been proven capable of delivering high enantioselectivities
in a variety of C-C bond forming processes, while exhibiting
good catalytic activity in the presence of a variety of common
functional groups and in aqueous reaction media.6 In addition to
a variety of additions reactions,7 we recently reported7d the
efficient and enantioselective 1,4-conjugate addition reaction of
arylboronic acids to β-nitroolefins, exploiting Rh(I)-catalysts
bearing novel chiral 2,5-diarylbicyclo[2.2.1]heptadiene ligands.7k
In fact, the screening of a library of these ligands revealed that
Department of Chemistry
National Taiwan Normal University
No. 88, Section 4, Tingzhou Road, Taipei, 11677, Taiwan (ROC)
E-mail: hlw@ntnu.edu.tw
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
1
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10.1002/chem.201604120
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the 2,5-di-naphth-1-yl substituted ligand provided the highest
enantioselectivity for a model substrate. While disclosures from
other groups8 have demonstrated additions to nitroolefins,
dienes9 have proven useful as Rh(I) ligands. As a logical
extension of our prior variant7d of the Hayashi−Miyaura reaction
using nitroolefins as Michael acceptors, we herein present for
the first time the Rh(I)-catalyzed enantioselective conjugate
addition of arylboronic acids to α-substituted β-nitroacrylates
offering α,α-disubstituted β-nitropropionates that contain
quaternary carbon centers. These compounds are useful en
routé to β2,2-amino acids and their derivatives.
respectively. Poignantly, entries 9–12 and 14–15 show that
higher conjugate addition regioselectivity occurs at the expense
of ee. Amidst the chiral diene ligands tested, none provided
better ee or yields than the 1-naphthyl substituted chiral diene
L1 (entry 6); it is notable that this ligand proved best for the
corresponding 1,4-conjugate additions to β-nitroolefins.7d In
addition our ligands examined above, a number of related
available ligands (L9–L13) that have been shown elsewhere to
provide good reactivity and enantioselectivity in asymmetric Rh-
catalyzed arylations of α,β-unsaturated carbonyl compounds
were tested. While the desired adduct 3ac was obtained in 53%
in the presence of Rh-catalyst comprising our diene ligand L1
(entry 6), dienes L9,12a L10,12bor L1112c all failed to provide any
of the desired product within 24 h under identical reaction
conditions as identified in entry 6 (entries 16–18). Similarly,
carrying out the arylation of 2c using sulfinamide-olefin hybrid
ligand L1212d or (S)-BINAP (L13)12e afforded none of the desired
addition product 3ac (entries 19 and 20).
Results and Discussion
The current study began by examining the conjugate
addition of phenylboronic acid (1a) to ethyl (2a) and tert-butyl
(2b) (E)-nitroacrylates, employing the previously identified7d
conditions found optimal for the corresponding addition reaction
of β-nitroolefins. Disconcertingly, however, reactions carried out
in the presence of 0.5–5 mol% of the Rh(I)/L1 catalyst using
KHF2 as an additive failed to yield the desired products 3aa or
3ab (Table 1, entries 1 and 2). When KOH was used instead of
KHF2, the desired products 3aa or 3ab were obtained, albeit in
Table 1. Conjugate addition of phenylboronic acid (1a) to β-nitroacrylates 2[a]
[RhCl(C2H4)2]2 (5.0 mol% of Rh)
L (6.0 mol%)
R2
R2
R2
Ph
+
+
PhB(OH)2
O2N
Ph
CO2R1
O2N
CO2R1
CO2R1
additive, toluene, temp, time
2a: R1 = Et, R2 = H
2b: R1 = tBu, R2 = H
2c: R1 = Et, R2 = Me
3aa: R1 = Et, R2 = H
3ab: R1 = tBu, R2 = H
3ac: R1 = Et, R2 = Me
5ac: R1 = Et, R2 = Me
1a
Ar
Ar
L1: Ar = 1-Naphthyl
L2: Ar = C6H5
L3: Ar = 4-Ph-C6H4
L4: Ar = 2-Naphthyl
Me
L5: Ar = 4-F-C6H4
L6: Ar = 4-Cl-C6H4
L7: Ar = 4-NO2-C6H4
L8: Ar = 4-CF3-C6H4
Ph
CO2Et
low
yields
(23%
and
31%)
with
only
moderate
NO2
4ac
enantioselectivities (79% and 83% ee) (entries 3 and 4). This
suggested that β-nitroacrylates were more challenging
substrates than the corresponding β-nitroolefines. While
frustrated by the results obtained when applying our proprietary7j
set of chiral 2,5-diarylbicyclo[2.2.1]heptadiene ligands (L2–L8)
to the reaction of 2a and 2b,10 when the addition reaction was
tested on the α-substituted nitroacrylate 2c instead, the
corresponding addition product 3ac was produced in 42% yield
with 97% ee (entry 5). A substantial amount of the reaction mass
balance was accounted for by the formation of styrene 5ac;
MeO
Me
Ph
H
O
Ph
Ph
PPh2
PPh2
S
N
tBu
H
Ph
H
Ph
L9
L10
L11
L12
L13
Additiv
e
t
Time
(h)
3ac/
Yield
(%)[c]
ee
Entry
2
L
(°C)
5ac[b]
(%)[d]
1
2
2a
2b
L1
L1
KHF2
KHF2
50
50
24
24
N.D.
N.D.
N.R.
N.R.
23
N.D.
N.D.
