Kinetic resolution of acyclic secondary allylic silyl ethers catalyzed by chiral ketones

Article abstract of DOI:10.1021/jo010068c

Kinetic resolution of acyclic secondary allylic silyl ethers by chiral dioxiranes generated in situ from chiral ketones (R)-1 and (R)-2 and Oxone was investigated. An efficient and catalytic method has been developed for kinetic resolution of those substrates with a CCl₃, tert-butyl, or CF₃ group at the α-position. In particular, high selectivities (S up to 100) were observed for kinetic resolutions of racemic α-trichloromethyl allylic silyl ethers 7 and 9-15 catalyzed by ketones (R)-2. Both the recovered substrates and the resulting epoxides were obtained in high enantiomeric excess. On the basis of steric and electrostatic interactions between the chiral dioxiranes and the racemic substrates, a model was proposed to rationalize the enantioselectivities and diastereoselectivities in the chiral ketone-catalyzed kinetic resolution process.

Full text of DOI:10.1021/jo010068c

J . Org. Chem. 2001, 66, 4619-4624
4619
Kin etic Resolu tion of Acyclic Secon d a r y Allylic Silyl Eth er s
Ca ta lyzed by Ch ir a l Keton es
Dan Yang,* Guan-Sheng J iao, Yiu-Chung Yip, Tsz-Hin Lai, and Man-Kin Wong
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong
yangdan@hku.hk
Received J anuary 22, 2001
Kinetic resolution of acyclic secondary allylic silyl ethers by chiral dioxiranes generated in situ
from chiral ketones (R)-1 and (R)-2 and Oxone was investigated. An efficient and catalytic method
has been developed for kinetic resolution of those substrates with a CCl3, tert-butyl, or CF3 group
at the R-position. In particular, high selectivities (S up to 100) were observed for kinetic resolutions
of racemic R-trichloromethyl allylic silyl ethers 7 and 9-15 catalyzed by ketones (R)-2. Both the
recovered substrates and the resulting epoxides were obtained in high enantiomeric excess. On
the basis of steric and electrostatic interactions between the chiral dioxiranes and the racemic
substrates, a model was proposed to rationalize the enantioselectivities and diastereoselectivities
in the chiral ketone-catalyzed kinetic resolution process.
In tr od u ction
attention was drawn to the resolution of R-trichlorom-
ethyl allylic alcohols and their derivatives for two rea-
sons. First, this particular class of chiral allylic alcohols
not only are important intermediates in the synthesis of
natural products of agricultural importance, e.g., sodium
cilastatin,6a NRDC 182,6b,c permethrin,6b decamethrin,6b
and cypermethrin,6c but also can be easily transformed
to other useful products such as allylic thiols,7a,b terminal
vinyl epoxides,7c R-fluoro acids,7d hydroxy acids,7e,f and
amino acids.7e,f Second, a number of methods have been
developed to conveniently prepare racemic R-trichloro-
methyl allylic alcohols, e.g., via nucleophilic addition to
R,â-unsaturated aldehydes by trichloromethide, which
can be generated from a 1:1 mixture of trichloroacetic
acid and sodium trichloroacetate in dimethylformamide,8a
cathodic reduction of carbon tetrachloride,8b or decom-
position of trichloroacetic acid in hexamethylphosphoric
triamide.8c However, preparation of enantiomerically
Both chiral secondary allylic alcohols1 and the corre-
sponding chiral epoxy alcohols1b are versatile building
blocks for asymmetric synthesis of biologically active
natural products. Kinetic resolution2-4 of readily avail-
able racemic secondary allylic alcohols or their deriva-
tives via an enantioselective epoxidation method, e.g.,
Sharpless asymmetric epoxidation method,4a,b offers a
feasible and efficient access to both kinds of chiral
intermediates. In recent years, chiral ketones have been
found to be efficient catalysts for asymmetric epoxidation
of trans-olefins and trisubstituted olefins.5 Thus, chiral
dioxiranes are expected to be sensitive to the preexisting
chirality in secondary allylic alcohols or their derivatives,
which is essential to the kinetic resolution. Herein we
report our results on chiral ketone-catalyzed kinetic
resolution of acyclic secondary allylic silyl ethers.
