Enantioselective synthesis of 2-aryl cyclopentanones by asymmetric epoxidation and epoxide rearrangement

Article abstract of DOI:10.1002/anie.200501520

(Chemical Equation Presented) Optically active epoxides are prepared by the highly enantioselective epoxidation of benzylidenecyclobutanes using a glucose-derived ketone as the catalyst and oxone as the oxidant. A subsequent Lewis acid catalyzed rearrange

Full text of DOI:10.1002/anie.200501520

Angewandte
Chemie
Synthetic Methods
DOI: 10.1002/anie.200501520
Enantioselective Synthesis of 2-Aryl
Cyclopentanones by Asymmetric Epoxidation and
Epoxide Rearrangement**
Yu-Mei Shen, Bin Wang, and Yian Shi*
Optically active 2-aryl cycloalkanones are a class of useful
molecules for organic synthesis and have received extensive
attention. A number of effective approaches have been
developed for the synthesis of 2-alkyl-2-aryl disubstituted
cycloalkanones,[1–7] including the Pd-catalyzed asymmetric a-
arylation of alkyl substituted cycloalkanones,[1] the allylic
alkylation of 2-aryl cycloalkanones,[2] and the chelation-
controlled Heck arylation of enol ethers.[3] In the preparation
of monosubstituted 2-aryl cycloalkanones, high ee values have
also been obtained for 2-aryl cyclohexanones and cyclo-
heptanones through the asymmetric protonation of the
corresponding silyl enol ethers and enolates.[7] Thus far,
monosubstituted 2-aryl cyclopentanones are still a challenge
to obtain, presumably because of facile racemization under
the reaction conditions. Herein, we wish to report our
preliminary efforts on the asymmetric epoxidation of benzyl-
idenecyclobutane and subsequent epoxide rearrangement
(Scheme 1).[8–12]
Scheme 1. Asymmetric epoxidation of benzylidenecyclobutane (1)and
subsequent epoxide rearrangement. AE=asymmetric epoxidation.
The initial epoxidation of benzylidenecyclobutane with
fructose-derived ketone 4, which has been shown to be
effective for a variety of trans- and trisubstituted olefins,[13]
gave only 42% ee. The low ee value obtained with 4 could be
attributed to the severe competition of the planar transition
state B with the favored spiro transition state A (Scheme 2).
Our recent studies with oxazolidinone-containing ketones
have shown that there is an attractive interaction between the
[*] Y.-M. Shen, B. Wang, Prof. Dr. Y. Shi
Department of Chemistry
Colorado State University
Fort Collins, CO 80523 (USA)
Fax: (+1)970-491-1801
E-mail: yian@lamar.colostate.edu
[**] We are grateful for generous financial support from the General
Medical Sciences of the National Institutes of Health (GM59705-
06).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Asymmetric epoxidation and epoxide rearrangement.[a–c]
Entry
Epoxide
Yield of (2)
[%] (ee)[d]
Conditions
Yield of 3
[%] (ee)[e]
Et2AlCl
LiI
90 (90)( S)
81 (90)( R)
Scheme 2. Transition states of ketone 4.
1
2
93 (90)
95 (91)
Et2AlCl
LiI
98 (82)( S)
81 (40)( R)
aryl group of the olefin and the oxazolidinone moiety of the
ketone catalyst.[14] These studies indicate that the desired
spiro transition state C could be further favored by such an
attraction (Scheme 3), thus resulting in higher enantioselec-
Et2AlCl
LiI
82 (88)( S)
91 (92)( R)
3
4
84 (93)
67 (94)
Et2AlCl
LiI
99 (91)( S)
86 (92)( R)
Et2AlCl
LiI
89 (94)( S)
87 (84)( R)
5
6
7
78 (96)
80 (96)
80 (95)
Et2AlCl
LiI
94 (93)( S)
87 (84)( R)
Et2AlCl
LiI
82 (92)( S)
92 (93)( R)
Scheme 3. Transition states of ketone 5.
