Desymmetrizing asymmetric ring expansion of cyclohexanones with α-diazoacetates catalyzed by chiral aluminum Lewis acid

Article abstract of DOI:10.1021/ja202070j

Chiral aluminum Lewis acid catalyst composed of Me₃Al and 3,3′-bis(trimethylsilyl)-BINOL in a 2:1 ratio was found to promote novel catalytic asymmetric ring expansion of cyclohexanone with α-substituted α-diazoacetates to give seven-membered rings with an all-carbon quaternary center. Application of this strategy to 4-substituted cyclohexanones opened up a novel way for the catalytic desymmetrizing asymmetric construction of cycloheptanones bearing remote α,δ-chiral centers.

Full text of DOI:10.1021/ja202070j

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pubs.acs.org/JACS
Desymmetrizing Asymmetric Ring Expansion of Cyclohexanones with
r-Diazoacetates Catalyzed by Chiral Aluminum Lewis Acid
Takuya Hashimoto, Yuki Naganawa, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
S Supporting Information
b
ABSTRACT: Chiral aluminum Lewis acid catalyst com-
posed of Me3Al and 3,30-bis(trimethylsilyl)-BINOL in a 2:1
ratio was found to promote novel catalytic asymmetric ring
expansion of cyclohexanone with R-substituted R-diazo-
acetates to give seven-membered rings with an all-carbon
quaternary center. Application of this strategy to 4-substi-
tuted cyclohexanones opened up a novel way for the
catalytic desymmetrizing asymmetric construction of cyclo-
heptanones bearing remote R,δ-chiral centers.
Figure 1
cid-catalyzed ring expansion of cyclohexanones with R-
diazoacetates or diazoalkanes has been known for more than
A
necessary to facilitate the ring expansion. Among the various
catalysts screened, we identified a chiral aluminum Lewis acid
composed of Me3Al and 3,30-disilyl-BINOL in a ratio of 2:1 as
having promise.11 The active bis-aluminum Lewis acid was
prepared by stirring a solution of 3,30-bis(trimethylsilyl)-BINOL
(S)-1a (20 mol %) and Me3Al (40 mol %) in toluene at room
temperature for 1 h, and this catalyst promoted the reaction of
methyl R-benzyl-R-diazoacetate and cyclohexanone at ꢀ40 °C
to give cycloheptanone in 97% yield with 76% ee (Table 1, entry
1). Replacement of the silyl substituents had a significant impact
on the selectivity, wherein even the sense of chirality was inverted
by use of the triphenylsilyl-substituted BINOL (S)-1c as ligand
(entries 2 and 3). For the successful implementation of the
catalysis, a 2:1 complex of Me3Al and BINOL was found to be
indispensable, as the 1:1 complex failed to promote the reaction
under the identical reaction conditions (entry 4).10,12,13 Use of
R-diazoacetates bearing a different ester moiety resulted in a
decrease in enantioselectivities, proving the importance of the
steric factor to control the stereoselectivity (entries 5 and 6).
Further optimization revealed the drastic effect of the tempera-
ture, as the enantioselectivity reached 90% when the reaction was
carried out at ꢀ78 °C (entries 7 and 8).
half a century as a practical strategy to synthesize seven-mem-
bered carbocycles.1,2 Recent innovative studies by our group and
Kingsbury et al. revealed that this method could be extended to
the incorporation of an all-carbon quaternary center by use of R-
substituted R-diazoacetates or internal diazoalkanes under the
influence of Lewis acid catalysts.3ꢀ5
The daunting challenge remaining in this research field is the
development of a catalytic asymmetric procedure which would
be achieved using chiral acid catalysts. Although chiral acid
catalysis has become a mature field owing to its extensive
development in the past decades,6 asymmetric ring expansion
of cyclohexanones with R-substituted R-diazoacetates poses a
problem distinct from these conventional acid catalyses: namely,
cyclohexanone to which chiral acid coordinates is not a prochiral
substrate unlike aldehydes,7 and the prochirality resides only on
R-substituted R-diazoacetates. Accordingly, the catalyst com-
plexed with cyclohexanone must discriminate the prochiral face
of the approaching R-diazoacetates relying only on the steric
factor. In addition, the pertinent problem of the formation of a
quaternary stereogenic center from sterically less biased and less
reactive substrates also remains as a laborious task.8,9
We report herein a breakthrough toward this end which has
culminated in the realization of highly enantioselective catalytic
ring expansion of cyclohexanones with R-substituted R-diazo-
acetates using chiral aluminum Lewis acid with 3,30-bis-
(trimethylsilyl)-BINOL as an effective ligand,10 providing an
unprecedented pathway for asymmetric formation of seven-
membered rings with an all-carbon quaternary center (Figure 1).
