Catalytic asymmetric synthesis of 2,2-disubstituted terminal epoxides via dimethyloxosulfonium methylide addition to ketones

Article abstract of DOI:10.1021/ja803864p

Catalytic asymmetric Corey-Chaykovsky epoxidation of ketones with dimethyloxosulfonium methylide 2 using an LLB 1a + Ar₃P=O complex proceeded smoothly at room temperature, and 2,2-disubstituted terminal epoxides were obtained in high enantioselectivity (91-97%) and yield (>88-99%) from a broad range of methyl ketones with 1-5 mol % catalyst loading. The use of achiral additive Ar₃P=O 5i was important to achieve high enantioselectivity. Copyright

Full text of DOI:10.1021/ja803864p

Published on Web 07/10/2008
Catalytic Asymmetric Synthesis of 2,2-Disubstituted Terminal Epoxides via
Dimethyloxosulfonium Methylide Addition to Ketones
Toshihiko Sone, Akitake Yamaguchi, Shigeki Matsunaga,* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received May 22, 2008; E-mail: mshibasa@mol.f.u-tokyo.ac.jp; smatsuna@mol.f.u-tokyo.ac.jp
Table 1. Optimization of Reaction Conditions
Optically active epoxides are versatile building blocks for the
synthesis of biologically active natural and unnatural compounds.
Although various useful catalytic asymmetric epoxidation methods
have been reported,1 2,2-disubstituted terminal epoxides remain
particularly challenging target compounds. Catalytic asymmetric
epoxidations of geminally disubstituted terminal unfunctionalized
alkenes (eq 1, path a) have been studied using enzymes,2 chiral
metal and organo-catalysts,3 but the enantioselectivity, yield, and/
or substrate generality of these reactions are not satisfactory.
entry REMB 1
R: 5 (x mol %)
time (h) yielda (%) ee (%)
1b LLB 1a none
48
12
12
12
12
12
12
12
12
12
12
12
12
12
12
79
80
25
17
77
99
61
87
99
97
82
84
98c
94
92
15
72
14
52
80
74
48
75
76
75
77
93
96
95
92
2
3
4
5
6
7
8
9
LLB 1a none
LSB 1b none
LPB 1c none
LLB 1a Ph- (5)
LLB 1a 4-Cl-C6H4- (5)
LLB 1a C6F5- (5)
LLB 1a nBu (5)
5a
5b
5c
5d
5e
5f
LLB 1a cyclohexyl (5)
Considering the importance of 2,2-disubstituted epoxides as key
building blocks for valuable chiral tertiary alcohols, a new strategy
to synthesize chiral 2,2-disubstituted terminal epoxides is highly
desirable.4,5 Herein, we report an alternative approach based on
Corey-Chaykovsky epoxidation6 of ketones (eq 1, path b). A
La-Li3-tris(binaphthoxide) (LLB 1a, Figure 1) complex with an
Ar3PdO additive (Ar ) 2,4,6-trimethoxyphenyl) promoted the
addition of dimethyloxosulfonium methylide to ketones, giving 2,2-
disubstituted terminal epoxides in >88-99% yield and 91-97%
ee.
10 LLB 1a 2,4,6-Me3-C6H2- (5)
11 LLB 1a 4-MeO-C6H4- (5)
12 LLB 1a 2,6-(MeO)2-C6H3- (5)
5g
5h
13 LLB 1a 2,4,6-(MeO)3-C6H2- (5) 5i
14 LLB 1a 2,4,6-(MeO)3-C6H2- (10) 5i
15 LLB 1a 2,4,6-(MeO)3-C6H2- (15) 5i
a Yield determined by 1H NMR analysis of crude mixture. b Reaction
was run in the absence of MS 5Å. (R)-4a was obtained in major.
c Isolated yield after purification by column chromatography.