Et2AlCl
LiI
83 (84)( S)
90 (80)( R)
8
9
77 (86)
88 (95)
tivity. The ee value of the epoxide increased to 90% when the
epoxidation was carried out with 20 mol% ketone 5 at À108C
(Table 1, entry 1). High enantioselectivities were also
obtained for a variety of other substituted benzylidenecyclo-
butanes (Table 1).[15]
Et2AlCl
LiI
94 (96)( S)
84 (87)( R)
[a] All epoxidations were carried out with the substrate (0.5 mmol), 5
(0.1 mmol), oxone (0.8 mmol), and K2CO3 (3.36 mmol)in dimethoxy-
ethane (DME)/dimethoxymethane (DMM) (3:1, v/v; 7.5 mL) and buffer
(0.1m K2CO3/AcOH, pH 9.3; 5 mL)at À10 or 08C for 4–12 h, except for
entry 9, in which the reaction was carried out in DME/DMM (1:1, v/v;
9.4 mL)and buffer (3.1 mL)at 0 8C for 8 h. The epoxides in entries 4, 5, 6,
8, and 9 were purified by column chromatography on silica gel (buffered
with Et3N). [b] All rearrangements were carried out with epoxide
With optically active epoxides in hand, the Lewis acid
catalyzed epoxide rearrangement was explored. The stereo-
selectivity of the rearrangement was found to be highly
sensitive to the Lewis acid and solvent. After optimization,
the rearrangement was effectively achieved with Et2AlCl in
toluene at À788C. The cyclopentanone product was obtained
cleanly after careful work up,[16] and high ee values were
generally maintained (Table 1). The rearrangement with
Et2AlCl is likely to go through a concerted process with
inversion of the configuration (pathway a; Scheme 4). Slightly
more enantioselectivity is lost for epoxides with electron-
donating groups, such as the 4-MeO moiety (Table 1, entry 2),
during the rearrangement. This lowered enantioselectivity
could be because of the competition from a stepwise SN1-type
process via a carbocation which is stabilized by electron-
donating groups. To probe the reaction mechanism further,
the rearrangement was then carried out with LiI.[17] The
opposite enantiomer of the rearrangement product was
obtained under these conditions (Table 1), and good ee values
were also obtained in most cases. The rearrangement with LiI
is likely to go via intermediate 6 with double inversion
(pathway b; Scheme 4). The low ee value obtained with the 4-
MeO substituted epoxide (Table 1, entry 2) could be because
of the competition from pathway a and/or the SN1-type
process. To support the above mechanistic pathways further,
the configurations of the 4-Cl substituted epoxide (Table 1,
entry 5) and the corresponding rearranged cyclopentanone
product with Et2AlCl were determined by using vibrational
circular dichroism (VCD; BioTools).[18] It is shown that the
(1.0 equiv)and Et 2AlCl (0.25 or 1.0 equiv)in PhCH at À788C for
3
0.25–3 h. The ketone products were not purified by column chromatog-
raphy on silica gel and were clean as judged by NMR spectroscopy. [c] All
rearrangements were carried out with LiI (1.0–3.0 equiv)in CH 2Cl2 at
room temperature for 5–30 min, except for entry 2, in which the reaction
was carried out at 08C. [d] The ee value (%)of the epoxide was
determined by chiral GC (Chiraldex B-DM), except for entry 2, for which
the ee value was determined by chiral HPLC (Chiralcel AD). The absolute
configuration was tentatively assigned based on the spiro reaction mode.
The absolute configuration of entry 5 was determined by using the VCD
spectra (BioTools). [e] The ee value (%)of the cyclopentanone was
determined by chiral HPLC (Chiralcel AD). The absolute configuration
was tentatively assigned based on the mechanistic consideration. The
absolute configuration was determined for entry 1 by comparison of the
measured optical-rotation value of the lactone product (obtained from
the Baeyer–Villiger oxidation of the ketone with mCPBA)with the
reported value.[20] The absolute configuration of entry 5 was determined
by using the VCD spectra (BioTools).
epoxide has an R configuration and the rearranged cyclo-
pentanone has an S configuration. The configuration of the
rearranged cyclopentanone was also determined for entry 1
by comparison with the measured optical-rotation value of
the lactone product (obtained from the Baeyer–Villiger
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Chemie
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Scheme 4. Possible reaction pathways for the epoxide rearrangement.
LA=Lewis acid.
oxidation of the ketone with meta-chloroperoxybenzoic acid
(mCPBA)[19]) with the reported value.[20]
In conclusion, we have shown that benzylidenecyclobu-
tanes can undergo epoxidation with the readily available
glucose-derived ketone 5 in high enantioselectivity. The
resulting epoxides can be rearranged to 2-aryl cyclopenta-
nones with either inversion or retention of configuration using
Et2AlCl or LiI. High ee values have been obtained for
cyclopentanones in most cases. This two-step process provides
a viable entry to optically active 2-aryl cyclopentanones,
which until now could not be readily obtained.