Resu lts a n d Discu ssion s
(5) For selected examples of asymmetric epoxidation mediated by
chiral ketones, see: (a) Curci, R.; D′Accolti, L.; Fiorentino, M.; Rosa,
A. Tetrahedron Lett. 1995, 36, 5831. (b) Yang, D.; Yip, Y.-C.; Tang,
M.-W.; Wong, M.-K.; Zheng, J .-H.; Cheung, K.-K. J . Am. Chem. Soc.
1996, 118, 491. (c) Yang, D.; Wang, X.-C.; Wong, M.-K.; Yip, Y.-C.;
Tang, M.-W. J . Am. Chem. Soc. 1996, 118, 11311. (d) Yang, D.; Wong,
M.-K.; Yip, Y.-C.; Wang, X.-C.; Tang, M.-W.; Zheng, J .-H.; Cheung, K.-
K. J . Am. Chem. Soc. 1998, 120, 5943. (e) Tu, Y.; Wang, Z.-X.; Shi, Y.
J . Am. Chem. Soc. 1996, 118, 9806. (f) Wang, Z.-X.; Tu, Y.; Frohn, M.;
Zhang, J .-R.; Shi, Y. J . Am. Chem. Soc. 1997, 119, 11224. (g) Tian, H.;
She, X.; Shu, L.; Yu, H.; Shi, Y. J . Am. Chem. Soc. 2000, 122, 11551.
(h) Adam, W.; Zhao, C.-G. Tetrahedron: Asymmetry 1997, 8, 3995. (i)
Denmark, S, E.; Wu, Z.; Crudden, C. M.; Matsuhashi, H. J . Org. Chem.
1997, 62, 8288. (j) Armstrong, A.; Hayter, B. R. J . Chem. Soc., Chem.
Commun. 1998, 621.
I. Resolu tion s of Ra cem ic r-Tr ich lor om eth yl Al-
lylic Alcoh ols a n d Th eir Der iva tives. Our initial
(1) (a) Wipf, P. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 5, p 827. (b)
J ohnson, R. A.; Sharpless, K. B. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 7,
p 389. (c) Lipshutz, B. H.; Sengupta, S. In Organic Reactions; Wiley:
New York, 1992; Vol. 41, p 135.
(2) For recent reviews of kinetic resolution, see: (a) Kagan, H. B.;
Fiaud, J . C. Top. Stereochem. 1988, 18, 249. (b) Finn, M. G.; Sharpless,
K. B. In Asymmetric Synthesis; Morrison, J . D., Ed.; Academic Press:
New York, 1985; p 247.
(3) For selected examples on kinetic resolution of cyclic allylic
alcohols and/or their derivatives, see: (a) Visser, M. S.; Harrity, J . P.
A.; Hoveyda, A. H. J . Am. Chem. Soc. 1996, 118, 3779. (b) Kitamura,
M.; Kasahara, I.; Manabe, K.; Noyori, R. J . Org. Chem. 1988, 53, 708.
(c) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483. (d) Frohn, M.; Zhou, X.; Zhang, J .-R.; Tang, Y.; Shi, Y.
J . Am. Chem. Soc. 1999, 121, 7718.
(4) For selected examples on kinetic resolution of acyclic allylic
alcohols and/or their derivatives, see: (a) Martin, V. S.; Woodard, S.
S.; Katsuki, T.; Yamada, Y.; Ikeda, M.; Sharpless, K. B. J . Am. Chem.
Soc. 1981, 103, 6237. (b) Gao, Y.; Hanson, R. M.; Klunder, J . M.; Ko,
S. Y.; Masamune, H.; Sharpless, K. B. J . Am. Chem. Soc. 1987, 109,
5765. (c) Vedejs, E.; Chen, X. J . Am. Chem. Soc. 1996, 118, 1809. (d)
Ruble, J . C.; Latham, H. A.; Fu, G. C. J . Am. Chem. Soc. 1997, 119,
1492. (e) Burgess, K.; J ennings, L. D. J . Am. Chem. Soc. 1991, 113,
6129.
