Enantioselective synthesis of 2-alkyl-2-aryl cyclopentanones by asymmetric epoxidation of tetrasubstituted cyclobutylidene olefins and epoxide rearrangement

Article abstract of DOI:10.1016/j.tetlet.2006.05.175

This letter describes a highly enantioselective epoxidation of tetrasubstituted benzylidenecyclobutanes using glucose-derived ketone as catalyst and oxone as oxidant. The Et₂AlCl promoted rearrangement of the resulting epoxides provides 2-alkyl

Full text of DOI:10.1016/j.tetlet.2006.05.175

Tetrahedron Letters 47 (2006) 5455–5458
Enantioselective synthesis of 2-alkyl-2-aryl cyclopentanones
by asymmetric epoxidation of tetrasubstituted
cyclobutylidene olefins and epoxide rearrangement
Yu-Mei Shen, Bin Wang and Yian Shi*
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
Received 27 April 2006; revised 19 May 2006; accepted 30 May 2006
Available online 16 June 2006
Abstract—This letter describes a highly enantioselective epoxidation of tetrasubstituted benzylidenecyclobutanes using glucose-
derived ketone as catalyst and oxone as oxidant. The Et
alkyl-2-aryl cyclopentanones with high ees.
2
AlCl promoted rearrangement of the resulting epoxides provides 2-
ꢀ
2006 Elsevier Ltd. All rights reserved.
The generation of chiral all-carbon quaternary stereo-
centers is of great interest in organic synthesis.
Optically active 2-alkyl-2-aryl cyclopentanones are poten-
1
tially useful intermediates for the synthesis of natural
2
products.
A number of approaches have been
developed for the synthesis of 2-alkyl-2-aryl disubsti-
tuted cycloalkanones, including asymmetric alkylation
Scheme 1.
3
,4
5
of a-aryl cycloalkanones, enzymatic resolution, and
6
epoxide rearrangement. High enantioselectivities have
Tetrasubstituted cyclobutylidene olefins were readily
prepared from ketones and 4-bromobutyltriphenylphos-
phonium bromide using t-BuOK in THF in a manner
also recently been achieved by the Pd-catalyzed asym-
metric a-arylation of alkyl-substituted cycloalkanones
0
7
in which the a -methylene carbon is blocked, and by
1
3
similar to the reported procedure. Asymmetric epoxi-
dation of 1-cyclobutylidene-1-phenylethane with ketone
8
the chelation-controlled Heck arylation of enol ethers.
1
4
4
(Scheme 2) gave only 58% ee. Encouragingly, the ee
Recently, we reported that 2-aryl cyclopentanones can
be obtained with high ees by the asymmetric epoxida-
tion of benzylidenecyclobutanes (R = H) and subse-
increased to 84% when ketone 5 was used (Table 1, entry
1
5
1
). Further studies showed that the epoxidation could
also be extended to a variety of phenyl substituted
olefins (Table 1, entries 2–9), and up to 91% ee was
9
–11
quent epoxide rearrangement (Scheme 1).
these observations, we decided to investigate whether
-alkyl-2-aryl cyclopentanones can also be obtained by
Based on
1
6
obtained. Generally, higher ees were obtained for the
olefins having substituents on the phenyl group, which
2
this approach. However, the feasibility of this route re-
quires highly enantioselective asymmetric epoxidation
of unfunctionalized tetrasubstituted olefins, which is a
1
2
challenging problem. Herein we wish to report our
studies on this subject.
Keywords: Asymmetric epoxidation; 2-Alkyl-2-aryl cyclopentanone;
Chiral dioxirane; Epoxide rearrangement; Chiral quaternary carbon;
Tetrasubstituted olefin.
*
Corresponding author. Tel.: +1 970 491 7424; fax: +1 970 491
801; e-mail: yian@lamar.colostate.edu
1
Scheme 2.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.175