Experimental Section
Representative procedure for asymmetric epoxidation (Table 1,
entry 5): Buffer (0.1m K2CO3/AcOH in aqueous ethylenediaminete-
traacetate (EDTA; 4 ” 10À4 m), pH 9.3; 5 mL) was added to a solution
of 1 (0.089 g, 0.5 mmol) and 5 (0.033 g, 0.1 mmol) in DME/DMM (3:1
v/v; 7.5 mL). After the mixture was cooled to À108C by using a NaCl/
ice bath, a 0.20m solution of oxone (0.492 g, 0.80 mmol) in aqueous
EDTA (4 ” 10À4 m, 4.0 mL) and a solution of 0.84m K2CO3 (0.464 g,
3.36 mmol) in aqueous EDTA (4 ” 10À4 m, 4.0 mL) were added
separately yet simultaneously by a syringe pump over a period of
10 h. The reaction mixture was quenched and extracted with hexane,
washed with brine, dried over Na2SO4, filtered, concentrated, and
purified by flash column chromatography (the silica gel was buffered
with 1% Et3N in organic solvent; hexane/EtOAc as the eluent) to
give the epoxide as a colorless oil (0.076 g, 78% yield, 96% ee).
Representative procedure for the epoxide rearrangement with
Et2AlCl (Table 1, entry 1): A solution of Et2AlCl (1.0m in hexane;
50 mL, 0.05 mmol) was added to a solution of the epoxide (90% ee;
0.032 g, 0.2 mmol) in dry toluene (2 mL) at À788C. The reaction
mixture was stirred at À788C until completion (about 3 h) and
quenched with saturated aqueous NaHCO3 (0.10 mL) at À788C.
Upon warming up to 08C, the reaction mixture was diluted with
hexane, washed with brine, dried over Na2SO4, filtered, and concen-
trated to give the ketone product as a colorless oil (0.029 g, 90% yield,
90% ee).[21]
[11] For asymmetric epoxidations of unfunctionalized cyclopropyli-
dene derivatives and subsequent rearrangement, see: a) M.
Yoshida, M. A.-H. Ismail, H. Nemoto, M. Ihara, Heterocycles
1999, 50, 673; b) H. Nemoto, M. Yoshida, K. Fukumoto, M.
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Ismail, H. Nemoto, M. Ihara, J. Chem. Soc. Perkin Trans. 1 2000,
2629.
[12] For asymmetric dihydroxylations of cyclopropylidene deriva-
tives and subsequent rearrangements, see: a) A. Krief, A.
Ronvaux, A. Tuch, Bull. Soc. Chim. Belg. 1997, 106, 699; b) A.
Krief, A. Ronvaux, A. Tuch, Tetrahedron 1998, 54, 6903; c) H.
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Lett. 1995, 36, 1055; d) H. Nemoto, J. Miyata, H. Hakamata, M.
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Diffendal, J. Filan, P. G. Spoors, Tetrahedron Lett. 1999, 40, 6137;
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[13] a) Z.-X. Wang, Y. Tu, M. Frohn, J.-R. Zhang, Y. Shi, J. Am.
Chem. Soc. 1997, 119, 11224; b) Y. Shi, Acc. Chem. Res. 2004, 37,
488, and references therein.
Received: May 3, 2005
Published online: January 30, 2006
Keywords: asymmetric synthesis · chirality · cyclopentanones ·
.
epoxidation · rearrangement
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Communications
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[15] Some epoxides underwent rearrangement on silica gel, thus they
were used directly without purification; these epoxides were
clean as judged by analysis with NMR spectroscopy and GC
analysis (see the Supporting Information).
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racemization on silica gel; the ketone products were not purified
by column chromatography on silica gel and were clean as
judged by NMR spectroscopy.
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above with a slight modification: cyclopentanone, solid NaHCO3
(2.0 equiv), and mCPBA (2.0 equiv) were mixed and then
CH2Cl2 was added.
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[21] Experimental procedures for the asymmetric epoxidation and
epoxide rearrangement, the characterization of the epoxides and
cyclopentanones, the determination of the ee values of the
epoxides and cyclopentanones, and the VCD spectra are given in
the Supporting Information.
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