Catalytic enantioselective carbon insertion into the β-vinyl C-H bond of cyclic enones

Article abstract of DOI:10.1021/ja402873b

Chiral oxazaborolidinium ion-catalyzed Csp²-H functionalization of enones using diazoacetate has been developed. Various β-substituted cyclic enones were synthesized in high yield (up to 99%) with high to excellent enantioselectivity (up to 99%

Full text of DOI:10.1021/ja402873b

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Communication
Catalytic Enantioselective Carbon Insertion
into the #-Vinyl C-H Bond of Cyclic Enones
Sung Il Lee, Geum-Sook Hwang, and Do Hyun Ryu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja402873b • Publication Date (Web): 02 May 2013
Downloaded from http://pubs.acs.org on May 3, 2013
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H Bond of Cyclic Enones
Sung Il Lee†,§, GeumꢀSook Hwang*,§, and Do Hyun Ryu*,†
†Department of Chemistry, Sungkyunkwan University, Suwon 440ꢀ746
§ Korea Basic Science Institute, 5St, AnamꢀDong, SeongbukꢀGu, Seoul, Korea.
Supporting Information Placeholder
nation7d, and Roskamp reaction5b (Figure 1). There is substantial
ABSTRACT: Chiral oxazaborolidinium ion catalyzed Csp2ꢀH
evidence for the formation of a complex between oxazaboroliꢀ
dinium ion and α,βꢀunsaturated ketones.8 We anticipated that the
oxazaborolidinium ion is a suitable Lewis acid catalyst for the
enantioselective CꢀH functionalization reaction. In this communiꢀ
cation, we present the first case of highly enantiocontrolled cataꢀ
lytic carbon insertion into the βꢀvinyl CꢀH bond of cyclic enones
with diazoacetates.
functionalization of enones using diazoacetate has been develꢀ
oped. Various βꢀsubstituted cyclic enones are synthesized with
high yield (up to 99%) and high to excellent enantioselectivity (up
to 99%). The synthetic utility of this reaction was demonstrated
by formal synthesis of (+)ꢀepijuvabione.
Direct CꢀH functionalizations provide potential advantages to
the synthetic strategies for making complex molecules1 and relatꢀ
ed methodologies have been extensively investigated.2 Despite the
recent progress in CꢀH functionalization, development of an enanꢀ
tioselective method with a chiral catalyst still remains one of the
most challenging topic in current organic synthesis. Transition
metal catalyzed asymmetric CꢀH functionalizations with a diazo
compound were reported via intraꢀ3 and intermolecular4 methods
during the last decade. In addition, recent research reveals that the
chiral Lewis acid catalyst is suitable for an enantioselective
formyl Csp2ꢀH functionalization.5
Figure 1. Structure of oxazaborolidinium ion.
Initially, the asymmetric CꢀH functionalization reaction beꢀ
tween 2ꢀcyclohexenꢀ1ꢀone (2) and various alkyl phenyldiazoesters
was examined in the presence of 20 mol% of the oxazaborolidiniꢀ
um 1a, which was prepared by activation of its precursor with
triflic imide. With methyl and benzyl ester, the desired CꢀH inꢀ
serted cyclohexenone was obtained in 44% and 68% yields, reꢀ
spectively, with poor ee (Table 1, entries 1 and 2). Replacement
of the ester substituents had a significant impact on the stereoseꢀ
lectivity. For the successful implementation of the diazoester, tertꢀ
butyl phenyldiazoester was selected for the CꢀH functionalization
reaction, and the enantioselectivity was greatly improved to 80%
(Table 1, entry 3). Our focus then moved to the screening for a
suitable catalyst structure. We found 1ꢀnaphthyl substituent at the
boron center of oxazaborolidinium catalyst (1b) effectively proꢀ
duced a CꢀH insertion product without a decline of stereoselectiviꢀ
ty (Table 1, entry 4). Triflic acid activated oxazaborolidinium (1c)
brought about a significant decrease in yield (Table 1, entry 5). At
ꢀ20 ºC, the carbon insertion reaction of diazoacetate was successꢀ
fully carried out and furnished 2ꢀsubstituted cyclohexenone with
improved enantioselectivity (Table 1, entry 6).