5456
Y.-M. Shen et al. / Tetrahedron Letters 47 (2006) 5455–5458
a,b
Table 1. Asymmetric epoxidation and epoxide rearrangement
c
d
Entry
1
Epoxide
Yield (ee) (%) (2)
Ketone
Yield (ee) (%) (3)
e
h
g
h
94 (84)
93 (84)
e
i
g
h
2
95 (87)
92 (88)
f
h
g
h
h
h
j
3
4
5
6
7
8
9
86 (88)
78 (88)
g
h
h
g
77 (89)
98 (90)
g
g
78 (91)
99 (90)
f
h
g
98 (88)
73 (87)
e
h
g
h
h
j
96 (87)
93 (88)
g
h
g
79 (88)
99 (89)
g
nd
65 (90)
g
h
g
j
1
1
0
1
67 (77)
88 (77)
g
h
g
i
48 (70)
99 (70)
a
b
c
All epoxidations were carried out with substrate (0.5 mmol), ketone 5 (0.1 mmol), oxone (0.8 mmol), and K
v/v) (7.5 mL) and buffer (0.1 M K CO
–AcOH, pH 9.3) (5 mL) at ꢀ10 or 0 ꢁC.
All rearrangements were carried out with epoxide (1.0 equiv) and Et AlCl (0.25 equiv) in PhCH
For entry 10, 0.5 equiv Et AlCl was used (60 min); for entry 11, 0.75 equiv Et AlCl was used (25 min).
2 3
CO (3.36 mmol) in DME/DMM (3:1,
2
3
2
3
at ꢀ78 ꢁC for 15–30 min unless otherwise noted.
2
2
The absolute configuration was tentatively assigned based on the spiro reaction mode. The absolute configurations of entries 1 and 5 were
determined using the VCD spectra by BioTools.
The cyclopentanone products were purified by silica gel column. For entries 3, 6, and 9, the yield is the two-step overall yield after purification. The
d
absolute configuration was tentatively assigned based on the mechanistic consideration. For entries 1 and 5, the absolute configuration was
determined using the VCD spectra by BioTools. For entries 1, 3, and 6, the configuration was determined by comparing the measured optical
rotations with the reported ones (Refs. 2b and 8).
Crude yield.
Conversion as determined by GC.
Isolated yield.
The enantioselectivity was determined by chiral GC (Chiraldex B-DM).
The enantioselectivity was determined by chiral HPLC (Chiralcel OJ).
The enantioselectivity was determined by chiral HPLC (Chiralpak AD).
e
f
g
h
i
j

Y.-M. Shen et al. / Tetrahedron Letters 47 (2006) 5455–5458
5457
is consistent with an earlier observation that substituents
design of new ketone catalysts for this class of olefin will
be pursued.
on the phenyl group of cis-b-methylstyrene have positive
1
5b
effects on the enantioselectivity of the epoxidation.
The epoxidation is likely to proceed mainly via spiro
transition state A (Scheme 3). Based on this model, this
transition state will be disfavored as the size of the R
group increases, thus giving lower ees, which was ob-
served when the methyl group was replaced by ethyl
and n-propyl groups (Table 1, entries 10 and 11).
Acknowledgements
We are grateful to the generous financial support from
the General Medical Sciences of the National Institutes
of Health (GM59705-07).
Some of the epoxide products were purified by column
chromatography on silica gel, but some underwent rear-
rangement on silica gel, thus they were used directly for
the subsequent rearrangement without purification.
When the epoxide rearrangement was carried out with
Supplementary data
Experimental procedures for asymmetric epoxidation
and epoxide rearrangement, the characterization of
epoxides and cyclopentanones, the data for the determi-
nation of ees of epoxides and cyclopentanones, and
VCD spectra (26 pages). Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2006.05.175.
Et AlCl in toluene, little ee was lost during the rear-
2
rangement, giving 2-methyl-2-aryl cyclopentanones in
1
7
high ees (Table 1). The absolute configurations of
the epoxides and rearranged products of entries 1 and
5
were determined using vibrational circular dichroism
1
8
(
VCD; BioTools). It was found that the epoxide is of
an R configuration and the rearranged cyclopentanone
has an S configuration. For entries 1, 3, and 6, the S
configuration of the cyclopentanone was further con-
firmed by comparing the measured optical rotations
References and notes
2
b,8
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2
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9
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In summary, we have shown that 1-cyclobutylidene-1-
phenylethane derivatives can be epoxidized with readily
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2
(
8
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ene olefins and epoxide rearrangement has recently been
9
reported by us, the results described herein show that
3
1
9
chiral dioxiranes have the potential to epoxidize
certain tetrasubstituted olefins in a high degree of
enantioselectivity, which is very encouraging, consider-
ing the fact that highly enantioselective epoxidation of
unfunctionalized tetrasubstituted olefins is a challenging
1
2
problem. Further studies with substrate scope and
1
990, 1, 265.
4
. For a leading reference on Pd-catalyzed asymmetric allylic
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2
002, 41, 3492.
5
6
. For examples of enzymatic resolution approach, see: (a)
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. For examples of rearrangement of aryl substituted 2,3-
epoxy acylates and sulfonates, see: (a) Kita, Y.; Furu-
kawa, A.; Futamura, J.; Higuchi, K.; Ueda, K.; Fujioka, H.
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Scheme 3.
7
. For leading references, see: (a) Ahman, J.; Wolfe, J. P.;
Troutman, M. V.; Palucki, M.; Buchwald, S. L. J. Am.
Chem. Soc. 1998, 120, 1918; (b) Hamada, T.; Chieffi, A.;
Scheme 4.