(6) (a) Fujisawa, T.; Ito, T.; Nishiura, S.; Shimizu, M. Tetrahedron
Lett. 1998, 39, 9735. (b) Hatch, C. E., III; Baum, J . S.; Takashima, T.;
Kondo, K. J . Org. Chem. 1980, 45, 3281. (c) Muljiani, Z.; Gadre, S. R.;
Modak, S.; Pathan, N.; Mitra, R. B. Tetrahedron: Asymmetry 1991, 2,
239.
(7) (a) Nicolaou, K. C.; Groneberg, R. D. J . Am. Chem. Soc. 1990,
112, 4085. (b) Bohme, A.; Gais, H. J . Tetrahedron: Asymmetry 1999,
10, 2511. (c) Corey, E. J .; Helal, C. J . Tetrahedron Lett. 1993, 34, 5227.
(d) Khrimian, A. P.; Oliver, J . E.; Waters, R. M.; Panicker, S.;
Nicholson, J . M.; Klun, J . A. Tetrahedron: Asymmetry 1996, 7, 37. (e)
Corey, E. J .; Link, J . O. Tetrahedron Lett. 1992, 33, 3431. (f) Corey, E.
J .; Link, J . O. J . Am. Chem. Soc. 1992, 114, 1906.
(8) (a) Corey, E. J .; Link, J . O.; Shao, Y. Tetrahedron Lett. 1992,
39, 3435. (b) Shono, T.; Ohmizu, H.; Kawakami, S.; Nakano, S.; Kise,
N. Tetrahedron Lett. 1981, 22, 871. (c) Ferraccioli, R.; Gallina, C.;
Giordano, C. Synthesis 1990, 327.
10.1021/jo010068c CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/23/2001

4620 J . Org. Chem., Vol. 66, No. 13, 2001
Yang et al.
Ch a r t 1
pure or enriched R-trichloromethyl allylic alcohols re-
mains a challenge for organic chemists and there is no
general and catalytic method available except one enzy-
matic approach.6c
(conversion <5% after 24 h, entry 6). The OTBDMS group
was found to be the best one in terms of resolution
efficiency (entry 5).
(2) Resolu tion s of r-Tr ich lor om eth yl Allylic TB-
DMS Eth er s Ca ta lyzed by Keton es (R)-1 a n d (R)-2.
Encouraged by the above results, a variety of TBDMS-
protected R-trichloromethyl allylic alcohols 7 and 9-20
were prepared and subjected to the kinetic resolution
conditions with ketones (R)-1 and (R)-2 as catalysts (5
mol % loading). The results are summarized in Table 2.
The recovered starting materials were enriched in the
(S)-enantiomers, the configuration of which was deter-
mined by Mosher’s method.10 The resulting epoxides had
the (R)-configuration at the C-2 position as determined
by X-ray crystallography.11 It was found that both steric
and electronic effects played important roles in determin-
ing the resolution efficiency. Generally, higher selectivi-
ties were obtained for substrates of bulkier para substit-
uents on the phenyl ring of the substrates (Table 2,
entries 2-5 vs 1 and 13-16 vs 12). A m-methyl group
on the phenyl ring did not significantly change the
resolution efficiency (entry 9 vs 1). The steric effect was
(1) Effect of P r otectin g Gr ou p s on th e Resolu tion
Efficien cies. We reported that C2 symmetric chiral
ketones (R)-1 and (R)-2 (Chart 1) were efficient catalysts
for asymmetric epoxidation of unfunctionalized olefins,
especially trans-stilbenes.5b-d Recent efforts made it
possible to prepare these ketones on a large scale.9 We
first examined the kinetic resolution of racemic R-tri-
chloromethyl allylic alcohol 3 mediated by the chiral
dioxirane generated in situ from Oxone and readily
available ketone (R)-1, and found, unfortunately, the
resolution efficiency to be rather poor (S ) 1.3, entry 1,
Table 1). We reasoned that the low selectivity could be
due to the small size of the OH group on substrate 3.