1
isolated in 32% yield. In fact, H NMR spectroscopic analysis of
the crude product mixture revealed that 3ac and 5ac were
formed in a 1.2:1 ratio indicating that the conjugate addition had
proceeded with only slight regioselectively. To explain the
formation of 5ac, it is probable that ethyl 2-methyl-3-nitro-3-
3
4
2a
2b
2c
2c
2c
2c
2c
L1
L1
L1
L1
L1
L1
L2
KOH
KOH
KHF2
KHF2
KHF2
KHF2
KHF2
50
50
50
40
40
24
40
24
24
3
N.D.
N.D.
1.2
79
(3aa)
31
(3ab)
83
97
99
96
98
51
phenylpropionate (4ac) was produced as
a
transient
intermediate that then underwent elimination of nitrous acid.11
The yield, regioselectivity and ee were slightly improved when
the reaction of 2c was performed at 40 °C (entry 6), but reducing
the catalyst loading to 3 mol% of Rh(I) resulted in a significant
decrease in reaction rate and a small decrease in the ee (entry
7). Conducting the reaction at room temperature garnered no
improvement (entry 8).
42
(3ac)
5[e]
53
(3ac)
6
3
1.3
42
(3ac)
7[f]
8
12
18
24
1.5
Having previously found that Rh(I)-catalyzed 1,2- and 1,4-
addition reactions each require different ligands for optimum ees
for each specific substrate class, we next screened our library7j
of 2,5-substituted chiral bicyclo[2.2.1]heptadiene ligands (entries
9–15) using the conditions of entry 6 (toluene, 40 °C, 3 h). In all
cases the ees and yields were lower than that of entry 6, despite
the regioselectivity being significantly improved (3ac/5ac ratio
was 4.7:1 and 4.5:1) when using the di-(4-fluorophenyl)- and di-
(4-trifluoromethylphenyl)- ligands L5 and L8 (entries 12 and 15),
36
(3ac)
1.0
12
(3ac)
9
3.2
14
(3ac)
10
11
2c
2c
L3
L4
KHF2
KHF2
40
40
24
24
3.8
3.7
44
62
18
2
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10.1002/chem.201604120
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FULL PAPER
(3ac)
3
4
NaHCO3
tBuOK
K2CO3
K3PO4
KF
toluene
toluene
toluene
toluene
toluene
toluene
toluene
xylene
THF
5
4
4
5
5
3
3
3
3
3
3
3
3
3
3
1.4
1.3
1.2
1.4
1.2
1.4
N.D.[e]
1.4
0.9
1.0
0.9
1.5
1.6
1.4
1.3
56
45
96
94
25
(3ac)
12
13
14
15
2c
2c
2c
2c
L5
L6
L7
L8
KHF2
KHF2
KHF2
KHF2
40
40
40
40
24
24
24
24
4.7
1.4
3.8
4.5
48
84
54
56
5
47
94
40
(3ac)
6
44
95
12
(3ac)
7
46
95
8
KOH
55
94
25
(3ac)
9
Et3N
N.R.[f]
45
N.D.[e]
96
16
17
18
19
20
2c
2c
2c
2c
2c
L9
KHF2
KHF2
KHF2
KHF2
KHF2
40
40
40
40
40
24
24
24
24
24
N.D.
N.D.
N.D.
N.D.
N.D.
N.R.
N.R.
N.R.
N.R.
N.R.
N.D.
N.D.
N.D.
N.D.
N.D.
10
11
12
13
14
15
16
17
KHF2
KHF2
KHF2
KHF2
KHF2
KHF2
KHF2
KHF2
L10
L11
L12
L13
28
96
dioxane
Et2O
38
96
22
97
CH2Cl2
MeOH
EtOH
39
95
[a] Conducted in toluene (0.8 mL) using β-nitroacrylate 2c (0.2 mmol), boronic
acid 1a (0.6 mmol, 3.0 equiv based on 2c) and KHF2 (3.0 M, 0.4 mL, 1.2
mmol) in the presence of Rh(I) catalyst prepared in situ from [RhCl(C2H4)2]2
(5.0 µmol, 5.0 mol% of Rh) and chiral diene L1 (12 µmol, 6.0 mol%); reactions
were worked up when TLC indicated completion, or at 24 h, whichever came
first. N.D. = not determined. N.R. = no reaction; recovered starting material. [b]
Ratios determined by 1H NMR spectroscopic analysis of the crude reaction
mixture. [c] Isolated yield. [d] Determined by HPLC analysis using chiral
columns. [e] A 32% yield of 5ac was isolated. [f] Rh(I) catalyst prepared in situ
from [RhCl(C2H4)2]2 (3.0 µmol, 3.0 mol% of Rh) and chiral diene L1 (7.2 µmol,
3.6 mol%).
37
95
37
95
iPrOH
41
96
[a] The reaction was conducted in toluene (0.8 mL), unless otherwise stated,
using β-nitroacrylate 2c (0.2 mmol), boronic acid 1a (0.6 mmol, 3.0 equiv
based on 2c) and KHF2 (3.0 M, 0.4 mL, 1.2 mmol), in the presence of rhodium
catalyst prepared in situ from [RhCl(C2H4)2]2 (5.0 µmol, 5.0 mol% of Rh) and
chiral diene L1 (12 µmol, 6.0 mol%); reactions were monitored by TLC.
Variation: other additives (1.0 M, 0.4 mL) or solvents were used. [b] Ratios
determined by 1H NMR spectroscopic analysis of crude reaction mixture. [c]
Isolated yield. [d] Determined by HPLC analysis using a chiral AS-H column.
[e] N.D. = not determined. [f] N.R. = no reaction; recovered starting material.
Using the general conditions specified in Table 1, entry 6, a
screen of base additives and solvents was conducted next using
phenylboronic acid (1a) and (E)-2-methyl-3-nitroacrylate (2c).