52% ee). Many trials to improve the enantioselectivity revealed
that the addition of achiral phosphine oxide 5 was effective. In the
presence of 5 mol % of Ph3PdO 5a, 4a was obtained in 80% ee
(entry 5). Among the various types of phosphine oxides screened
(entries 5-13),9 Ar3PdO 5i (Ar ) 2,4,6-trimethoxyphenyl) was
the best, giving 4a in 98% isolated yield and 96% ee after 12 h
(entry 13). A molar ratio of LLB 1a:Ar3PdO 5i ) 1:1 was sufficient
to achieve high enantioselectivity (entries 13-15).
The optimized reaction conditions using an LLB 1a:Ar3PdO 5i
) 1:1 mixture were applicable to various ketones (Table 2). Aryl
methyl ketones 3a-3h gave epoxides in >93-99% yield and
92-97% ee (entries 1-8). Ketones 3c-3e with an electron-
withdrawing substituent at either the para-, meta-, or ortho-positions
gave epoxides in high yield and enantioselectivity (entries 3-5).
The broad generality of aryl methyl ketones is synthetically useful
because the methods for producing chiral 2-aryl-2-methyl terminal
epoxides in high enantioselectivity are limited to biocatalytic kinetic
resolution approaches.4b,c It is noteworthy that pyridyl methyl
ketone 3i and alkyl methyl ketones 3j-3m were also applicable
and afforded epoxides in >88-99% yield and 91-96% ee (entries
9-13). Catalyst loading was successfully reduced to 2.5 and 1 mol
%, and good enantioselectivity was maintained (entries 14 and 15).
To demonstrate the synthetic utility of epoxides, transformations
of products into chiral tertiary alcohols were investigated (Scheme
1). Ring opening of epoxide with an amine nucleophile proceeded
in isopropanol at 90 °C, giving ꢀ-amino tert-alcohol 6b in 90%
yield. Reaction with alkynyl lithium reagent also proceeded
regioselectively and afforded 7b in >99% yield.
Figure 1. Structures of (S)-RE-M3-tris(binaphthoxide) complex (REMB,
RE ) rare earth), LLB 1a, LSB 1b, and LPB 1c.
Initial screening of several chiral multimetallic catalysts devel-
oped in our group revealed that heterobimetallic rare earth-alkali
metal RE-M3-tris(binaphthoxide) complexes (REMB, Figure 1)7,8
were the most promising candidates for the addition of a sulfur
ylide to ketones. Optimization studies with dimethyloxosulfonium
methylide 2 and ketone 3a using REMB complexes are summarized
in Table 1. LLB 1a promoted the reaction at room temperature in
79% yield, but the enantioselectivity was poor (entry 1, 15% ee).
In the presence of MS 5Å, enantioselectivity improved to 72% ee
(entry 2). Other metal combinations, such as La-Na (LSB, 1b)
and La-K (LPB, 1c), resulted in much less satisfactory yield and
enantioselectivity (entry 3, 25% yield, 14% ee, entry 4, 17% yield,
9
10078 J. AM. CHEM. SOC. 2008, 130, 10078–10079
10.1021/ja803864p CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Catalytic Asymmetric Synthesis of 2,2-Disubstituted
Acknowledgment. This work was supported by Grant-in-Aid
for Scientific Research (S) and Grant-in-Aid for Scientific Research
on Priority Areas (No. 20037010, Chemistry of Concerto Catalysis
for SM) from JSPS and MEXT. We thank Dr. S. Uchiyama, Dr.
H. Kakei, and Mr. S. Mouri at the University of Tokyo for technical
assistance. A.Y. thanks financial support by JSPS fellowship.
Terminal Epoxides from Various Methyl Ketonesa
cat. 1a/5l
epoxide (x mol %) time (h) yield (%)b ee (%)
entry
ketone 3: R
Supporting Information Available: Experimental procedures,
spectral data of new compounds, determination of absolute configura-
tions, and 31P NMR charts. This material is available free of charge
via the Internet at http://pubs.acs.org.