More importantly, the reaction system could be successfully
applied to catalytic desymmetrizing asymmetric ring expansion
of symmetrically substituted cyclohexanones, giving seven-mem-
bered rings with an additional stereogenic center.
With these optimized conditions in hand, we investigated the
scope of this catalytic asymmetric ring expansion (Table 2). In
the variation of the R-benzyl group attached to the diazoacetate,
use of 3- and 4-methylbenzyl-substituted R-diazoacetates 2e and
2f was tolerated to give ring-expanded products with 81% and
84% ee, respectively, whereas R-(2-methylbenzyl)-R-diazoace-
tate 2d was poorly reactive under this reaction condition (entries
2ꢀ4). The electronic property of the benzylic moiety did not
affect the reactivity or selectivity of the reaction (entries 5 and 6).
2-Naphthylmethyl-substituted R-diazoacetate 2i could also be
In the preliminary experiments to identify a chiral acid catalyst
of choice, we examined some chiral boron and aluminum Lewis
acids, given the fact that the use of strong, hard Lewis acid was
Received: March 7, 2011
Published: May 09, 2011
r
2011 American Chemical Society
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COMMUNICATION
Table 1. Optimization of the Reaction Conditionsa
Table 3. Catalytic Desymmetrizing Asymmetric Ring
Expansiona
entry
R
1
temp (°C), time (h)
yield (%)b
ee (%)c
1
2
3
4d
5
6
7
8
Me (2a)
Me
1a
1b
1c
1a
1a
1a
1a
1a
ꢀ40, 24
ꢀ40, 24
ꢀ40, 24
ꢀ40, 24
ꢀ40, 15
ꢀ40, 15
ꢀ60, 24
ꢀ78, 48
97 (4a)
91
76
58
Me
99
ꢀ40
Me
no reaction
Bn (2b)
t-Bu (2c)
Me
76 (4b)
90 (4c)
84
58
54
86
90
Me
72
a Reactions were performed with cyclohexanone (0.20 mmol) and R-
benzyl-R-diazoacetate (0.22 mmol) in the presence of 20 mol % chiral
bis-aluminum catalyst (0.04 mmol) in toluene (2.0 mL). b Isolated yield.
c Determined by chiral HPLC analysis. d Performed with a catalyst
composed of 20 mol % (S)-1a and 20 mol % Me3Al.
Table 2. Catalytic Asymmetric Ring Expansiona
a Reactions were performed with cyclohexanone (0.20 mmol) and
methyl R-substituted R-diazoacetate (0.22 mmol) in the presence of
20 mol % chiral aluminum catalyst (0.04 mmol) in toluene (2.0 mL).
Yields reported were isolated. Enantiomeric excesses were determined
by chiral HPLC analysis. b Determined by 1H NMR of the crude mixture.
c Performed at ꢀ60 °C for 24 h.
entry
R1
X
yield (%)b
ee (%)c
utilized for this ring expansion, affording seven-membered rings
containing a heteroatom with good enantioselectivities (entries
10 and 11). As for the other cycloalkanones, cyclobutanone was
found to be a potentially viable substrate, although the yield and
ee remained low under our reaction conditions (<25% yield,
19% ee, data not shown).