While the majority of the common bases tested afforded
comparable yields of 3ac (44–47%) and ees (94–95%), NaHCO3
(entry 3) and KOH (entry 8) provided moderately improved
yields of 56% and 55%, respectively (Table 2, entries 1–8).
While amines bases have proven optimal in some addition
reactions of boronic acids to Michael acceptors,7a,7f,7g no reaction
was observed when Et3N was employed in the present study
(entry 9). In terms of ee, however, no base additive provided
better results than was achieved with KHF2 (Table 1, entry 6),
and therefore this was used in subsequent tests. While the
reaction performed effectively in a variety of solvents with ees of
95–97% (entries 10–17), yields of 3ac were inferior to that
achieved in toluene (Table 1, entry 6). Notably, carrying out the
reaction in MeOH or iPrOH in the presence of KHF2 produced no
transesterification products (entries 15 and 17).
Using the preferred conditions (Table 1, entry 6), the
asymmetric addition of a variety of electron rich and electron
poor arylboronic acids 1 to β-nitroacrylate 2c was examined next
(Table 3). While the reactions of 3-tolyl- and 4-tolylboronic acids
(1b and 1c) gave addition products 3bc and 3cc in 50 and 47%
yield, respectively, with high stereoselectivities (entries 1 and 2),
no reaction was observed when the conjugate addition of 2-
tolylboronic acid (1d) (entry 4) was attempted, presumably a
result of the bulky ortho substituent. The chemical yield of 3cc
was slightly higher when the reaction of 2c and 4-tolylboronic
acid (1c) was conducted in the presence of NaHCO3 (entry 3)
instead of KHF2. Arylboronic acids bearing electron releasing
groups at their 3- or 4-positions were good reaction partners
(entries 5–8), providing addition products 3ec–3hc in 45–63%
yield with 94–97% ee. While the asymmetric addition of sterically
encumbered 1-naphthylboronic acid (1i) proceeded very
inefficiently (entry 9), reaction of its isomer, 2-naphthylboronic
acid (1j), afforded 3jc in a relatively pleasing 51% yield with 95%
ee (entry 10). Arylboronic acids possessing electron withdrawing
groups were examined next (entries 11–17). While 4-
fluorophenylboronic acid (1k) afforded a satisfying 59% yield of
3kc with 94% ee (entry 11), 4-chloro- (1l), 3,4-dichloro- (1m), 3-
NO2- (1n), 3-CF3- (1o) and 4-CF3-phenylboronic acid (1p) all
proceeded slowly giving low 7–24% yields (18–49% yield based
on recovered starting material) of addition products 3lc–3pc
Table 2. Additive and solvent screening[a]
[RhCl(C2H4)2]2 (5.0 mol% of Rh)
Me
CO2Et
Me
CO2Et
Me
L1 (6.0 mol%)
Ph
+
+
PhB(OH)2
O2N
O2N
Ph
CO2Et
additive, solvent, 40 °C, time
1a
2c
3ac
5ac
Time
(h)
Entry
Additive
Solvent
3ac/5ac[b]
3ac (%)[c]
ee (%)[d]
1
2
LiOH
toluene
toluene
5
1.3
1.4
47
44
95
95
NaOH
7
3
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10.1002/chem.201604120
Chemistry - A European Journal
FULL PAPER
after 24 hours of reaction (entries 12–17). Despite this, good to
high enantioselectivities (87–95% ee) were witnessed for these
substrates. Moreover, conducting the asymmetric addition
reaction employing (E)-styrylboronic acid (1q) furnished the
corresponding adduct 3qc in 20% yield and with diminished
stereoselectivity (75% ee) (entry 18).
also investigated. Keeping the α-substituent fixed as methyl,
addition to esters 2d–2h afforded the desired nitropropionates
3ad–3ah in 20–41% yields with 99% ee in all cases (entries 1–
5). A substantial decrease in stereoselectivity was observed
when the α-substituent of nitroacrylates 2 was changed to ethyl
((E)-2i and (E)-2j) with the corresponding addition products
produced in 33% and 23% yield with 84% and 73% ee,
respectively (entries 6 and 7). Again fixing the primary α-
substituent as methyl, conjugate addition of 1a to the (Z)-
geometric isomers 2c–2g proceeded with comparably lower
levels of reactivity (entries 8–12 versus entries 1–4 and Table 1,
entry 6). As with the other 2-ethyl-3-nitropropionate substrates 3,
addition to (Z)-2i and (Z)-2j also proved challenging with
diminished yields and selectivities being witnessed (entries 13
and 14). Notably, the major enantiomers obtained from
conjugate additions to (E)-2 or (Z)-2 were determined to have R-
configuration in all cases. The scalability of the method was
demonstrated on a 1.0 g scale of (E)-2c using phenylboronic
acid (1a). (R)-1,1-Methyl-1-phenyl-3-nitropropionate (3ac) was
isolated in 55% yield with 99% ee (entry 15), consistent with the
small scale result reported in Table 1, entry 6.
Table 3. Asymmetric addition of arylboronic acids 1 to β-nitroacrylate 2c[a]
[RhCl(C2H4)2]2 (5.0 mol% of Rh)
Me
CO2Et
Me
L1 (6.0 mol%)
Ar
+
ArB(OH)2
O2N
O2N
KHF2, toluene, 40 °C, time
CO2Et
1
2c
3
Entry
Ar
Time (h)
3 (%)[b]
ee (%)[c]
1[d]
2
3-Me-C6H4 (1b)
4-Me-C6H4 (1c)
4-Me-C6H4 (1c)
2-Me-C6H4 (1d)
4-tBu-C6H4 (1e)
4-Ph-C6H4 (1f)
3-MeO-C6H4 (1g)
4-MeO-C6H4 (1h)
1-Naphthyl (1i)
2-Naphthyl (1j)
4-F-C6H4 (1k)
24
3
50 (3bc)
47 (3cc)
53 (3cc)
N.R.