Recently, we developed a boron Lewis acid catalyzed Csp2ꢀH
functionalization of cyclic enones using diazoacetates.6 BF3ꢁEt2O
and the newly designed achiral oxazaborolidinium ion successfulꢀ
ly catalyzed the CꢀH functionalization reaction and afforded CꢀH
inserted cyclic enones in a moderate to high yield (Scheme 1). We
believed development of an asymmetric carbon insertion reaction
of a cyclic enone is highly valuable for generating useful chiral
building blocks in the synthesis of biologically active molecules
and pharmaceuticals.
Scheme 1. Boron Lewis acid catalyzed carbon insertion
reaction of cyclic enones.
The chiral oxazaborolidinium ion 1, which is generated from
the corresponding oxazaborolidine by protonation with strong
Brønsted acids, behaves as powerful Lewis acid and has proven
to be an effective catalyst for asymmetric DielsꢀAlder reactions,7a
cyanosilylations,7b tandem Michaelꢀaldol reaction,7c cyclopropaꢀ
Table 1. Screening of the Reaction Conditions for Oxazab-
orolidinium Ion-Catalyzed Enantioselective Carbon Inser-
tion Reaction of 2-Cyclohexen-1-onea.
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9
ee
Entry
Cat
R
Temp. (ºC)
Time (h)
Yield (%)b
(%)c
2
Yiel
d
Entr
y
Tim
e (h)
ee
1
R2
Product
(%)c
1
2
1a
1a
1a
1b
1c
1b
Me
Bn
24
ꢀ20
0
16
16
9
44
64
25
74
16
73
(%)b
8
1d
2d
3d
i
j
1b
1b
1b
1b
Bn
Allyl
Me
Et
8
8
3
3
84
97
82
98
89
90
90
97
3
tꢀBu
tꢀBu
tꢀBu
tꢀBu
80
81
79
85
10
11
12
13
14
15
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17
18
19
20
21
22
23
24
25
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60
4
0
6
k
l
5
0
2
4d, e
6
ꢀ20
19
5f
6f
m
n
1b
1b
Bn
5
5
99
95
95g
96g
a
The reaction was performed using 1.0 equiv. of alkyl pheꢀ
nyldiazoester and 1.2 equiv. of 2ꢀcyclohexenꢀ1ꢀone. Isolated
b
Allyl
yield. c Determined by chiral HPLC analysis.
7
8
o
p
1d
1b
Bn
5
3
96
99
93
86
Table 2. Substructure Scope of the Chiral Oxazaboroli-
dinium Ion Catalyzed Carbon Insertion Reaction of 2-
Cyclohexen-1-onea.
nꢀHex
9e
q
r
1d
1d
Bn
8
5
75
68
97
98
4ꢀ
BrBn
10
11e
12
s
t
1d
1d
Allyl
13
5
97
91
95
99
nꢀHex
Yield
R1
Time (h)
ee (%)c
13
14
15
u
v
1d
1d
1d
Bn
2
2
2
77
73
83
96
97
98
Entry
1
(%)b
73
99
99
99
99
97
87
60
Allyl
nꢀHex
1
2
a
b
c
d
e
f
1b
1d
1d
1d
1b
1d
1d
1d
Ph
Bn
19
1
85
95
94
97
91
92
96
97
w
3
4ꢀBrBn
Allyl
Propargyl
Me
1
a
4
1
The reaction was performed using 1.0 equiv of tertꢀbutyl diꢀ
b
c
azoester and 1.2 equiv of cyclic enone. Isolated yield. Deterꢀ
5
6d
1
mined by chiral HPLC analysis. d Reaction was performed at ꢀ5ºC.
<1
<1
<1
e
f
40 mol % of oxazaborolidinium catalyst was used. Reaction
was performed at ꢀ30ºC. Diastereomeric excess of anti(major)
and syn.
