Chiral Synthesis via Organoboranes. 42. Selective Reductions. 57. Efficient Kinetic Resolution of Representative α-Tertiary Ketones with B-Chlorodiisopinocampheylborane

Article abstract of DOI:10.1021/jo951206z

Kinetic resolution of racemic α-tertiary ketones with 0.5-0.6 molar equiv of B-chlorodiisopinocampheylborane provides the product alcohols in very high diastereomeric and enantiomeric excess, with the unreacted ketone recovered in very high ee.For example, ethyl 1-methyl-2-oxocyclopentane- and cyclohexanecarboxylates are partially reduced to recover the ketone in 91 to >/=99percent ee and the product alcohols in up to 94percent de, with >90percent ee for the major diastereomer.Bicyclic ketones, such as 1-methyl- and 1-ethylnorcamphor, camphor, and camphenilone, are readily resolved to provide the ketone in 92 to >/=99percent ee, with the product alcohol recovered in high de and ee.Dihydrospirooctane-2,2'(3'H)-furan>-3-one is resolved to provide the ketone in >/=99percent ee and the product alcohol in >/=99percent de.In all the cases studied, the R-isomer of the ketone is recovered when ^dIpc₂BCl is used for kinetic resolution, while ^lIpc₂BCl provides the S-ketone.Optimum conditions for obtaining the product alcohol, or the ketone, or both, in very high yields and ee have been established.

Full text of DOI:10.1021/jo951206z

88
J . Org. Chem. 1996, 61, 88-94
Ch ir a l Syn th esis via Or ga n obor a n es. 42. Selective Red u ction s.
57. Efficien t Kin etic Resolu tion of Rep r esen ta tive r-Ter tia r y
Keton es w ith B-Ch lor od iisop in oca m p h eylbor a n e
P. Veeraraghavan Ramachandran, Guang-Ming Chen,1 and Herbert C. Brown*
H. C. Brown and R. B. Wetherill Laboratories of Chemistry, Purdue University,
West Lafayette, Indiana 47907
Received J uly 5, 1995X
Kinetic resolution of racemic R-tertiary ketones with 0.5-0.6 molar equiv of B-chlorodiisopinocam-
pheylborane provides the product alcohols in very high diastereomeric and enantiomeric excess,
with the unreacted ketone recovered in very high ee. For example, ethyl 1-methyl-2-oxocyclopen-
tane- and -cyclohexanecarboxylates are partially reduced to recover the ketone in 91 to g99% ee
and the product alcohols in up to 94% de, with >90% ee for the major diastereomer. Bicyclic ketones,
such as 1-methyl- and 1-ethylnorcamphor, camphor, and camphenilone, are readily resolved to
provide the ketone in 92 to g99% ee, with the product alcohol recovered in high de and ee.
Dihydrospiro[bicyclo[3.2.1]octane-2,2′(3′H)-furan]-3-one is resolved to provide the ketone in g99%
ee and the product alcohol in g99% de. In all the cases studied, the R-isomer of the ketone is
l
recovered when dIpc2BCl is used for kinetic resolution, while Ipc2BCl provides the S-ketone.
Optimum conditions for obtaining the product alcohol, or the ketone, or both, in very high yields
and ee have been established.
In tr od u ction
in stereoselective organic synthesis.4,8 However, kinetic
resolution of racemic ketones using organic reagents has
not been studied seriously.9 The importance of these
types of chiral R-tertiary alkyl ketones and alcohols
persuaded us to develop a very simple approach for their
easy access via asymmetric reduction. Almost a decade
ago, as part of a study of the reduction of hindered
ketones with (-)-B-chlorodiisopinocampheylborane (dIpc2-
BCl; Aldrich; (-)-DIP-Chloride, (-)-1),10 we observed the
kinetic resolution of methyl 1-methyl-2-oxocyclopentane-
carboxylate (2), in THF at -25 °C, providing the alcohol
in 96% diastereomeric and 96% enantiomeric excesses
(de and ee).11 A systematic study of this reaction to
optimize the conditions for the successful resolution of
several cyclic R-alkyl-â-keto esters and bicyclic R-tertiary
ketones with (+)- and (-)-1 with the simultaneous
preparation of the alcohols in high de and g95% ee has
now been completed.