96
97
97
N.D.
97
94
96
95
72
95
94
93
93
87
95
92
92
75
3[e]
3
4
24
24
16
16
16
24
3
5[d]
63 (3ec)
48 (3fc)
47 (3gc)
45 (3hc)
7 (11)[f] (3ic)
51 (3jc)
59 (3kc)
Table 4. Asymmetric addition of phenylboronic acid (1a) to β-nitroacrylates 2[a]
6[d]
7[d]
[RhCl(C2H4)2]2 (5.0 mol% of Rh)
R1
R1
L1 (6.0 mol%)
Ph
+
PhB(OH)2
O2N
O2N
CO2R2
CO2R2
KHF2, toluene, 40 °C, time
8[d]
1a
2
3
9[d]
Tim
e (h)
Entry
2
3 (%)[b]
ee (%)[c]
10
11[d]
12[d]
13[d]
14
24
24
24
12
24
24
24
24
1
2
R1 = Me, R2 = Me [(E)-2d]
R1 = Me, R2 = iPr [(E)-2e]
R1 = Me, R2 = tBu [(E)-2f]
R1 = Me, R2 = Bn [(E)-2g]
3
3
32 (3ad)
99
99
4-Cl-C6H4 (1l)
24 (49)[f] (3lc)
7 (38)[f] (3mc)
12 (21)[f] (3nc)
18 (49)[f] (3oc)
13 (18)[f] (3pc)
15 (31)[f] (3pc)
20 (39)[f] (3qc)
34 (3ae)
32 (3af)
20 (3ag)
41 (3ah)
33 (3ai)
23 (3aj)
36 (3ac)
42 (3ad)
38 (3ae)
26 (3af)
19 (3ag)
18 (3ai)
19 (3aj)
55 (3ac)
3,4-Cl2-C6H3 (1m)
3-NO2-C6H4 (1n)
3-CF3-C6H4 (1o)
4-CF3-C6H4 (1p)
4-CF3-C6H4 (1p)
C6H5CH=CH (1q)
3
3
99[d]
99
4
3
15[d]
16[d]
17[e]
18[d]
5
R1 = Me, R2 = 2,6-DMP[e] [(E)-2h]
R1 = Et, R2 = Me [(E)-2i]
R1 = Et, R2 = Et [(E)-2j]
R1 = Me, R2 = Et [(Z)-2c]
R1 = Me, R2 = Me [(Z)-2d]
R1 = Me, R2 = iPr [(Z)-2e]
R1 = Me, R2 = tBu [(Z)-2f]
R1 = Me, R2 = Bn [(Z)-2g]
R1 = Et, R2 = Me [(Z)-2i]
R1 = Et, R2 = Et [(Z)-2j]
3
99
6
12
12
12
12
12
12
12
12
12
7
84
7
73
8
86
9
96
[a] Conducted in toluene (0.8 mL) using β-nitroacrylate 2c (0.2 mmol), boronic
acids 1 (0.6 mmol, 3.0 equiv based on 2c) and KHF2 (3.0 M, 0.4 mL, 1.2
mmol) in the presence of rhodium catalyst prepared in situ from [RhCl(C2H4)2]2
(5.0 µmol, 5.0 mol% of Rh) and chiral diene L1 (12 µmol, 6.0 mol%); reactions
were worked up when TLC indicated completion, or at 24 h, whichever came
first; ratios of regioisomers 3/5 ranged 0.3–1.7, as determined by 1H NMR
spectroscopic analysis of crude mixtures. [b] Isolated yield. [c] Determined by
HPLC analysis. [d] Additional KHF2 (3.0 M, 0.4 mL) was added after 12 h. [e]
NaHCO3 (1.0 M, 0.4 mL, 0.4 mmol) was used as an additive. [f] Yield based on
recovered 2c.
10
11
12[f]
13
14[g]
15[h]
86
91[d]
73
77
73
Having shown that a variety of aryl substituents could be
stereoselectively incorporated into the α-position of 1-methyl-3-
nitropropionates 3 by conjugate addition (Table 3), we next
examined the variation of the other α-substituent using
phenylboronic acid (1a) as the nucleophile donor (Table 4). The
influences of the ester group and double bond geometry were
R1 = Me, R2 = Et [(E)-2c]
99
[a] Conducted in toluene (0.8 mL) using β-nitroacrylates
2
(0.2 mmol),
phenylboronic acid (1a) (0.6 mmol, 3.0 equiv based on 2c) and KHF2 (3.0 M,
0.4 mL, 1.2 mmol) in the presence of rhodium catalyst prepared in situ from
[RhCl(C2H4)2]2 (5.0 µmol, 5 mol% Rh) and chiral diene L1 (12 µmol, 6.0
4
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10.1002/chem.201604120
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mol%); reactions were worked up when TLC indicated completion, or at 12 h,
whichever came first; ratios of regioisomers 3/5 ranged 0.7–2.6, as determined
by 1H NMR spectroscopic analysis of crude mixture. [b] Isolated yield. [c]
Determined by HPLC analysis. [d] The ee was determined by converting 3af
into 3ad. [e] 2,6-Dimethylphenyl. [f] 46% of (E)-2g and 24% of (Z)-2g were
isolated, respectively. [g] 38% of (E)-2j and 16% of (Z)-2j were isolated,
respectively. [h] Conducted on a 1.0 g (6.4 mmol) scale.