1
2
3
4
5
6
7
8c
9
Ph
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4b
4b
5
5
5
5
5
5
5
5
5
5
5
5
5
2.5
1
12
12
12
12
12
12
12
12
12
12
12
12
12
18
60
98
97
>99
>99
96
94
94
97
97
96
96
94
94
95
97
94
92
92
93
93
96
91
94
92
2-naphthyl
4-Cl-C6H4
3-Cl-C6H4
2-Cl-C6H4
4-F-C6H4
4-EtO2C-C6H4 3g
4-Me-C6H4
3-pyridyl
References
(1) General reviews of catalytic asymmetric epoxidations: (a) Xia, Q.-H.; Ge,
H.-Q.; Ye, C.-P.; Liu, Z.-M.; Su, K.-X. Chem. ReV. 2005, 105, 1603. (b)
Bonini, C.; Righi, G. Tetrahedron 2002, 58, 4981. For sulfur ylide-mediated
epoxidations, see: (c) Aggarwal, V. K.; Winn, C. L. Acc. Chem. Res. 2004,
37, 611.
(2) Enzymatic approach: (a) Dexter, A. F.; Lakner, F. J.; Campbell, R. A.;
Hager, L. P. J. Am. Chem. Soc. 1995, 117, 6412. (b) Lakner, F. J.; Hager,
L. P. J. Org. Chem. 1996, 61, 3923.
3h
3i
3j
3k
3l
10 PhCH2CH2
11 n-octyl
99
>99
12c cyclohexyl
88d
13 EtO2C-(CH2)3- 3m
14 2-naphthyl
15 2-naphthyl
>99
96
96
(3) General reviews: (a) Jacobsen, E. N.; Wu, M. H. In ComprehensiVe
Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, 1999; p 649. (b) Katsuki, T. In Catalytic Asymmetric
Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000; p 287.
(c) Shi, Y. Acc. Chem. Res. 2004, 37, 488. See also ref 1a. Geminally
disubstituted terminal alkenes gave only modest enantioselectivity.
(4) (Salen)Cr-catalyzed kinetic resolution of 2,2-disubstituted terminal epoxides
using an azide nucleophile: (a) Lebel, H.; Jacobsen, E. N. Tetrahedron
Lett. 1999, 40, 7303. For biocatalytic kinetic resolutions, see reviews: (b)
Steinreiber, A.; Faber, K. Curr. Opin. Biotechnol. 2001, 12, 552. (c)
Archelas, A.; Furstoss, R. Curr. Opin. Chem. Biol. 2001, 5, 112.
(5) Geminally disubstituted terminal allyl alcohols are suitable substrates in
Sharpless asymmetric epoxidation systems (>90% ee); see a review: Katsuki,
T. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 1999; p 621, and references therein.
(6) (a) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353. For
early trials of catalytic asymmetric reaction with ketone (23% ee with 3a),
see: (b) Zhang, Y.; Wu, W. Tetrahedron: Asymmetry 1997, 8, 2723.
(7) Review of heterobimetallic rare earth-alkali metal-BINOL complexes: (a)
Shibasaki, M.; Yoshikawa, N. Chem. ReV. 2002, 102, 2187. For recent
selected examples, see also: (b) Tosaki, S.-y.; Hara, K.; Gnanadesikan, V.;
Morimoto, H.; Harada, S.; Sugita, M.; Yamagiwa, N.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2006, 128, 11776. (c) Yamagiwa, N.;
Qin, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 13419.
(d) Mihara, H.; Sohtome, Y.; Matsunaga, S.; Shibasaki, M. Chem. Asian
J. 2008, 3, 359.
3b
3b
a Reaction was performed in THF (0.1
M ketone 3) at room
temperature (20-23 °C) with MS 5Å; 1.2 equiv of ylide 2 prepared
from trimethyloxosulfonium chloride and NaH were used. b Isolated
yield after purification by column chromatography. c Enantiomeric
excess was determined after epoxide ring opening; see Supporting
Information for detail. d NMR yield was >95%, but the isolated yield
decreased because epoxide 4l was volatile.