The efficient syntheses of enantiomerically pure mul-
tifunctional molecules containing a chiral quaternary
carbon have long fascinated organic chemists because of
their considerable utility as building blocks for several
biologically important compounds.2 Fujisawa’s synthesis
of malyngolide and frontalin by the bakers’ yeast reduc-
tion of ethyl 2-cyclopentanethiocarboxylate followed by
alkylation,3 and Westermann’s synthesis of the Nitraria
alkaloids, nitramine and isonitramine, via a resolution
of ethyl 1-(2-cyanoethyl)-2-oxocyclohexanecarboxylate with
pig liver esterase,4 are representative examples of these.
Sakai and co-workers carried out the asymmetric alky-
lation of 2-oxocyclopentanecarboxylates by preparing
their acetals with optically pure diols, prior to the
alkylation,5 and Enders et al. used RAMP-/SAMP-hydra-
zone to synthesize 2-alkyl-2-cyanocycloalkanones and
other polyfunctionalized chirons in high ee.6 R-Alkyl
Dieckmann esters have been used as starting material
in several syntheses.5,7
Resu lts a n d Discu ssion
The reductions of the ketones or keto esters with 0.50
molar equiv of 1, carried out under neat conditions at
room temperature (rt) and monitored by 11B NMR
spectroscopy of a methanolyzed aliquot (δ 32), are
complete in 2-12 h. The usual diethanolamine10 or
Enzymatic kinetic resolution via the hydrolysis of
racemic keto esters is a commonly employed procedure
X Abstract published in Advance ACS Abstracts, December 15, 1995.
(1) Postdoctoral Research Associate on a Grant from the U.S. Army
Research Office.
(2) Fuji, K. Chem. Rev. 1993, 93, 2037.
(3) Sato, T.; Maeno, H.; Noro, T.; Fujisawa, T. Chem. Lett. 1988,
1739.
(8) (a) For a review on kinetic resolutions, see: Kagan, H. B.; Fiaud,
J . C. Top. Stereochem. 1988, 18, 249. (b) For a review on dynamic
kinetic resolutions, see: Noyori, R.; Tokunaga, M.; Kitamura, M. Bull.
Chem. Soc. J pn. 1995, 68, 36. (c) For reviews on bakers’ yeast as a
reagent in organic synthesis, see: Servi, S. Synthesis 1990, 1. (d) Csuk,
R.; Glanzer, B. I. Chem. Rev. 1991, 91, 49.
(4) (a) Westermann, B.; Scharmann, H. G.; Kortmann, I. Tetrahe-
dron: Asymmetry 1993, 4, 2119.
(5) Kato, K.; Suemune, H.; Sakai, K. Heterocycles 1994, 37, 413.
(6) (a) Enders, D.; Zamponi, A.; Raabe, G.; Runsink, J . Synthesis
1993, 725. (b) Enders, D.; Zamponi, A.; Schafer, T.; Nubling, C.;
Eichenauer, H.; Demir, A. S.; Raabe, G. Chem. Ber. 1994, 127, 1707.
(7) (a) Sohda, T.; Meguno, K.; Kawamatsu, Y. Chem. Pharm. Bull.
1984, 32, 2267. (b) Sugai, T.; Kakeya, H.; Ohta, H. Morrroka, M.; Ohba,
S. Tetrahedron 1989, 45, 6135. (c) Isobe, et al. Chem. Pharm. Bull.
1986, 34, 3029. (d) Fujii, M.; Kawaguchi, K.; Nakamura, K.; Ohno, A.
Chem. Lett. 1992, 1493. (e) Nakamura, N.; Sakai, K. Tetrahedron Lett.
1976, 2049.
(9) Woodward and co-workers have described the resolution of dl-
camphor using l-menthyl N-aminocarbamate. Woodward, R. B.; Koh-
man, T. P.; Harris, G. C. J . Am. Chem. Soc. 1941, 63, 120.
(10) (a) Brown, H. C.; Chandrasekharan, J .; Ramachandran, P. V.
J . Am. Chem. Soc. 1988, 110, 1539. DIP-Chloride is the trademark of
Aldrich Chemical Co. (b) The superscripts d and l refer to (+)- and
(-)-R-pinene, respectively, used to prepare the corresponding (-)- and
(+)-DIP-Chloride, respectively.
(11) Brown, H. C.; Ramachandran, P. V.; Chandrasekharan, J . J .
Org. Chem. 1986, 51, 3394.