Re-face of (E)-2d in complex 9a, which would give rise to the
observed product (R)-3ad, was preferred by 3.3 kcal/mol over
the corresponding Si-face-coordinated complex 9b due to
repulsion between the nitro group and the 1-naphthyl group of
the ligand backbone. Furthermore, complex 9a, where the ester
group directs away from the ligand substituent, explains the high
stereoselectivity observed for the addition to (E)-substrates
containing distinct ester groups (Table 3, entries 1–5).
NiCl2·6H2O, NaBH4
0 °C to rt, 1 h
HCl, H2O
> 99%
Me Ph
O2N
Me Ph
H2N
Me Ph
H3N
87%
CO2Et
CO2Et
CO2H
Cl
3ac (99% ee)
6
7
iPrMgCl, THF
0 °C to rt, 19 h
40%
CO2Me
O2N
Ph
O
Me
Me
NH
3ad
8 (99% ee)
Scheme 2. Syntheses of β2,2-amino acid 7 and β2,2-lactam 8
9a (0.0 kcal/mol)
To demonstrate the utility of the method, the syntheses of a
β2,2-amino acid and a β2,2-lactam were conducted. Treatment of
3-nitropropionate 3ac with in situ-generated nickel boride
afforded β-amino ester 6 in 87% yield, from which β2,2-amino
acid 7 was obtained in quantitative yield upon acid-catalyzed
hydrolysis (Scheme 2). Single crystal X-ray analysis of 7
unambiguously confirmed that the absolute configuration was R.
Base-promoted cyclization13 of β-amino ester 6, on the other
hand, furnished chiral α,α-disubstituted β-lactam 8 in 40% yield,
notably without the loss of the high ee of precursor 3ac. Further
demonstration of the utility of our method was obtained by the
synthesis of a tripeptide consisting of a β2,2-amino acid and α-
amino acids (Scheme 3). Dipeptide 11 was obtained in 91%
yield from amide bond formation between β-amino ester 6 and
N-tosyl-protected L-phenylalanine 10 under standard reaction
conditions.14 Coupling of acid 12, obtained following the base
hydrolysis of 11, with L-alanine methyl ester (13) furnished
tripeptide 14 in 87% yield.
9b (+3.3 kcal/mol)
9c (+7.3 kcal/mol)
9d (+10.1 kcal/mol)
Figure 1. DFT optimized stereochemical structures and energy diagrams of
the putative intermediates of (E)-2d and (Z)-2d, and Rh(I)/L1
In contrast to that observed empirically, however, according
to the calculations coordination of the Rh(I) center to the Re-face
of (Z)-2d (complex 9d), that would lead to the (R)-product, is
disfavored over the corresponding Si-face coordination complex
9c, that would afford the (S)-product, by 2.8 kcal/mol. This
discrepancy
between
the
calculated
and
observed
stereoselectivity can be explained by in situ isomerization of the
(Z)-isomers to the (E)-isomers. Indeed, this was supported by
the observation that the crude 1H NMR spectra from the
reactions of (Z)-substrates comprised mixtures of unreacted (Z)-
nitroacrylates as well as their (E)-isomers. This phenomenon
was particularly evident in the conjugate addition reaction of (Z)-
2g (Table 3, entry 12) where purification of the crude product
mixture yielded 24% of unreacted (Z)-2g and 46% of (E)-2g.
Similarly, in the case of (Z)-2j (entry 14), 38% of (E)-2j and 16%
of unreacted (Z)-2j were isolated following termination of the
reaction. The driving force for the isomerization might be
explained by the calculated energies of both 9c and 9d being
greater than that of 9a by 7.3 and 10.1 kcal/mol, respectively.
Moreover, calculations show that the (E)-isomer, (E)-2d, is 2.3
kcal/mol lower in energy than its (Z)-isomer, (Z)-2d. The
generally much lower ees observed in conjugate additions to the
(Z)-nitroacrylates (Table 4, entries 8 and 10–14), as compared
to addition to the corresponding (E)-nitroacrylates, is consistent
with incomplete (Z)- to (E)-isomerization during the reaction.
Ph
Ph
H
cat. DMAP, EDCI
N
6
+
+
TsHN
H2N
CO2Me
CH2Cl2, 0 °C to rt
16 h, 91%
TsHN
CO2H
O
CO2R
Ph
10
11 R = Et
13
LiOH, THF / H2O
12 R= H
reflux, 6 h, quant.
Ph
H
N
cat. DMAP, EDCI
TsHN
H
CH2Cl2, 0 °C to rt
16 h, 87%
O
N
Ph
O
CO2Me
14
Scheme 3. Syntheses of tripeptide 14 comprising a β2,2-amino acid
To understand the observed stereochemical outcome of the
addition reaction, DFT calculations employing the restricted
M06L method15 with Ahlrichs’ basis set16 were performed using
the Gaussian 09 program.17 As depicted in Figure 1, these
calculations indicated that coordination of the Rh(I) center to the
5
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FULL PAPER
analysis on Chiralpak AD-H, AS-H, or IA columns, or on a Chiralcel OJ-H
column (Daicel Chemical Industries, Ltd). Boronic acids 1 that were
commercially available were used as supplied and/or were prepared
using methods reported in the literature.18 Substrates 2 were prepared
according to the literature.4d,4g,19 Chiral diene ligands L1-L87a and L1212d
were prepared according to the reported procedure; ligands L9–L13 are
commercially available.