7
g
h
Et
g
8
iPr
a
The reaction was performed using 1.0 equiv of tertꢀbutyl diꢀ
azoester and 1.2 equiv of cyclic enone. Isolated yield. Deterꢀ
mined by chiral HPLC analysis. The absolute configuration was
Catalytic asymmetric carbon insertion reaction was successfulꢀ
ly carried out with substituted cyclohexenone. 5,5ꢀDisubstituted
cyclohexenone furnished a corresponding CꢀH functionalized
product with both high yield and enantioselectivities (Table 3,
entries 1ꢀ4), while Rꢀ6ꢀmethylꢀ2ꢀcyclohexenꢀ1ꢀone produced the
desired product with near quantitative yield and diastereoselectiviꢀ
ties (Table 3, entries 5 and 6). To further investigate the substrate
scope of the present catalytic system, we applied the catalytic
asymmetric CꢀH functionalization reaction to various sizes of
cyclic enones. The asymmetric carbon insertion reaction using an
oxazaborolidinium catalyst is a powerful method for preparation
of highly enantiopure βꢀsubstituted 2ꢀcyclopentenꢀ1ꢀone (Table 3,
entries 7 and 8). In addition, medium ring sizes of cyclic enones
are subjected to CꢀH functionalization with a range of alkyl diazꢀ
oesters. In all cases, excellent enantioselectivities are observed
(Table 3, entries 9ꢀ15). However, the reaction with acyclic enones,
for instance methyl vinyl ketone, ethyl vinyl ketone and 3ꢀpentenꢀ
2ꢀone produced 2ꢀpyrazoline as a major product.9
b
c
d
determined to be R. See supporting information.
After optimization of the asymmetric CꢀH functionalization reꢀ
action, the scope of this methodology was investigated with variꢀ
ous diazoacetates and cyclic enones (Tables 2 and 3). The carbon
insertion reaction is more suitable for an αꢀalkyl substituted tertꢀ
butyl diazoester than αꢀaryl substituted diazoester (Table 2, enꢀ
tries 1ꢀ7). Regardless of the alkyl group structure at αꢀposition of
diazoesters, CꢀH functionalization reactions proceeded in a highly
stereoselective manner, and the corresponding βꢀsubstituted 2ꢀ
cyclohexenꢀ1ꢀone variants were obtained in high yields (Table 2,
entries 2ꢀ7). Since the tertꢀbutyl isopropyldiazoacetate was slowly
decomposed in the presence of oxazaborolidinium catalyst, its
yield was reduced to 60% under the optimized reaction condition
(Table 2, entry 8).
Table 3. Substructure Scope of the Chiral Oxazaboroli-
dinium Ion Catalyzed Carbon Insertion Reaction of Cyclic
Enonesa.
Scheme 2. Enantio- and Diastereoselective Carbon Inser-
tion Reaction of 6-Methyl-2-cyclohexen-1-onea.
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Figure 2. Proposed mechanism for the asymmetric carbon inꢀ
sertion reaction between cyclic enones and tertꢀbutyl diazoaceꢀ
tates.
The observed stereochemistry of the oxazaborolidinium ion
catalyzed asymmetric carbon insertion reaction can be explained
by the transition state model shown in Figure 2. The coordination
mode of the cycloalkenone to an oxazaborolidinium ion is the
same as that previously shown for the absolute configuration of
chiral DielsꢀAlder adducts8aꢀc and Michael products8d from α,βꢀ
unsaturated enones. In that complex the electronꢀdeficient α,βꢀ
enone subunit attracts the phenyl or 3,5ꢀdimethylphenyl group by
a πꢀπ donorꢀacceptor interaction7a, 13 and the double bond of the
cyclic enone is situated above the phenyl or 3,5ꢀdimethylphenyl
group. This effectively shields the back of the cyclic enone from
approach by the diazoacetate. Since the dipoleꢀdipole interaction
between two carbonyl groups increases the transition state energy,
the tertꢀbutyl ester group is placed away from the ketone group. In
addition, the sterically bulkier R group is situated on the same
side of hydrogen. As a result, approach of the diazoacetate to the
front side of the cyclic enone affords the enolate intermediate 7;
subsequent loss of nitrogen molecule by βꢀhydride migration6
furnishes the (R)ꢀβꢀsubstituted cyclic enone as the major enantioꢀ
mer.
a
Reaction was performed using 1.0 equiv of tertꢀbutyl diazꢀ
oester and 2.1 equiv of racꢀ6ꢀmethylꢀ2ꢀcyclohexenꢀ1ꢀone. b Based
on diazoacetate. c Determined by NMR analysis. d Determined by
chiral GC analysis.