0022-3263/96/1961-0088$12.00/0 © 1996 American Chemical Society

Chiral Synthesis via Organoboranes
J . Org. Chem., Vol. 61, No. 1, 1996 89
Ta ble 1. Kin etic Resolu tion of r-Hin d er ed Cyclic â-Keto Ester s w ith (-)-1 u n d er Nea t Con d ition s a t Room Tem p er a tu r e
hydroxy ester, % recovered keto ester
keto ester
keto ester:reagent
yield,a
%
cis:trans,b %
(1S,2S)
(1S,2R)
(1R,2R)
(1R,2S)
yield,a
%
ee,c %
config
2
2
2
4
4
4
4
6
6
2:1
73
89
68
72
80
74
80
75
85
3:97
12:88
16:84
7:93
95
85
80
91
88
80
5
0
0
0
0
0
0
14
0
2
3
4
2
3
3
12
16
7
9
15
0
86
86
70
79
89
61
72
81
91
90
96
g99
75
(R)
(R)
(R)
2:1.2
2:1.3
2:1
2:1.2
2:1.3
2:1.3e
2:1
(R)d
(R)d
(R)d
(S)d
(R)
9:91
96
15:85
14:86
5:95
5
g99
g99
72
81
11
14
84
83
5
3
2:1.2
3:97
0
91
(R)
a
b
Isolated yield. Determined as the TFA derivative on a Chiraldex-GTA capillary column. c Determined as such on a Chiraldex-GTA
capillary column. On the basis of analogy. e For a reaction using (+)-1.
d
acetaldehyde12 workup provides diastereomeric mixtures
of the product alcohol and the unreacted ketone. The
ketone, product alcohol, and R-pinene, liberated during
the reduction, are separated using column chromatog-
raphy. The ee of the ketone is determined by gas
chromatographic (GC) analysis on a Chiraldex-GTA
capillary column.13 The diastereomeric ratio of the
alcohols is determined by GC analysis using a SPB-5
capillary column. Their ee values are determined by
converting them either to the corresponding menthyl
chloroformate (MCF)14 or to the methoxy(trifluorometh-
yl)phenylacetates (MTPA derivative),15 followed by analy-
sis on a SPB-5 capillary column. Frequently, the alcohols
are esterified to the corresponding trifluoroacetates and
analyzed using a Chiraldex-GTA capillary column.
Kin etic Resolu tion of r-Hin d er ed Cyclic â-Keto
Ester s. Meth yl 1-Meth yl-2-oxocyclop en ta n eca r box-
yla te (2). We had reported the reduction of 2 with 0.50
molar equiv of (-)-1, at rt, when the major diastereomer
of the alcohol was obtained in 93% ee.11 But the config-
uration of the product alcohol and recovered ketone was
not established. This reaction was repeated, complete
in 2 h, to reproduce our earlier results (eq 1). The usual
the recovered ketone coupled with the identification of
the major diastereomer as the trans-alcohol. The pro-
posed mechanism of reduction with dIpc2BCl supports
this assignment.10 This methodology is used to assign
the configurations for all of the products reported herein.
The cis isomer shows g99% ee. The excess ketone,
recovered in 86% yield, is enriched in the (R)-isomer in
90% ee (eq 1). A good correspondence between the % ee
of the recovered ketone and the product alcohols formed
is obvious.
The efficiency of the kinetic resolution increases when
0.60 equiv of the reagent is used, al beit at the expense
of the de and ee values of the product alcohol.17 Utiliza-
tion of 0.65 equiv of the reagent provides essentially
optically pure ketone.
Eth yl 1-Meth yl-2-oxocyclopen tan ecar boxylate (4).
The effect of the ester grouping on the stereochemical
outcome was tested by reducing 4, the ethyl ester analog
of 2, with (-)-1. Essentially similar results are realized
(eq 1). On the basis of the analogous reaction of 2, we
believe that we have recovered (R)-4 in g99% ee.
Eth yl 1-Meth yl-2-oxocycloh exa n eca r boxyla te (6).
The results are similar also for the reduction of the
cyclohexane analog of 4, namely 6 (eq 2). The diastere-
omeric ratio of the product alcohol is again determined
by comparing it with the product obtained from the
reduction of 6 with NaBH4. Unlike 4, the reduction of 6
with NaBH4 produces the cis alcohol as the predominant
d
isomer, as reported in the literature.16 However, Ipc2-
BCl provides the (1S,2S)-isomer (trans) as the major
diastereomer, consistent with the stereochemistry of the
product obtained from 2 and 4. The recovered ketone
shows an ee of 91% (R) when 0.60 equiv of the reagent is
used for kinetic resolution. The results of the kinetic
resolution of these keto esters are summarized in Table
1.