Conclusions
In conclusion, the enantioselective 1,4-conjugate addition
reaction of arylboronic acids to α-substituted β-nitroacrylates in
the presence of Rh(I)-catalysts comprising chiral diene ligands
has been reported for the first time. Chiral diene ligand L1 was
found to give the best results. While the corresponding 1,4-
conjugate addition reaction to β-nitroolefins that we reported7d
General procedures for rhodium-catalyzed 1,4-addition reactions:
Under a N2 atmosphere, to a mixture of [RhCl(C2H4)2]2 (1.93 mg, 5.0
µmol, 5.0 mol% of Rh), chiral ligand L1 (4.63 mg, 12.0 µmol, 6.0 mol%),
phenylboronic acid 1a (0.6 mmol, 3.0 equiv) and (E)-nitroacrylate 2c (0.2
mmol, 1.0 equiv) was added toluene (0.8 mL) and aqueous KHF2 (3.0 M,
0.4 mL, 1.2 mmol, 6.0 equiv). The resulting mixture was heated to 40 °C.
After TLC indicated completion, or at 24 h, whichever came first, the
product mixture was concentrated in vacuo and the residue was purified
by column chromatography over silica gel (hexanes / ethyl acetate, 50 / 1
to 3 / 1) to afford the desired product 3ac (25.1 mg, 53% yield) as a
colorless oil.
earlier
displayed
excellent
results,7d
the
moderate
regioselectivies and the relatively modest yields in the current
study clearly show that α-substituted β-nitroacrylates are
considerably more challenging substrates. In fact, this and the
fact that related ligands L9–L13 failed to provide any product in
the presence of Rh(I) might explain the absence of prior
publications for this conversion employing variants of the
Hayashi−Miyaura reaction. Despite this, the stereoselectivities
achieved in the study described herein were generally high to
very high (up to 99% ee) and the method tolerated a host of
arylboronic acids as nucleophile donors, providing (R)-
configured α,α-disubstituted β-nitropropionates. Screening
studies showed that a diverse range of bases and solvents could
be used, and this might prove useful when optimizing the
reaction conditions for a specific set of reactants and their target.
The conjugate addition to (E)- and (Z)-α-substituted β-
nitroacrylates both furnished (R)-configured products, contrary to
that anticipated based on in silico analysis. This is explained by
in situ geometric isomerization, driven by the higher
thermodynamic stability of the (E)-isomer, before the Rh(I)-
catalyzed asymmetric reaction takes place.
(R)-Ethyl 2-methyl-3-nitro-2-phenylpropanoate (3ac)
Rf 0.65 (hexanes / ethyl acetate, 3 / 1). On a 1.0 g reaction scale, 830 mg,
55% yield, of 3ac was isolated. Ee was determined on a Daicel Chiralpak
AS-H column (250 mm) eluting with hexanes / 2-propanol, 95 / 5, flow =
1.0 mL/min; retention times: 11.36 min ((S)-enantiomer) and 13.09 min
((R)-enantiomer). 99% ee; [α]!!" +29.7 (c 1.00 in CHCl3); 1H NMR (400
MHz, CDCl3): δ 7.40–7.30 (m, 5H), 5.19 (d, J = 13.4 Hz, 1H), 4.69 (d, J =
13.4 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 1.79 (s, 3H), 1.25 (t, J = 7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3): δ 172.5, 138.5, 129.0, 128.2, 125.8,
81.9, 62.0, 49.8, 20.9, 13.9; FT-IR (KBr, neat): ν̃ 2980, 2930, 1734, 1557,
1456, 1378, 1227, 1128, 1022, 868, 770, 702, 661, 606, 536 cm-1; HRMS
(EI): m/z calcd for C12H15NO4 [M] 237.1001, found 237.1000.
Finally, the utility of the reaction was demonstrated by the
synthesis of non-proteinogenic β2,2-amino acid 7 that contains a
chiral, all-carbon quaternary center; obtained from α,α-
disubstituted β-nitropropionate 3ac. Additionally, conversion of
3ac to β2,2-lactam 8 and the conversation of β-amino ester 6 to
tripeptide 14 were established. Studies towards the development
of a catalytic system that can enhance the chemical yields of this
transformation are currently under investigation in our laboratory.
Reduction of 3ac: To a suspension of 3ac (39.2 mg, 0.17 mmol) and
NiCl2•6H2O (40.0 mg, 0.17 mmol) in MeOH (1.3 mL) was added NaBH4
(32.3 mg, 0.85 mmol) at 0 °C and the mixture was stirred at rt for 1 h.
The mixture was quenched with sat. NH4Cl(aq) at 0 °C and extracted with
CH2Cl2 (5 mL ×3). The combined organic layer was washed with brine,
dried over Na2SO4, filtered and concentrated under reduced pressure.
The crude product was purified by column chromatography on silica gel
(eluting with MeOH / CH2Cl2, 1 / 10) to afford product 6 (29.8 mg, 87%)
as an orange liquid.
(R)-Ethyl 3-amino-2-methyl-2-phenylpropanoate (6)
1
Rf 0.10 (hexanes / ethyl acetate, 1 / 1); [α]!!" +10.9 (c 1.00 in CHCl3); H
Experimental Section
NMR (400 MHz, CDCl3): δ 7.37–7.31 (m, 3H), 7.29–7.23 (m, 2H), 4.23–
4.12 (m, 2H), 3.17 (d, J = 13.4 Hz, 1H), 3.03 (d, J = 13.4 Hz, 1H), 1.65
(br, 2H), 1.60 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3): δ 175.6, 141.6, 128.6, 127.0, 126.2, 60.8, 52.7, 51.1, 21.0, 14.1;
General
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 monitored by TLC using Merck
60 F 254 silica gel plates; zones were detected visually under ultraviolet
irradiation (254 nm) or by spraying with KMnO4 solution followed by
heating with a heat 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
relative to the deuterated solvent signal for 13C NMR spectroscopy or the
residual 1H-solvent signal for 1H NMR spectroscopy. First order spin
multiplicities are abbreviated as singlet (s), doublet (d), triplet (t),
quadruplet (q), doublet of doublets (dd) and septet (sep); multiplets are
abbreviated as (m). High-resolution mass spectra were obtained using EI
and ESI ionization methods. Optical rotations were measured on a Jasco
P-2000 polarimeter. Enantiomeric excessed were determined by HPLC
FT-IR (KBr, neat): ν̃ 3378, 2971, 2930, 1724, 1456, 1379, 1249, 1147,
1024, 863, 762, 699 cm-1; HRMS (ESI) m/z calcd for C12H18NO2 [M + H+]
208.1338, found 208.1339.