The OH group was then protected as acetate, benzoyl
ester, or TMS, TBDMS, and TBDPS ethers, and the
resulting substrates 4-8 were subjected to the kinetic
resolution conditions. We found that substrates of smaller
OR group, such as OH, acetate, benzoyl ester, and OTMS,
gave lower S values (entries 2-4), while very bulky
groups such as OTBDPS almost prohibited the reaction
(10) (a) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969,
34, 2543. (b) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95,
512.
(9) For convenient preparations of enantiopure ketones (R)-1 and
(R)-2 on a large scale, see: (a) Seki, M.; Furutani, T.; Hatsuda, M.;
Imashiro, R. Tetrahedron Lett. 2000, 41, 2149. (b) Kuroda, T.; Imashiro,
R.; Seki, M. J . Org. Chem. 2000, 65, 4213.
(11) The erythro-epoxides 12a , 14a , and 15a were found to have the
(S,S,R) configuration by X-ray analysis. Other erythro-epoxides 7a , 9a -
11a , 13a , and 16a -20a were assumed to have the same absolute
configuration as that of 12a , 14a , and 15a .

Kinetic Resolution of Secondary Allylic Silyl Ethers
J . Org. Chem., Vol. 66, No. 13, 2001 4621
Ta ble 1. Effect of P r otectin g Gr ou p on Efficien cies of Kin etic Resolu tion Ca ta lyzed by Keton e (R)-1a ,b
recovd SM
epoxide
entry
substrate
time (h)
convn (%)c
yield (%)d
ee (%)e,f
E/T ratiog
yield (%)d
Sh
1
2
3
4
5
6
3
4
5
6
7
8
4
3
4
24
24
24
75
81
70
50
56
<5
80
88
86
86
81
i
16 (S)
13
3
27 (S)
70 (S)
i
3:1
1.2:1
1.1:1
>49:1
>49:1
i
85
82
83
80
78
i
1.3
1.2
1.1
2
7
i
a
Reaction conditions were as follows: room temperature, 0.2 mmol of substrate, 0.01 mmol of ketone (R)-1, 0.5 mmol of Oxone, 1.55
mmol of NaHCO3, 1.5 mL of CH3CN, and 1 mL of aqueous Na2‚EDTA solution (4 × 10-4 M) (R)-1: 98% ee. Ketone (R)-1 was recovered
b
in over 80% yield by flash column chromatography and reused without loss of catalytic activity and chiral induction. c Conversion was
determined by 1H NMR of the crude reaction mixture after workup. Yield based on the conversion. e The ee value was determined by
d
HPLC (Chiralcel OD column). f The absolute configuration was determined by Mosher’s method. The ratio of erythro/ threo-epoxides
g
was determined by 1H NMR. The selectivity (S) was calculated by the equation S ) ln[(1 - C)(1 - ee)]/ln[(1 - C)(1 + ee)], where C is
h
i
conversion and ee is percentage enantiomeric excess of the recovered substrate. Not determined.
F igu r e 1. Hammett plot of the logarithm of selectivity (S),
obtained with ketone (R)-2 as the catalyst, against the Taft
steric substituent constants Es.
further confirmed by a linear Hammett plot (F ) -0.564,
r ) 0.975) of the logarithm of the S values, obtained with
ketone (R)-2 as the catalyst, against the Taft steric
substituent constants Es of para substituents on sub-
strates 9-12 (Me, Et, iPr, and tBu groups) (Figure 1).
On the other hand, substrates with electron-donating
12
F igu r e 2. The most stable conformers A and B of substrate
7.