(1)
diethanolamine workup provides the recovered ketone in
86% yield with a 73% yield of methyl 1-methyl-2-
hydroxycyclopentanecarboxylate (3). The diastereomeric
ratio of the alcohols was determined by gas chromato-
graphic and 1H NMR spectroscopic comparison of the
product alcohols with that obtained from the reduction
with NaBH4, as described in the literature.16 The
analysis shows that the reduction of 2 with 0.50 equiv of
1 provides 94% de for the (1S,2S)-trans isomer 3 in 96%
ee. The configurations of all of the diastereomers of the
product are assigned on the basis of the configuration of
(2)
Kin et ic R esolu t ion of Bicyclo[2.2.1]h ep t a n -2-
on es. Due to their application in the syntheses of several
natural products,18 medicinal compounds,19 and chiral
(12) Ramachandran, P. V.; Teodorovic, A. V.; Rangaishenvi, M. V.;
Brown, H. C. J . Org. Chem. 1992, 57, 5379.
(13) Chiraldex-GTA is a trademark of Alltech Associates, Inc.
(14) Westley, J . W.; Halpern, B. J . Org. Chem. 1968, 33, 3978.
(15) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543.
(17) We had reported that the reaction of 2 with 1 in THF at -25
°C is complete in 60 h11 and obtained the product alcohol in 96% de
and ee. In this case the recovered ketone was also obtained in 96% ee.
(18) Woodward, R. B. Pure Appl. Chem. 1968, 17, 519.
(19) (a) Suchocki, J . A.; May, E. L.; Martin, T. J .; George, C.; Martin,
B. R. J . Med. Chem. 1991, 34, 1003. (b) Richou, O.; Vaillancourt, V.;
Faulkner, D. J .; Albizati, K. F. J . Org. Chem. 1989, 54, 4729.
(16) Nerdel, F.; Frank, D.; Barth, G. Chem. Ber. 1969, 102, 395.

90 J . Org. Chem., Vol. 61, No. 1, 1996
Ramachandran et al.
Ta ble 2. Kin etic Resolu tion of r-Hin d er ed Bicyclic Keton es w ith 1 u n d er Nea t Con d ition s a t Room Tem p er a tu r e
product alcohol
endoc
recovered ketone
ee,d
% config
exoc
ketone
reagent ketone:reagent yield,a
%
endo:exob (1R), % (1S), % (1R), % (1S), % yield,a
%
1-methylnorcamphor (8)
1-methylnorcamphor (8)
(-)-1
(-)-1
2:1
89
91
92
93
84
94
95
94
91
92
78
84
90
9:91
13:87
16:84
21:79
14:86
1:99
2:98
3:97
94:6
86:14
g99:0
g99:0
g99:0
9
13
16
0
14
1
0.2
3
2
0
0
0
21
0
0
5
3
4
76
2
3
96
4
6
14
0
0
86
84
80
3
84
96
2
93
0
0
97
92
91
91
78
89
91
94
92
98
81
94
96
63 (1R)
88 (1R)
g99 (1R)
g99 (1S)
92 (1R)f
66 (1R)
64 (1S)
98 (1R)
78 (1R)
97 (1R)
89 (1R)
94 (1S)
g99 (1R)
2:1.2
2:1.4
2:1.4
2:1:2
2:1
2:1
2:1.2
2:1
2:1.2
2:1.2
2:1.2
2:1.45
1-methylnorcamphor (8)e (-)-1
1-methylnorcamphor (8)e (+)-1
1-ethylnorcamphor (10)
camphor (12)
camphor (12)
camphor (12)
camphenilone (14)
camphenilone (14)
spirofuranone (16)
spirofuranone (16)
spirofuranone (16)e
(-)-1
(-)-1
(+)-1
(-)-1
(-)-1
(-)-1
(-)-1
(+)-1
(-)-1
1.8
0
92
84
77
22
71
2
23
78
29
0
0
0
0
a
b
d
Isolated yield. Determined by analysis on a SPB-5 capilary column. c Determined as a derivative on a capillary column. Determined
by direct analysis on a Chiraldex-GTA capillary column. e At 0 °C. f On the basis of analogy.
