Catalytic asymmetric insertion of diazoesters into Aryl-CHO bonds: Highly enantioselective construction of chiral all-carbon quaternary centers

Article abstract of DOI:10.1021/ja408196g

This paper describes a catalytic enantioselective route to synthesize functionalized all-carbon quaternary acyclic systems via a boron Lewis acid-promoted formal C-C insertion of diazoesters into aryl-CHO bonds. In the presence of chiral (S)-oxazaborolidinium cation 1d as a catalyst, the reaction proceeded in good yield (up to 83%) with good regioselectivity (up to 88:12) and excellent enantioselectivity (up to 99% ee). The synthetic potential of this method was illustrated by conversion of the products to both α-and β-amino esters.

Full text of DOI:10.1021/ja408196g

Communication
pubs.acs.org/JACS
Catalytic Asymmetric Insertion of Diazoesters into Aryl-CHO Bonds:
Highly Enantioselective Construction of Chiral All-Carbon Quaternary
Centers
Lizhu Gao, Byung Chul Kang, and Do Hyun Ryu*
Department of Chemistry, Sungkyunkwan University, Suwon, Gyeonggi-do 440-746, Korea
S
* Supporting Information
= H) and aryl aldehydes. In 2008, the Maruoka group
ABSTRACT: This paper describes a catalytic enantiose-
presented a chiral auxiliary-based approach to formal C−C
insertion of aryl diazoacetates into aldehydes.2j To the best of
lective route to synthesize functionalized all-carbon
quaternary acyclic systems via a boron Lewis acid-
promoted formal C−C insertion of diazoesters into aryl-
CHO bonds. In the presence of chiral (S)-oxazaborolidi-
nium cation 1d as a catalyst, the reaction proceeded in
good yield (up to 83%) with good regioselectivity (up to
88:12) and excellent enantioselectivity (up to 99% ee).
The synthetic potential of this method was illustrated by
conversion of the products to both α- and β-amino esters.
our knowledge, no catalytic asymmetric example of this
reaction has been reported to date. In connection with our
work on asymmetric Roskamp reactions,4c herein, we describe
the first example of the catalytic asymmetric formal carbon
insertion of alkyldiazoesters into aryl-CHO bonds. This
methodology is highly valuable since it leads to the
enantioselective construction of all-carbon quaternary stereo-
genic centers in acyclic systems, which is one of the most
challenging topics in current synthetic organic chemistry.5
Initially, an asymmetric formal C−C insertion reaction
between ethyl α-benzyl diazoester and benzaldehyde was
examined in the presence of 20 mol % oxazaborolidinium ion
1a6 activated by triflic imide. When the reaction was carried out
at −78 °C in toluene, the α-benzyl-β-ketoester 3 was obtained
as the major product via a selective 1,2-hydride shift (Table 1,
entry 1). Use of the polar solvent propionitrile led to an
increased ratio of the quaternary aldehyde in 96% ee (Table 1,
entry 2).2f,g Since partial decomposition of the quaternary
aldehyde was observed during purification on a silica gel
column,7 product 2 was isolated by silica gel chromatography at
−40 °C. Replacement of the ethyl group of the diazoester with
a less sterically hindered methyl group afforded the quaternary
aldehyde 2b as the major product in 55% yield in 95% ee (entry
3). We then investigated the effect of changing boracycle
catalyst substituents and found that the best boron aryl
substituent was the 2,4-dimethyl derivative (entries 3−6). To
further improve the regioselectivity and yield, the reaction was
performed at −95 °C. The yield of 2 was enhanced to 72%,
with a 2:3 ratio of 74:26 and in 97% ee (entry 7).