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The oxazaborolidinium catalyzed CꢀH functionalization reacꢀ
tion was diastereoselectively performed in the presence of both
enantiomers of 6ꢀmethylꢀ2ꢀcyclohexenꢀ1ꢀone. Under the optiꢀ
mized reaction condition, Rꢀ6ꢀmethylꢀ2ꢀcyclohexenꢀ1ꢀone reacts
faster than its Sꢀenantiomer and furnished the corresponding antiꢀ
βꢀsubstituted cyclic enone in 87/13 d.r, excellent yield, and enanꢀ
tiomeric excess. Chiral gas chromatography analysis revealed the
remaining Sꢀ6ꢀmethylꢀ2ꢀcyclohexenꢀ1ꢀone has 71% ee. A selecꢀ
tivity factor was calculated based on conversion and the ee of 6ꢀ
methylꢀ2ꢀcyclohexenꢀ1ꢀone (s = 16.5, Scheme 2).
Scheme 3. Multigram Scale Carbon Insertion Reactions
Using Lower Catalyst Loading and Stereoselective Formal
Synthesis of (+)-epijuvabione.
In conclusion, the first case of highly enantiocontrolled catalytꢀ
ic Csp2ꢀH functionalization reaction of cyclic enones using diazoꢀ
acetates has been developed. The insertion of a carbon atom of
diazoacetates affords βꢀfunctionalized cyclic enones from simple
cyclic enones in a single step, excellent yields, and enantioselecꢀ
tivities. We believe that the resulting chiral βꢀfunctionalized cyꢀ
clic enones could be highly valuable for the synthesis of useful
complex molecules.
ASSOCIATED CONTENT
Supporting Information
Experimental details and spectroscopic data for all products. This
information is available free of charge via the internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
The feasibility of reducing catalyst loading and increasing reacꢀ
tion scale to a multiꢀgram scale was examined (Scheme 3). The
loading of catalyst 1d could be reduced to 5 mol% while mainꢀ
taining excellent chemical yields and enantioselectivities.
dhryu@skku.edu; gshwang@kbsi.re.kr
Notes
The authors declare no competing financial interests.
(+)ꢀJuvabione and (+)ꢀepijuvabione, a natural sesquiterpene
exhibiting selective insect juvenile hormone activity was isolated
from Balsam fir by Bowers and coworkers.10 (+)ꢀJuvabione and
(+)ꢀepijuvabione have been the target of numerous synthetic inꢀ
vestigations because of their interesting continuous stereogenic
centers on a ring and side chain.11 Using the oxazaborolidinium
ion catalyzed carbon insertion reaction, synꢀcyclohexanone 5 was
synthesized from simple 2ꢀcyclohexenꢀ1ꢀone in two steps
(Scheme 3). Cyclohexanone 5 could be converted to a known
intermediate for the synthesis of (+)ꢀepijuvabione 6 according to
the literature procedure.12
ACKNOWLEDGMENT
This work has supported by grants NRFꢀ2012ꢀR1A6A1040282
(Priority Research Center Program), NRFꢀ2011ꢀ0029186 (Midꢀ
career Researcher Program) and the Korea Basic Science Institute
(T33409).
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(13) The slower reaction rate of Sꢀ6ꢀmethylꢀ2ꢀcyclohexenꢀ1ꢀone comꢀ
pared to Rꢀenantiomer is likely because the 6ꢀmethyl group of Sꢀ
enantiomer interferes with this πꢀπ donorꢀacceptor interaction
(Scheme 2).
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