Ta ble 3. Kin etic Resolu tion of Ca m p h en ilon e w ith 1 u n d er Differ en t Con d ition s
product alcohol
recovered ketone
endoc
exoc
reagent ketone:reagent reactn temp yield,a
%
endo:exob (1R), % (1S), % (1R), % (1S), % yield,a
%
ee,d
%
config
(-)-1
(-)-1
(-)-1
(-)-1
(-)-1
(-)-1
(+)-1e
(-)-1
2:0.9
2:1
rt
rt
rt
0 °C
rt
0 °C
0 °C
rt
92
91
93
92
92
90
95
87
95:5
94:6
91:9
97:3
86:14
91:9
91:9
82:18
1
2
1
0
2
1
90
2
94
92
90
92
84
90
1
3
6
6
3
14
6
2
0
3
5
0
3
6
4
85
92
89
86
98
88
98
90
70
78
92
95
97
g99
g99
g99
(1R)
(1R)
(1R)
(1R)
(1R)
(1R)
(1S)
(1R)
2:1.1
2:1.1
2:1.2
2:1.2
2:1.2
2:1.3
3
14
80
c
aIsolated yield. bDetermined by analysis on a SPB-5 capillary column. Determined as a derivative on a capillary column. dDetermined
e
by direct analysis on a Chiraldex-GTA capillary column. Large-scale reaction, acetaldehyde workup.
auxiliaries,20 the kinetic resolution of bicyclo[2.2.1]heptan-
2-ones has been attempted in the past.21 The applicabil-
ity of 1 for the resolution of representative bicyclic
ketones with an R-tertiary center in excellent de and ee
is summarized in Tables 2 and 3. The discussion of the
kinetic resolution of individual ketones is continued
below.
lower than that calculated to be [R]22D ) -52 (CHCl3) by
Berson and co-workers.23
1-Meth yln or ca m p h or . We had earlier reported that
1-methyl-2-norbornanone (8) is partially reduced with
(-)-1 in THF at rt to produce the (1S,2S)-isomer of the
alcohol in 89% ee (eq 3).11 Repetition of this reaction
under neat condition at rt provides a 90% yield of the
product alcohol showing an exo/endo ratio of 91:9, the exo-
alcohol in 94% ee and the endo-isomer in g99% ee. The
exo/endo ratio is determined by GC comparison with the
product obtained from a sodium borohydride reduction
of 8.22 The (1R)-isomer of the excess ketone is recovered
in 95% yield and 63% ee. A reaction of the ketone with
0.60 molar equiv of the reagent provides the recovered
ketone in 88% ee. Increasing the amount of the reagent
to 0.70 equiv, while lowering the reaction temperature
to 0 °C, provides enantiomerically pure 8. The optical
rotation of the sample of enantiopure 8 prepared by this
(3)
1-Eth yln or cam ph or . The kinetic resolution of 1-ethyl-
2-norbornanone (10) provides essentially similar results
as the methyl analog (eq 3). On the basis of the
analogous reaction of 8, we believe that we have recov-
ered (1R)-10 in 92% ee.
Ca m p h or . The reaction of camphor (12) with 0.50
molar equiv of (-)-1 provides 99% of the exo-alcohol in
94% ee, and the excess ketone is recovered in 66% ee in
the (R)-isomer. However, 0.60 molar equiv of 1 provides
the recovered ketone, (1R)-12, in 98% ee (eq 4).
(4)
procedure, [R]25 ) -45.50 (c 5.03, CHCl3) for the (1R)-
D
8, or [R]25 ) +45.91 (c 4.57, CHCl3) for the (1S)-8, is
D
(20) (a) Hoffman, R. W.; Harold, T. Chem. Ber. 1981, 114, 375. (b)
Boeckman, R. K., J r.; Nelson, S. G.; Gaul, M. D. J . Am. Chem. Soc.
1992, 114, 2258. (c) Keegan, D. S.; Midland, M. M.; Werley, R. T.;
McLoughlin, J . I. J . Org. Chem. 1991, 56, 1185. (d) ShengJ ian, L.;
Yaozhong, J .; Aiqiao, M. Tetrahedron: Asymmetry 1992, 3, 1467.
(21) Irwin A. J .; J ones, J . B. J . Am. Chem. Soc. 1976, 98, 8476.