ild and selective C−C bond insertion reactions provide
M
potential advantages for synthetic strategies to make
useful molecules.1,2 Among developments in this area, the
formal diazo carbon insertion into C−C bonds is a powerful
tool for the homologation of aldehydes and ketones (Scheme
1).2 In this type of reaction, the formal C−H bond insertion
Scheme 1. Asymmetric Formal Insertion of a Diazoester into
the Carbon-CHO Bond
With optimized reaction conditions for the catalytic
asymmetric formal C−C insertion reaction in hand, we
evaluated this methodology with a range of substituted
diazoesters. As summarized in Table 2, catalytic formal C−C
insertion reactions were favored when the diazoester R2 group
had a π bond, especially a phenyl group (Table 2, entries 1 and
2). In the absence of a π bond in the R2 group, the formal C−H
insertion reaction was preferred (entry 3). Regardless of the
electronic properties of the R2 group in the diazoester, the
reaction proceeded with good regioselectivity, and the
corresponding products were obtained in good yields and
reaction of aldehydes via a 1,2-hydride shift, namely, the
Roskamp reaction, has been well established,3 and asymmetric
methods providing chiral β-keto esters have recently been
achieved (path a).4 However, the corresponding formal C−C
bond insertion to provide one-carbon homologated aldehydes
is more challenging due to the difficulty of promoting the
selective 1,2-shift of the R3 group in preference to the hydride
(path b).
To date, Hossain,2a−d Kanemasa,2e Kirchner,2f,g and other
groups2h,i have independently reported catalytic variants of the
insertion reaction, which can allow the 1,2-shift of an R3 group
in preference to a hydride, using simple ethyl diazoacetates (R2
Received: August 9, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja408196g | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
As summarized in Table 3, although the electronic properties
of the aryl aldehydes varied significantly, the reactions produced
Table 1. Optimization of Asymmetric Formal Insertion of α-
Benzyl Diazoester into Ph−CHO Bond
a
Table 3. Asymmetric Formal Insertion of Diazoesters into
a
Various Aryl-CHO Bonds
b
c
d
entry
2
R2
R3
2:3
yield (%)
ee (%)
1
2
2e
2l
4-BrBn
4-BrBn
4-BrBn
4-BrBn
4-BrBn
4-BrBn
4-BrBn
4-BrBn
4-BrBn
4-BrBn
Bn
Ph
80:20
88:12
70:30
86:14
83:17
72:28
69:31
70:30
84:16
87:13
81:19
66:34
75
82
65
82
80
55
64
67
80
83
78
63
97
97
95
4-BrPh
b
c
d
e
entry
2
cat.
R1
t
2:3
yield (%)
ee (%)
3
2m
2n
2o
2p
2q
2r
4-MeOPh
4-MePh
3-MePh
4-CF3Ph
2-Furyl
e
f
1
2a
2a
2b
2b
2b
2b
2b
1a
1a
1a
1b
1c
1d
1d
Et
1.5 h
9:91
7
30
55
47
56
67
72
4
5
6
98
2
3
4
5
6
Et
1 h
33:67
60:40
49:51
59:41
70:30
74:26
96
95
83
97
97
97
98
92
94
98
99
98
97
Me
Me
Me
Me
Me
30 min
40 min
30 min
40 min
1 h
e
7
e
8
2-Thienyl
1-Naph
2-Naph
4-BrPh
9
2s
f
7
10
11
12
2t
a
2u
2v
The reaction of diazoester (0.27 mmol) with benzaldehyde (0.32
mmol) was performed in the presence of 1 (20 mol %), in 1.0 mL of
solvent at −78 °C for the time indicated. Determined by H NMR
analysis of the crude reaction mixture. Isolated yield of 2. The ee of
2 was determined by chiral HPLC. The reaction was performed in
toluene. The reaction was performed at −95 °C.
g
Allyl
3-MeOPh
94
b
1
a
The reaction of diazoester (0.27 mmol) with aldehyde (0.32 mmol)
c
d
was performed in the presence of 1d (20 mol %), in propionitrile (1.0
e
b
mL) at −95 °C. Determined by 1H NMR analysis of the crude
f
c
reaction mixture. Isolated yield of 2 after silica gel chromatography at
d
e
−40 °C. The ee of 2 was determined by chiral HPLC. The reaction
f
Table 2. Asymmetric Formal Insertion of Various α-Alkyl
was performed at −50 °C. The absolute configuration was assigned as
a
g
Diazoesters into the Ph−CHO Bond
R by conversion to the hydrazone and X-ray analysis. The absolute
configuration was assigned as R by conversion to the known carboxylic
acid. For details see the Supporting Information.
b
c
d
entry
2
R2
t
2:3
yield (%)
ee (%)
the corresponding quaternary aldehydes 2 in good yields and
regioselectivities with excellent enantioselectivities (entries 1−
8, 11, and 12). It is notable that large naphthyl rings can
effectively migrate in the selective formal C−C insertion
process to give good results (entries 9 and 10). Reaction of an
allyl substituted diazoester with meta-anisaldehyde provided 2v,
an important intermediate in the synthesis of bioactive
pyrrolidinones, in moderate yield and excellent enantioselec-
tivity (entry 12).8 The absolute configuration of the newly
generated all-carbon quaternary stereocenter was confirmed
unambiguously by X-ray crystallographic analysis after trans-
formation of 2n to the corresponding hydrazone.