(3) Tr a n sition Sta tes for Kin etic Resolu tion of
Su bstr a tes 7 a n d 9-20 Ca ta lyzed by Keton es (R)-1
groups on the phenyl ring always gave higher selectivities
than those with electron-withdrawing groups (entries 7
a n d (R)-2. The most stable conformers of substrate 7,
vs 6, 9 vs 10, and 17 vs 18). As expected, ketone (R)-2
namely A ( OCCdC about 0°) and B ( OCCdC about
gave a much higher selectivity than ketone (R)-1 for
resolution of the same substrate (entries 1-8 and 12-
19).
120°), were located by using the MacroModel program13
(Figure 2). The free energies of A and B were comparable
(∆G°rel ) 0.1 kcal/mol) but much lower than those of other
conformers (structure not shown) by >20 kcal/mol. As
Two additional features of the present kinetic resolu-
tion method are worth noting. First, the present method
shown in Figure 2, in the kinetic resolution process, the
was more effective for resolution of substrates with an
bulky CCl3 group in conformers A and B could shield one
aryl group on the double bond than those with an alkyl
group (entries 12-19 vs 20 and 21). In particular, the S
values ranged from 18 to 100 for resolution of substrates
face of the olefinic double bond and is thus anti to the
approaching dioxirane in the transition states.14 The
7 and 9-15 with ketone (R)-2 as the catalyst. Second,
the present kinetic resolution method showed very high
(13) MacroModel version 4.5: Mohamadi, F.; Richards, N. G. J .;
Guida, W. C.; Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.;
diastereoselectivities. Almost a single diastereomeric
epoxide was exclusively formed with ratios of erythro/
threo-epoxides over 49:1.11 The erythro-epoxides also
showed reasonably high enantiomeric excesses (77-93%
ee; Table 2, entries 12-16).
Hendrickson, T.; Still, W. C. J . Comput. Chem. 1990, 11, 440.
(14) Theoretical studies by Houk et al. indicated that stereoselective
attack of an electrophilic reagent to acyclic chiral olefins, with different
substituents on the allylic position, preferentially passes through the
“staggered” or “anti-periplanar” transition states which have the
largest group anti to the partially formed bonds. See: (a) Houk, K. N.;
Moses, S. R.; Wu, Y.-D.; Rondan, N. G.; J a¨ger, V.; Schohe, R.; Fronczek,
F. R. J . Am. Chem. Soc. 1984, 106, 3880. (b) Houk, K. N.; Duh, H.-Y.;
Wu, Y.-D.; Moses. S. R. J . Am. Chem. Soc. 1986, 108, 2754.
(12) Taft, R. W., J r. J . Am. Chem. Soc. 1952, 74, 3120.

4622 J . Org. Chem., Vol. 66, No. 13, 2001
Yang et al.
Ta ble 2. Kin etic Resolu tion of Acyclic Secon d a r y Allylic Silyl Eth er s Ca ta lyzed by Keton es (R)-1 a n d (R)-2a
recovd SM
epoxide
entry
substrate
ketoneb
time (h)
convn (%)c
yield (%)d
ee (%)e,f
E/ T ratiog
yield (%)d
ee (%)h
Si
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
7
9
(R)-1
(R)-1
(R)-1
(R)-1
(R)-1
(R)-1
(R)-1
(R)-1
(R)-1
(R)-1
(R)-1
(R)-2
(R)-2
(R)-2
(R)-2
(R)-2
(R)-2
(R)-2
(R)-2
(R)-2
(R)-2
(R)-2
(R)-2
(S)-1
(R)-1
24
24
24
24
24
24
44
24
24
48
24
10
1.5
2.5
3
56
53
56
53
63
66
59
32
55
49
53
55
45
56
48
50
38
62
46
36
34
45
55
52
97
81
90
65
82
84
83
55
84
60
75
67
84
86
86
94
87
80
82
94
86
88
86
85
84
j
70 (S)
65 (S)
64 (S)
79 (S)
96 (S)
98 (S)
75 (S)
38 (S)
66 (S)
30 (S)
46 (S)
96 (S)
74 (S)
99 (S)
87 (S)
94 (S)
58 (S)
98 (S)
78 (S)
27 (S)
20 (S)
63 (S)