(22) The reduction of 1-methylnorcamphor and camphenilone with
NaBH4 in ethanol at rt provides the product alcohol with an endo/exo
ratio of 95:5 and 96:4, respectively.
Ca m p h en ilon e. The reaction of camphenilone (14)
also provides similar results (eq 5). The reduction of 14
(23) A rotation of -12.5 (c 2.41, CHCl3) is reported for partially pure
(1R)-8. On the basis of this, the optical rotation of optically pure (1R)-8
was calculated to be -52.0 (c, CHCl3). Berson, J . A.; Walia, J . S.;
Remanick, A.; Suzuki, S. J . Am. Chem. Soc. 1961, 83, 3986.

Chiral Synthesis via Organoboranes
J . Org. Chem., Vol. 61, No. 1, 1996 91
with 0.5 equiv of (-)-1 provides 94% of the endo-alcohol
in 96% ee as the major isomer. The exo/endo ratio is
determined by GC comparison with the product obtained
from a sodium borohydride reduction of 14.22 The
recovered ketone is analyzed to be 78% ee in the (1R)-
isomer. Increasing the reagent used to 60% improves the
ee of the ketone, (1R)-14, to 92%.
ketone. In the case of 16, we were interested in observing
whether the chiral center at the 1-position of the starting
norcamphor or the newly created R-chiral center controls
the kinetic resolution. The reaction of 16 with 0.60 equiv
of (-)-1 provides the product alcohol in g99% de, and
the excess ketone is recovered in 89% ee. Utilization of
0.7 equiv of 1 provides 16 in g99% ee (eq 7). The
(7)
(5)
stereochemistry of the recovered ketone and the product
alcohol are determined as follows. Paquette has reported
that the reduction of 16 with Dibal-H produces the endo-
alcohol as the major isomer.24 Comparison of the product
obtained from the Dibal-H reduction with that realized
from the DIP-Chloride reduction shows it to be exclu-
sively endo. This is confirmed by an X-ray crystal-
lographic analysis of the 3,5-dinitrobenzoate derivative
(18)25 of the alcohol obtained from the DIP-Chloride
reduction of optically pure 16 recovered from kinetic
resolution with (-)-1. The X-ray analysis confirms that
the recovered ketone is 1R,2S, showing that the chirality
at the 1-position still influences the rate of reduction.
In some of these kinetic resolution experiments, we
utilized (+)-1 (lIpc2BCl) to yield the opposite isomer of
the alcohol and recover the (S)-isomer of the ketone
(Tables 1-3). The scaling up26 of this kinetic resolution
methodology was tested by resolving 0.5 mol of 14 with
0.6 equiv of (+)-1 using acetaldehyde workup.12 The
alcohol is obtained in 95% yield, and the ketone is
recovered in 98% yield and g99% ee, while the chiral
auxiliary, R-pinene, is recovered in 95% yield in a readily
recyclable form.
Effect of Stoich iom etr y. The effect of the stoichi-
ometry and temperature on this kinetic resolution pro-
cedure was studied for the reduction of 14. Thus, the
treatment of 14 with 0.45-0.65 equiv of 1, in increments
of 0.05 equiv, at different temperatures clearly shows the
effect on the % ee of the recovered ketone as summarized
in Table 3. Optically pure 14 is obtained by carrying out
the kinetic resolution either with 0.60 equiv of 1 at 0 °C
or with 0.65 equiv of the reagent at rt.
The product alcohol is obtained in higher diastereo-
meric excess by using slightly less than 0.50 equiv of the
reagent and by conducting the reaction at the lower
temperature.
Tw o-Step Kin etic Resolu tion . The procedures dis-
cussed thus far produce either the ketone or the alcohol
in high ee. The ee of the recovered ketone is increased
at the expense of the % de and % ee of the product
alcohol. To achieve maximum optical purity for the
alcohol and the ketone, a two-step procedure was devel-
oped. The reduction of 14 with 0.45 molar equiv of the
reagent at rt provides 95% endo-15 in 98% ee. The
ketone and the alcohol are separated by column chro-
matography, and the recovered 14 is then treated with
0.20 equiv of 1 at rt and worked up when the % ee is
improved from 70% to 96% (eq 6). Adopting this proce-
dure, we can obtain both the product alcohol and the
ketone in very high ee.