5458
Y.-M. Shen et al. / Tetrahedron Letters 47 (2006) 5455–5458
Ahman, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
261.
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ꢀ10 ꢁC (bath temperature) via NaCl–ice bath, a solution
ꢀ
4
1
of oxone (0.20 M in 4 · 10 M aqueous EDTA, 4.0 mL)
8
9
(0.492 g, 0.80 mmol) and a solution of K CO (0.84 M in
2
3
ꢀ4
4 · 10 M aqueous EDTA, 4.0 mL) (0.464 g, 3.36 mmol)
were added separately and simultaneously via a syringe
pump over a period of 8 h. The reaction mixture was
quenched with hexane, extracted with hexane, washed
. Shen, Y.-M.; Wang, B.; Shi, Y. Angew. Chem., Int. Ed.
2006, 45, 1429, and references cited therein.
1
0. For leading reviews on acid-promoted epoxide rearrange-
ment, see: (a) Magnusson, G. Org. Prep. Proced. Int. 1990,
2 4
with brine, dried (Na SO ), filtered, concentrated, and
22, 547; (b) Rickborn, B. In Comprehensive Organic
purified by flash chromatography [the silica gel was
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 3, p 733; (c) Fujioka, H.;
Yoshida, Y.; Kita, Y. Yuki Gosei Kagaku Kyokaishi 2003,
buffered with 1% Et N in organic solvent; hexane–EtOAc
(1/0 to 50/1) was used as eluent] to give the epoxide as a
colorless oil (0.080 g, 77% yield, 89% ee).
3
6
1, 133.
Entry 1, ꢀ10 ꢁC, 8 h; entry 2, ꢀ10 ꢁC, 4 h; entry 3,
ꢀ10 ꢁC, 6 h; entry 5, 0 ꢁC, 8 h; entry 6, ꢀ10 ꢁC, 4 h; entry
7, ꢀ10 ꢁC, 8 h; entry 8, ꢀ10 ꢁC, 8 h; entry 9, ꢀ10 ꢁC, 8 h;
entry 10, ꢀ10 ꢁC, 8 h; entry 11, 0 ꢁC, 10 h.
1
1. For leading references on the rearrangement of oxaspiro-
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Bogdanowicz, M. J. J. Am. Chem. Soc. 1972, 94, 4777; (b)
Trost, B. M.; Bogdanowicz, M. J. J. Am. Chem. Soc. 1973,
17. Representative procedure for the epoxide rearrangement
95, 5321; (c) Trost, B. M.; Scudder, P. H. J. Am. Chem.
with Et AlCl (Table 1, entry 1). To a solution of the
2
Soc. 1977, 99, 7601; (d) Crandall, J. K.; Conover, W. W. J.
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epoxide (0.035 g, 0.2 mmol) (84% ee) in dry toluene
(2 mL) at ꢀ78 ꢁC was added a solution of Et
2
AlCl
1
(1.0 M in hexane, 50 lL, 0.05 mmol). Upon stirring at
ꢀ78 ꢁC to completion (about 15 min), the reaction was
3
quenched with saturated aqueous NaHCO (0.10 mL) at
(
b) Nakata, K.; Takeda, T.; Mihara, J.; Hamada, T.; Irie,
ꢀ78 ꢁC. Upon warming up to 0 ꢁC, the reaction mixture
R.; Katsuki, T. Chem. Eur. J. 2001, 7, 3776.
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1
3. (a) Utimoto, K.; Tamura, M.; Sisido, K. Tetrahedron
2 4
Na SO , filtered, and concentrated to give the ketone
1
973, 29, 1169; (b) Scherer, K. V., Jr.; Lunt, R. S., III. J.
product as a colorless oil (0.032 g, 93% yield, 84%
ee).
Org. Chem. 1965, 30, 3215.
1
1
4. Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J.
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Entries 2, 3, 6, 7, and 9, 0.25 equiv Et AlCl, 15 min;
2
entries 4 and 5, 0.25 equiv Et
0.25 equiv Et AlCl, 30 min; entry 10, 0.5 equiv Et
60 min; entry 11, 0.75 equiv Et AlCl, 25 min.
2
AlCl, 20 min; entry 8,
2
2
AlCl,
5, 293; (b) Shu, L.; Shi, Y. Tetrahedron Lett. 2004, 45,
2
8
115.
18. Freedman, T. B.; Cao, X.; Dukor, R. K.; Nafie, L. A.
Chirality 2003, 15, 743.
1
6. Representative procedure for asymmetric epoxidation
Table 1, entry 4). To a solution of the olefin (0.096 g,
.5 mmol) and ketone 5 (0.033 g, 0.1 mmol) in DME–
DMM (3:1, v/v) (7.5 mL) was added buffer (0.1 M
(
0
19. For leading reviews on chiral ketone catalyzed asymmetric
epoxidations, see: (a) Denmark, S. E.; Wu, Z. Synlett
1999, 847; (b) Frohn, M.; Shi, Y. Synthesis 2000, 1979; (c)
Shi, Y. Acc. Chem. Res. 2004, 37, 488; (d) Yang, D. Acc.
Chem. Res. 2004, 37, 497.
ꢀ4
K
2
CO
3
–AcOH in 4 · 10 M aqueous EDTA, pH 9.3)
(
5 mL) with stirring. After the mixture was cooled to