75 (S)
43 (R)
51
>49:1
>49:1
>49:1
>49:1
>49:1
>49:1
>49:1
>49:1
>49:1
>49:1
>49:1
>49:1
>49:1
>49:1
>49:1
>49:1
>49:1
>49:1
>49:1
>49:1
>49:1
>49:1
5:1
78
83
69
88
82
52
51
76
64
88
64
85
90
76
88
82
76
81
85
74
82
87
82
80
j
j
j
j
j
j
j
j
j
j
7
7
6
13
13
13
7
13
6
10
11
12
13
14
15
16
17
18
7
j
j
2
4
77
89
77
93
93
j
j
j
j
j
30k
39k
37k
72
9
10
11
12
13
14
15
19
20
21
22
21
23
4
100
1.5
10
6
12
10.5
2
3
23
1
55
18
54
4
3
76
j
38
j
14k
9
>49:1
3
1.4
2:1
a
Reaction conditions were as follows: room temperature, 0.2 mmol of substrate, 0.01 mmol of ketone (R)-1 or (R)-2, 0.5 mmol of Oxone,
1.55 mmol of NaHCO3, solvents (for ketone (R)-1, 1.5 mL of CH3CN, and 1 mL of aqueous Na2‚EDTA solution (4 × 10-4 M); for ketone
b
(R)-2, 1 mL of DMM, 2 mL of CH3CN, and 2 mL of aqueous Na2‚EDTA solution (4 × 10-4 M)). (R)-1 and (R)-2: 98% ee. Ketones (R)-1
and (R)-2 were recovered in over 80% yield by flash column chromatography and reused without loss of catalytic activity and chiral
induction. c Conversion was determined by 1H NMR of the crude reaction mixture after workup. In cases where the ee of epoxides has
d
been determined, the conversion was cross-checked according to the equation: ee(olefin)/ee(epoxide) ) C/(1 - C). Yield based on the
conversion. e The ee value was determined by HPLC analysis of the corresponding allylic alcohol after deprotection except for substrate
g
7. f The absolute configuration was determined by Mosher’s method. The ratio of erythro/ threo-epoxides was determined by 1H NMR.
h
i
The ee value was determined by HPLC (Chiralcel OD column). The selectivity (S) was calculated by the equation S ) ln[(1 - C)(1 -
j
ee)]/ln[(1 - C)(1 + ee)], where C is conversion and ee is percentage enantiomeric excess of the recovered substrate. Not determined.
k
The selectivity (S) was the average of two runs.
large OTBDMS group blocks the other face of the double
bond in conformer B, rendering the double bond in-
accessible to dioxiranes. Therefore, only conformer A of
the lowest free energy can be possibly epoxidized by
dioxiranes approaching from the face opposite to the CCl3
group. This explains the observed excellent diastereo-
selectivities in the kinetic resolution process with the
erythro-epoxides as the major products.
Since the large OTBDMS group in conformer A blocks
the approach of dioxiranes from the H-4 side of the double
bond, the proposed spiro transition states6,15 for epoxi-
dation catalyzed by (R)-1 or (R)-2 could be simplified as
the favored C and the disfavored D (Figure 3), in which
chiral dioxiranes can only approach the double bond of
the substrate from the phenyl side. In the favored TS-C,
the phenyl ring of the (R)-enantiomer of the substrate is
F igu r e 3. Transition states for kinetic resolution reactions
far away from the steric sensors, i.e., H-3 (Cl-3) or H-3′
catalyzed by ketone (R)-2.
(15) (a) Baumstark, A. L.; McCloskey, C. J . Tetrahedron Lett. 1987,
(Cl-3′) of the (R)-dioxirane, and there is little steric or
electrostatic interaction between the substrate and the
dioxirane. In contrast, in the disfavored TS-D, the phenyl
ring of the (S)-enantiomer of the substrate severely
28, 3311. (b) Baumstark, A. L.; Vasquez, P. C. J . Org. Chem. 1988,
53, 3437. (c) Houk, K. N.; Liu, J .; DeMello, N. C.; Condroski, K. R. J .