Hydrolysis of 6: To 6 (30.0 mg, 0.15 mmol) was added 6 N HCl (1.0 mL)
and the mixture was stirred at 80 °C overnight. Water was then removed
under reduced pressure to give 7 (26.8 mg, quant.) as a white solid.
(R)-3-Amino-2-methyl-2-phenylpropanoic acid hydrochloride (7)
Mp 282–283 °C; [α]!!" +29.5 (c 1.00 in H2O); 1H NMR (400 MHz, D2O): δ
7.54–7.49 (m, 2H), 7.46–7.41 (m, 3H), 3.46 (s, 2H), 1.75 (s, 3H); 13C
NMR (100 MHz, D2O): δ 178.1, 138.3, 129.4, 128.6, 126.4, 49.0, 46.9,
20.4. HRMS (ESI) m/z calcd for C10H14NO2 [M + H+] 180.1025, found
180.1024.
6
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10.1002/chem.201604120
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Synthesis of 8: To a solution of 6 (56.0 mg, 0.27 mmol) in dry THF (1.0
mL) was added PrMgCl (2.0 M in THF, 0.67 mL, 1.35 mmol) dropwise
126.2, 125.7, 61.4, 52.5, 47.5, 41.2, 21.2, 20.4. HRMS (ESI) m/z calcd
for C26H29N2O5S [M + H+] 481.1797, found 481.1794.
i
from a syringe at 0 °C. The resulting reaction mixture was stirred at rt for
19 h. The reaction was quenched with sat. NH4Cl(aq) (5.0 mL) and
extracted with ethyl acetate (8 mL ×3). The organic layer was washed
with brine, dried over Na2SO4, filtered and the volatiles were removed
under reduced pressure. The crude product was purified by column
chromatography on silica gel (eluting with ethyl acetate / hexanes, 1.5 /
1) to give 8 (17.4 mg, 40%) as a yellow liquid.
Synthesis of 14: To a solution of carboxylic acid 12 (45.5 mg, 0.09
mmol) and L-alanine methyl ester hydrochloride 13 (12.2 mg, 0.12 mmol)
in dry CH2Cl2 (1.0 mL) was added DMAP (1.1 mg, 0.01 mmol) and
EDCI•HCl (18.1 mg, 0.09 mmol) at 0 °C. After 1 h the reaction
temperature was warmed up to rt. After being stirred overnight, the
reaction mixture was diluted with CH2Cl2 and the organic layer was
washed with water, brine, dried over Na2SO4, filtered and concentrated in
vacuo. The residue was purified by column chromatography over silica
gel (eluting with hexanes / ethyl acetate, 3 / 1) to afford product 14 (46.6
mg, 87%) as a white solid.
(R)-3-Methyl-3-phenylazetidin-2-one (8)
Rf 0.25 (hexanes / ethyl acetate, 1 / 1). Ee was determined on a Daicel
Chiralcel OJ-H column (250 mm) eluting with hexanes / 2-propanol, 60 /
40, flow = 1.0 mL/min; retention times: 5.97 min ((S)-enantiomer) and
6.77 min ((R)-enantiomer). > 99.5% ee; [α]!!" −2.6 (c 1.00 in CHCl3); 1H
NMR (400 MHz, CDCl3): δ 7.45–7.40 (m, 2H), 7.38–7.32 (m, 2H), 7.30–
7.23 (m, 1H), 3.60 (d, J = 5.2 Hz, 1H), 3.46 (d, J = 5.2 Hz, 1H), 1.71 (s,
3H), 1.59 (br, 1H); 13C NMR (100 MHz, CDCl3): δ 172.6, 140.8, 128.7,
(S)-Methyl 2-((R)-2-methyl-3-((S)-2-(4-methylphenylsulfonamido)-3-
phenylpropanamido)-2-phenylpropanamido)propanoate (14)
Rf 0.70 (ethyl acetate); mp 49–50 °C; [α]!!" −47.0 (c 1.00 in CHCl3); 1H
NMR (400 MHz, CDCl3): δ 7.47 (d, J = 8.2 Hz, 2H), 7.40–7.29 (m, 5H),
7.18–7.05 (m, 5H), 6.93 (d, J = 7.1 Hz, 2H), 5.77 (d, J = 7.2 Hz, 1H), 5.11
(d, J = 7.2 Hz, 1H), 4.54 (quintet, J = 7.3 Hz, 1H), 3.87 (dd, J = 7.3, 13.4
Hz, 1H), 3.72 (s, 3H), 3.65 (dd, J = 5.4, 13.6 Hz, 1H), 3.47 (dd, J = 7.4,
13.6 Hz, 1H), 2.97 (dd, J = 5.9, 14.0 Hz, 1H), 2.84 (dd, J = 7.7, 14.0 Hz,
1H), 2.39 (s, 3H), 1.47 (s, 3H), 1.33 (d, J = 7.3 Hz, 3H); 13C NMR (100
MHz, CDCl3): δ 175.7, 173.6, 170.3, 143.5, 141.1, 136.1, 135.4, 129.6,
129.2, 128.8, 128.7, 127.7, 127.1, 127.0, 126.8, 58.1, 52.5, 51.6, 48.3,
127.1, 125.9, 60.3, 51.1, 23.5; FT-IR (KBr, neat): ν̃ 3938, 3855, 3446,
3336, 3024, 2925, 1739, 1647, 1024, 667, 509, 461 cm-1; HRMS (ESI)
m/z calcd for C10H12NO [M + H+] 162.0919, found 162.0919.