1
2
3
4
5
6
7
8
9
2b
2c
2d
2e
2f
Bn
1 h
74:26
64:36
33:67
80:20
73:27
82:18
81:19
73:27
79:21
62:38
72
62
29
75
70
78
78
69
76
55
97
92
77
98
99
99
99
94
99
94
Allyl
40 min
5 min
40 min
1 h
Me
4-BrBn
4-MeOBn
4-NO2Bn
4-CF3Bn
4-MeBn
3-BrBn
1-NpCH2
2g
2h
2i
3 h
1.5 h
1 h
2j
40 min
2 h
e
10
2k
a
The reaction of diazoester (0.27 mmol) with benzaldehyde (0.32
The observed stereochemistry for the asymmetric formal C−
C insertion reaction using oxazaborolidinium ion catalyst 1d
can be rationalized using the transition state model shown in
Figure 1. The mode of coordination of benzaldehyde to 1d is
the same as has been previously observed in enantioselective
mmol) was performed in the presence of 1d (20 mol %), in
b
propionitrile (1.0 mL) at −95 °C for the time indicated. Determined
c
by 1H NMR analysis of the crude reaction mixture. Isolated yield of 2
d
after silica gel chromatography at −40 °C. The ee of 2 was
e
determined by chiral HPLC. The reaction was performed at −95 °C
for 1 h and at −78 °C for 1 h.
excellent enantioselectivities (entries 1, 2, and 4−9). As the 1-
naphthylmethyl group (1-NpCH2) in the diazoester was
sterically hindered, preferential migration of the phenyl group
over hydride led to the desired product in moderate yield with
consistently high enantioselectivity (entry 10).
Encouraged by the good results illustrated in Table 2, we
applied this catalytic methodology to formal C−C insertion
reactions with a range of substituted benzaldehydes. Since the
4-bromo group in the product of entry 4 in Table 2 is easily
replaced by a large variety of other substituents using Pd(0)
catalysis, methyl α-4-bromobenzyl diazoester was selected as
the coupling partner.
Figure 1. Transition state model for the asymmetric formal C−C
insertion of α-benzyl diazoester into Ph−CHO catalyzed by 1d.
B
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Journal of the American Chemical Society
Communication
cyanosilylation,9a 1,3-dipolar cycloaddition,9b cyclopropana-
tion,9c and Roskamp reactions.4c In the pre-transition-state
assembly 4, shown in Figure 1, the aldehyde group is situated
above the phenyl group, which effectively shields the re face
(back) from attack by the diazoester. Because of the dipole−
dipole interaction between the two carbonyl groups, the
diazoester approaches the aldehyde group for nucleophilic
addition with the ester group situated away from the aldehyde
group. Meanwhile, an apparent π−π interaction between the
aryl ring of the aldehyde with the diazoester aryl group holds
the two aryl rings together.10,11 Thus, nucleophilic addition of
the diazoester from the si face (front) of the aldehyde is
facilitated, leading to intermediate 5. Chemoselective phenyl
ring migration with loss of nitrogen provides the quaternary
aldehyde R-2 as the major enantiomer.12
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, full analytical data, and crystallo-
graphic data (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
dhryu@skku.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Dedicated to Professor Sung Ho Kang on the occasion of his
honorable retirement. This research was supported by Basic
Science Research Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of
Education (2009-0094023 and 2011-0029186).
Further chemical transformations of the resulting optically
active all-carbon quaternary aldehyde are illustrated in Scheme
2. Reductive amination of 2n with sodium triacetoxyborohy-
Scheme 2. Application of Oxazaborolidinium Ion Catalyzed
Asymmetric Formal Insertion of Diazoesters into Aryl-CHO
Bond
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