Am. Chem. Soc. 1997, 119, 10147. (d) Bach, R. D.; Andres, J . L.;
Owensby, A. L.; Schlegel, H. B.; McDouall, J . J . W. J . Am. Chem. Soc.
1992, 114, 7207.

Kinetic Resolution of Secondary Allylic Silyl Ethers
J . Org. Chem., Vol. 66, No. 13, 2001 4623
Ta ble 3. Dep r otection of r-Tr ich lor om eth yl Allylic
TBDMS Eth er s 7 a n d 9-20 to th e Cor r esp on d in g
r-Tr ich lor om eth yl Allylic Alcoh ols
bumps into H-3 (Cl-3) or H-3′ (Cl-3′) of the (R)-dioxirane.
Consequently, the (S)-enantiomer of the substrate would
be less reactive than its corresponding (R)-form and is
expected to be enriched in the recovered substrate.
Docking experiments using the MacroModel program13
suggested that the steric sensors of dioxiranes can
recognize the para and meta substituents on the phenyl
rings of substrates. Thus, when the para substituent
becomes bulkier, the steric interactions in the disfavored
TS-D will be more severe, resulting in higher selectivity.
Furthermore, electron-donating substituents intensify
the electrostatic repulsion between the phenyl rings of
substrates and the Cl atom or naphthyl ring of the
dioxirane in the disfavored TS-D, which leads to higher
selectivity. For the same substrate, ketone (R)-2 gave
much higher selectivity than ketone (R)-1 because the
presence of the Cl atom at the 3 and 3′ positions increases
both steric interaction and electrostatic repulsion in the
disfavored TS-D.
(4) Dep r otection of th e TBDMS Gr ou p on Su b-
str a tes a n d Ep oxid es. To obtain the R-trichloromethyl
allylic alcohols, we tested several reagents such as
HF‚pyridine,16a Bu4NF,16b BF3‚Et2O,16c concentrated HCl,16d
CF3COOH,16e and AcOH16b for the deprotection of the
TBDMS group on substrates 7 and 9-20. While concen-
trated HCl, CF3COOH, and AcOH were totally ineffec-
tive, Bu4NF and BF3‚Et2O removed the TBDMS group
quickly but yielded some undesired side products due to
their reactions with R-trichloromethyl allylic alcohols.7d
HF‚pyridine proved to be the most effective reagent,
which generally gave clean R-trichloromethyl allylic
alcohols in high yield (Table 3).17
entry
substrate
product
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
7
9
7c
9c
88
91
89
90
92
86
90
91
71
85
83
82
89
10
11
12
13
14
15
16
17
18
19
20
10c
11c
12c
13c
14c
15c
16c
17c
18c
19c
20c
Sch em e 1
On the other hand, the TBDMS group on epoxides can
be deprotected by Bu4NF.16b,18
(5) Syn th etic Ap p lica tion s of r-Tr ich lor om eth yl
Allylic Alcoh ols. Two important transformations were
investigated to demonstrate the synthetic utilities of
chiral R-trichloromethyl allylic alcohols.
(a ) Hyd r ogen a tion . Chiral allylic alcohol 3 was
quantitatively converted to 4-phenyl-1,1,1-trichloro-2-
butanol 24 without loss of enantioselectivity under high-
pressure hydrogenation conditions (Scheme 1). The prod-
uct 24 has been shown to be an important precursor for
the preparation of chiral R-fluoro acids,7d R-hydroxy
acids,7e,f or R-amino acids.7e,f
Sch em e 2
(b) On e-P ot Rea r r a n gem en t. As shown in Scheme
2, chiral allylic alcohol 3 with a 64% ee was coupled with
(16) (a) Masamune, S.; Lu, L. D.-L.; J ackson, W. P.; Kaiho, T.;
Toyoda, T. J . Am. Chem. Soc. 1982, 104, 5523. (b) Corey, E. J .;
Venkateswarlu, A. J . Am. Chem. Soc. 1972, 94, 6190. (c) Kelly, D. R.;
Roberts, S. M.; Newton, R. F. Synth. Commun. 1979, 9, 295. (d) Cunico,
R. F.; Bedell, L. J . Org. Chem. 1980, 45, 4797. (e) Baker, R.; Cummings,
W. J .; Hayes, J . F.; Kumar, A. J . Chem. Soc., Chem. Commun. 1986,
1237.