Scheme 1. Transformations of 2,2-Disubstituted Terminal Epoxide
(8) For related catalytic asymmetric Corey-Chaykovsky cyclopropanation of
enones with a heterobimetallic REMB-type complex, see: Kakei, H.; Sone,
T.; Sohtome, Y.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2007,
129, 13410. In the cyclopropanation of enones, biphenyldiol ligands showed
better enantioselectivity than BINOL, and mixed alkali metal La-Li2-
Na-(biphenyldiol)3 system gave the best enantioselectivity. In the present
epoxidation of ketones, neither biphenyldiol ligand nor mixed alkali metal
system gave positive effects.
(9) Steric and electronic modification of achiral phosphine oxides have
beneficial effects in other rare earth metal-catalyzed asymmetric reactions.
See: (a) Kino, R.; Daikai, K.; Kawanami, T.; Furuno, H.; Inanaga, J. Org.
Biomol. Chem. 2004, 2, 1822, and references therein. (b) Tian, J.;
Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2002,
41, 3636. (c) Yamagiwa, N.; Tian, J.; Matsunaga, S.; Shibasaki, M. J. Am.
Chem. Soc. 2005, 127, 3413. (d) Hara, K.; Park, S.-Y.; Yamagiwa, N.;
Matsunaga, S.; Shibasaki, M. Chem. Asian J. 2008, Early view DOI:
10.1002/asia.200800035 and references therein.
(10) For structural analysis of LLB and related complexes, see a review in ref
7a. See also: (a) Wooten, A. J.; Carroll, P. J.; Walsh, P. J. J. Am. Chem.
Soc. 2008, 130, 7407. (b) Wooten, A. J.; Carroll, P. J.; Walsh, P. J. Angew.
Chem., Int. Ed. 2006, 45, 2549. (c) Aspinall, H. C.; Bickley, J. F.; Dwyer,
J. L. M.; Greeves, N.; Kelly, R. V.; Steiner, A. Organometallics 2000, 19,
5416. (d) Di Bari, L.; Lelli, M.; Pintacuda, G.; Pescitelli, G.; Marchetti,
F.; Salvadori, P. J. Am. Chem. Soc. 2003, 125, 5549.
(11) Preliminary investigation with propiophenone gave epoxide in 91% yield
and 80% ee (with 5 mol % catalyst, at rt, 12 h). Aldehydes are not suitable
substrates under identical conditions. Further optimization studies are
ongoing.
In the present system, the best yield and enantioselectivity were
obtained with Ar3PdO 5i additive. The results shown in Table 1,
entries 5-13, suggested that the electron-donating and coordinating
MeO substituents at the 2,6-positions were key to improving
enantioselectivity. 31P NMR analysis of Ar3PdO 5i alone (3.50
ppm) and Ar3PdO 5i with LLB (16.3 ppm) indicated that Ar3PdO
5i coordinates to LLB 1a. We speculated that the LLB:Ar3PdO 5i
) 1:1 complex would be the active species in the present system.
Electron-rich and bulky achiral additive 5i would suitably modify
the chiral environment of LLB,9,10 resulting in better yield and
enantioselectivity in the present reaction. Further mechanistic studies
to elucidate the precise role of Ar3PdO 5i on enantioselectivity
are ongoing.
In summary, we developed a catalytic asymmetric Corey-
Chaykovsky epoxidation of ketones with dimethyloxosulfonium
methylide 2 using an LLB 1a + Ar3PdO complex. The reaction
proceeded smoothly at room temperature, and 2,2-disubstituted
terminal epoxides were obtained in high enantioselectivity (91-97%
ee) and yield (>88-99%) from a broad range of methyl ketones
with 1-5 mol % catalyst loading. The use of achiral additive
Ar3PdO 5i was important to achieve high enantioselectivity. Studies
to further broaden the substrate generality to other ketones, such
as ethyl ketones, are ongoing.11
JA803864P
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J. AM. CHEM. SOC. VOL. 130, NO. 31, 2008 10079