Synthesis of 11: To a solution of N-tosyl-protected L-phenylalanine 10
(31.9 mg, 0.10 mmol) and 6 (25.9 mg, 0.13 mmol) in dry CH2Cl2 (1.0 mL)
were added DMAP (1.2 mg, 0.01 mmol) and EDCI•HCl (20.0 mg, 0.10
mmol) at 0 °C. After 1 h the reaction temperature was warmed to rt. After
being stirred overnight, the reaction mixture was diluted with CH2Cl2, and
the organic layer was washed with water, brine, dried over Na2SO4,
filtered and concentrated in vacuo. The residue was purified by column
chromatography over silica gel (eluting with hexanes / ethyl acetate, 3 /
1) to afford product 11 (46.3 mg, 91%) as a white solid.
47.3, 38.7, 22.4, 21.5, 17.5; FT-IR (KBr, neat): ν̃ 3337, 3022, 2993, 2943,
1739, 1661, 1521, 1449, 1331, 1221, 1162, 1091, 949, 813, 754, 700,
667, 554 cm-1; HRMS (ESI) m/z calcd for C30H36N3O6S [M + H+]
566.2325, found 566.2325.
Acknowledgements
(R)-Ethyl 2-methyl-3-((S)-2-(4-methylphenylsulfonamido)-3-phenyl-
propanamido)-2-phenylpropanoate (11)
Rf 0.80 (ethyl acetate); mp 123–124 °C; [α]!!" −17.6 (c 1.00 in CHCl3); 1H
NMR (400 MHz, CDCl3): δ 7.46 (d, J = 8.2 Hz, 2H), 7.36–7.29 (m, 2H),
7.29–7.20 (m, 3H), 7.20–7.09 (m, 5H), 6.87 (d, J = 6.9 Hz, 3H), 4.77 (d, J
= 6.0 Hz, 1H), 4.29–4.08 (m, 2H), 3.76 (dd, J = 6.0, 13.8 Hz, 1H), 3.60
(qd, J = 7.2, 13.8 Hz, 2H), 2.94 (dd, J = 6.0, 14.0 Hz, 1H), 2.75 (dd, J =
Financial support from Ministry of Science and Technology of
Republic of China (102-2113-M-003-006-MY2 & 104-2628-M-
003-001-MY3) is gratefully acknowledged. We thank Dr. Julian P.
Henschke for assistance with the preparation of this manuscript.
8.0, 14.0 Hz, 1H), 2.41 (s, 3H), 1.52 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H); 13
C
Keywords: conjugate addition • β2,2-amino acid • rhodium •
NMR (100 MHz, CDCl3): δ 175.4, 170.1, 143.8, 140.9, 135.5, 135.2,
chiral diene • enantioselective synthesis
129.7, 129.0, 128.9, 128.6, 127.3, 127.19, 127.16, 125.9, 61.4, 58.0,
51.7, 47.3, 38.3, 21.5, 20.5, 14.0; FT-IR (KBr, neat): ν̃ 3268, 2986, 2937,
1719, 1664, 1453, 1330, 1251, 1158, 1092, 1025, 947, 813, 753, 699,
669, 554 cm-1; HRMS (ESI) m/z calcd for C28H33N2O5S [M + H+]
509.2110, found 509.2111.
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[2]
F. Kudo, A. Miyanaga, T. Eguchi, Nat. Prod. Rep. 2014, 31, 1056–1073.
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Antibiotics; Academic Press: New York, 1982; Vols. 1–3; b) B. Alcaide,
P. Almendros, C. Aragoncillo, Chem. Rev. 2007, 107, 4437–4492; c) R.
P. Cheng, S. H. Gellman, W. F. DeGrado, Chem. Rev. 2001, 101,
3219–3232; d) D. Seebach, J. Gardiner, Acc. Chem. Res. 2008, 41,
1366–1375.
Hydrolysis of 11: To a solution of 11 (25.4 mg, 0.05 mmol) in THF / H2O
(4 / 1, v / v, 1.0 mL), LiOH (3.6 mg, 0.15 mmol) was added at rt. The
reaction mixture was heated to reflux for 6 h, and then the volatiles were
removed under reduced pressure. The residue was diluted with distilled
H2O and the aqueous layer was washed with diethyl ether. The aqueous
phase was concentrated to give the amino acid 12 (25.0 mg, quant.) as a
white solid.
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13.3 Hz, 1H), 3.15 (d, J = 13.3 Hz, 1H), 2.75–2.65 (m, 1H), 2.57–2.43 (m,
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[RhCl(C2H4)2]2 (5.0 mol% of Rh)
L1 (6.0 mol%)
R1
R1
Ar
Ar
+
ArB(OH)2
O2N
O2N
Page No. – Page No.
CO2R2
CO2R2 KHF2, toluene, 40 °C, 3–24 h
Ar
L1 : Ar = 1-Naphthyl
23 examples
7–63% yield
72–99% ee
Title
The asymmetric conjugate addition of arylboronic acids to α-substituted β-
nitroacrylates in the presence of 5 mol% of chiral Rh(I) catalysts afforded the
corresponding α,α-disubstituted β-nitropropionates in up to 63% yield and 99% ee
at 40 °C.
9
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