(17) We also carried out the kinetic resolution of racemic R-trichlo-
romethyl allylic alcohol 3 by Sharpless asymmetric epoxidation method,
but low selectivity was obtained (S ) 1.1). This is in line with the
literature reports that Sharpless asymmetric epoxidation method is
ineffective for resolutions of acyclic secondary allylic alcohols with a
tert-butyl, CF3, or difluoroethyl group at the R-position. See: (a)
Schweiter, M. J .; Sharpless, K. B. Tetrahedron Lett. 1985, 26, 2543.
(b) Kitano, Y.; Matsumoto, T.; Sato, F. Tetrahedron 1988, 44, 4073. (c)
Hanzawa, Y.; Kawagoe, K. I.; Ito, M.; Kobayashi, Y. Chem. Pharm.
Bull. 1987, 35, 1633.
thiocarbonyldiimidazole in CH2Cl2. The crude residue 25
after the aqueous workup was used directly in the
rearrangement step without purification. The overall
yield from 3 to the rearranged product 26 was 75% and
the product also showed a 64% ee. The corresponding
allylic thiol is a versatile intermediate in the synthesis
of many sulfur-containing natural products.7a,b
(18) As an example, epoxide 7a was deprotected to corresponding
epoxy alcohol by Bu4NF in 79% yield.

4624 J . Org. Chem., Vol. 66, No. 13, 2001
Yang et al.
II. Resolu tion s of Oth er Acyclic Secon d a r y Allylic
TBDMS Eth er s. To extend the scope of our kinetic
resolution method, substrates 21-23, with a tert-butyl,
CF3, or phenyl group at the R-position instead of a CCl3
group, were subjected to the same kinetic resolution
conditions. The results (Table 2, entries 22-25) revealed
that the present method was also effective for resolution
of substrates with a tert-butyl or CF3 group at the
R-position. In particular, S values of 14 and 9 were
obtained in the resolutions of substrates 21 and 22,
respectively, with ketone (R)-2 as the catalyst (entries
22 and 23). The smaller CF3 group is less efficient than
CCl3 and tert-butyl groups in shielding one face of the
double bond in the substrates, leading to lower diaste-
reoselectivity and poorer resolution efficiency (entries 23
vs 22 and 12). Similar results were obtained for the
phenyl group (entries 25 vs 24 and 1).
proposed to rationalize the observed enantioselectivities
and diastereoselectivities in the kinetic resolution process
based on steric and electrostatic interactions between the
chiral dioxiranes and the racemic substrates. Since the
TBDMS group on the substrates and epoxides can be
easily removed,16a,b the present method provided a con-
venient access to both chiral secondary allylic alcohols
with a CCl3, tert-butyl, or CF3 group at the R-position
and chiral epoxy alcohols. With the ready availability of
chiral R-trichloromethyl allylic alcohols by our method,
future work will be directed at exploring their potential
applications in organic synthesis.
Ack n ow led gm en t. This work was supported by The
University of Hong Kong and Hong Kong Research
Grants Council. We thank Dr. K. K. Cheung for deter-
mination of the X-ray structures of epoxides 12a , 14a ,
and 15a .
Con clu sion s
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails of kinetic resolution reactions; X-ray structural analysis
of epoxides 12a , 14a , and 15a containing tables of atomic
coordinates, thermal parameters, bond lengths, and angles.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Kinetic resolution of acyclic secondary allylic alcohols
and their derivatives catalyzed by chiral ketones has been
investigated in some detail. It was found that the chiral
ketone-catalyzed kinetic resolution method was effective
for the acyclic secondary allylic silyl ethers with a CCl3,
tert-butyl, or CF3 group at the R-position. A model was
J O010068C