1
2d
Bn (2a)
CH2 (3a)
CH2
72 (4a)
24 (4d)
72 (4e)
94 (4f)
93 (4g)
50 (4h)
58 (4i)
92 (4j)
69 (4k)
67 (4l)
74 (4m)
90
71
81
84
84
89
80
14
43
80
77
2-MeC6H4CH2 (2d)
3-MeC6H4CH2 (2e)
4-MeC6H4CH2 (2f)
4-MeOC6H4CH2 (2g)
4-BrC6H4CH2 (2h)
2-NpCH2 (2i)
Me (2j)
3
CH2
4
CH2
5
CH2
Our recent study disclosed that achiral Lewis acid-catalyzed
ring expansion of 4-alkyl- or 4-arylcyclohexanones with R-sub-
stituted R-diazoacetates gave cylcoheptanones projecting two
functionalities in a cis fashion with high diastereoselectivity. This
moved our focus to the use of 4-substituted cyclohexanones in
this catalytic asymmetric ring expansion, as it would provide
seven-membered carbocycles having an additional stereocenter
via the stereoselective desymmetrization of the pendant func-
tionality. As shown in Table 3, this catalytic desymmetrizing
asymmetric ring expansion of 4-substituted cyclohexanones with
methyl R-benzyl-R-diazoaceate provided the corresponding se-
ven-membered carbocycles 6aꢀd as an essentially single diaster-
eomer. Irrespective of the 4-substituents of the corresponding
cyclohexanones, the enantioselectivities of these heptanones
were remarkably high, ranging from 86% to 93% ee. In contrast
to 4-alkyl- and 4-arylcyclohexanones, use of 4-silyloxycyclohex-
anones is known to give cycloheptanones bearing the R-sub-
stituent of diazoacetates and the siloxy group in a trans fashion,
6
CH2
7
CH2
8
CH2
9e
10
11d
i-Bu (2k)
CH2
Bn (2a)
O (3b)
S (3c)
Bn (2a)
a Reactions were performed with cyclohexanone (0.20 mmol) and
methyl R-substituted R-diazoacetate (0.22 mmol) in the presence of
20 mol % chiral aluminum catalyst (0.04 mmol) in toluene (2.0 mL).
b Isolated yield. Determined by chiral HPLC analysis. d Performed at
c
ꢀ60 °C for 24 h. e Performed for 66 h.
employed (entry 7). Application of this strategy to R-diazoace-
tates bearing an aliphatic side chain was found to be even more
challenging, as the reaction furnished the product with poor to
modest enantioselectivity (entries 8 and 9). Not only cyclohex-
anone but also its oxa and thia analogues 3b and 3c could be
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COMMUNICATION
Scheme 1. Use of r-Unsubstituted r-Diazoacetate for
Traceless Catalytic Desymmetrizing Asymmetric Expansion
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details and char-
b
acterization data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
maruoka@kuchem.kyoto-u.ac.jp
’ ACKNOWLEDGMENT
This work was partially supported by a Grant-in-Aid for
Scientific Research from MEXT (Japan). T.H. and Y.N. thank
a Grant-in Aid for Young Scientists (B) and the Research
Fellowships of JSPS for Young Scientists, respectively.
presumably due to the tendency of these cyclohexanones to
project their silyloxy group in an axial fashion. Accordingly, this
catalytic desymmetrizing asymmetric ring expansion with 4-(tert-
butyldimethyl)silyloxycyclohexanone furnished the cyclohepta-
none 6e as the single expected isomer with 88% ee. In the
reaction with cyclohexanone having 4-alkyl- and 4-silyloxy
groups, a considerable decrease of the enantioselectivity was
observed, although the product 6f was obtained as a single
diastereomer. This strategy could be extended to the use of
3,5-cis-dimethylcyclohexanone to give 6g having three stereo-
genic centers with 58% ee. At last, we also examined the variation
of the R-substituent of diazoacetates, as exemplified in the
reaction with 4-phenylcyclohexanone and 4-silyloxycyclohexa-
none. Irrespective of the substituents attached at the benzylic
position of R-diazoacetates, the ring expansion proceeded to give
the corresponding carbocycles 6h, 6i, 6k, and 6l, respectively,
with high enantioselectivities. It should be noted that R-alkyl-R-
diazoacetate could be utilized as well, giving the cycloheptanone
6j with moderate enantioselectivity.
As a unique application of this catalytic desymmetrizing
asymmetric ring expansion, we turned our attention to the use of
simple R-unsubstituted R-diazoacetate 7 as a substrate (Scheme 1).3b
Ring expansion of 4-phenylcyclohexanone with ethyl diazo-
acetate 7a under the identical reaction conditions furnished
seven-membered cyclic β-keto ester having an R-hydrogen.
While the stereocenter at the R-position generated by the
primary action of the chiral catalyst easily disappeared via the
epimerization, it is strongly anticipated that the stereogenic
center at the remote δ-position imparted by the desymme-
trization would be retained. To confirm this, decarboxylation
of this cyclic β-keto ester 8 (R = Et) was implemented to give
4-phenylcycloheptanone 9 with 75% ee, offering a novel route
for the traceless asymmetric one-carbon homologation of
4-substituted cyclohexanones. Further optimization revealed
that use of benzyl diazoacetate 7 (R = Bn) drastically improved
the enantioselectivity of this desymmetrization, giving cyclo-
heptanone 9 with 97% ee.
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aluminum Lewis acid-catalyzed asymmetric ring expansion of
cyclohexanones by controlling the stereochemistry of approach-
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asymmetric ring expansion with the desymmetrization of 4-sub-
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