Con clu sion s
In conclusion, we have demonstrated the use of 1 for
the kinetic resolution of representative R-tertiary cyclic
and bicyclic ketones. Optimum conditions to obtain
either the product alcohol or the ketone or both, in very
high yields and ee, have been established. This proce-
dure can be used as an excellent alternative to asym-
metric alkylations of carbonyls for the generation of
tertiary chiral centers. This adds to the attractiveness
of our reagent, one that has already found a number of
applications in organic syntheses.
(6)
Exp er im en ta l Section
Gen er a l Meth od s. Techniques for handling air-sensitive
compounds have been previously described.27 Analyses of the
MTPA esters or MCF derivatives were performed on a gas
chromatograph (GC) using a SPB-5 capillary column (30 m),
at appropriate temperatures. Some of the product alcohols
were converted to the trifluoroacetates and analyzed on a
Chiraldex-GTA capillary column (23 m).
Dih ydr ospir o[bicyclo[3.2.1]octan e-2,2′(3′H)-fu r an ]-
3-on e (16). Recently, Paquette described the synthesis
of dihydrospiro[bicyclo[3.2.1]octane-2,2′(3′H)-furan]-3-one
(16) by an oxonium ion initiated pinacol-like rearrange-
ment.24 We considered 16 to be an ideal compound to
test the capability of 1 for kinetic resolution since it
contains an R-quaternary carbon center. So far, the
(25) Paquette and co-workers could crystallize only the minor (15%)
exo-isomer of 18 for X-ray data.
(26) DIP-Chloride has been utilized for preparative-scale reactions.
For example, see: King, A. O.; Corley, E. G.; Anderson, R. K.; Larsen,
R. D.; Verhoeven, T. R.; Reider, P. J .; Xiang, Y. B.; Belley, M.; Leblanc,
Y.; Labelle, M.; Prasit, P.; Zamboni, R. J . Org. Chem. 1993, 58, 3731.
(27) Brown, H. C.; Kramer, G. W.; Levy, A. B.; Midland, M. M.
Organic Syntheses via Boranes; Wiley-Interscience: New York, 1975;
Chapter 9.
d
kinetic resolution of ketones with Ipc2BCl provided the
(R)-isomer for the quaternary center of the recovered
(24) (a) Paquette, L. A.; Andrews, J . F. P.; Vanucci, C.; Lawhorn,
D. E.; Negri, J . T.; Rogers, R. D. J . Org. Chem. 1992, 57, 3956.

92 J . Org. Chem., Vol. 61, No. 1, 1996
Ramachandran et al.
Ma ter ia ls. Ethyl ether (EE) (Mallinckrodt) was used as
received. (()-Camphenilone was a sample previously obtained
from the Chemical Samples Co. All other chemicals were
purchased from Aldrich Chemical Co. R-Methoxy-R-(trifluo-
romethyl)phenylacetic acid (MTPA) obtained from Aldrich
Chemical Co. was converted to the acid chloride using Mosher’s
procedure.15
(b) 2:1.3 Rea ction . 4 (126 mmol, 21.42 g) was treated with
26.27 g (81.9 mmol) of (-)-1 at rt. The reaction was complete
in 2 h. Workup as above provided 4.57 g (61%) of the recovered
keto ester and 10.42 g (74%) of the hydroxy ester. The keto
ester was analyzed to be of g99% ee in the (R)-isomer. [R]22
D
) -16.09 (c 5.9, CHCl3).28 The hydroxy ester has an isomeric
composition of 80% (1S,2S)-5, 5% (1R,2R)-5, and 15% (1R,2S)-
5.
Kin etic Resolu tion of Keton es w ith 1. Gen er a l P r o-
ced u r e. An oven-dried 50 mL round bottom flask equipped
with a septum-capped side arm, magnetic stirring bar, and a
connecting tube was cooled to rt in a stream of nitrogen. The
ketone (20 mmol) and DIP-Chloride (10 mmol) were trans-
ferred to the flask in a glovebag. The reaction mixture was
stirred at appropriate temperatures until the reaction was
complete as shown by the 11B NMR spectrum of a methano-
lyzed aliquot (δ 32). EE (25 mL) was added, followed by
diethanolamine (22 mmol), and the mixture was stirred for 2
h when the boron components precipitated as a complex. This
precipitate was filtered and washed with pentane. The
combined filtrates were concentrated and chromatographed
using vacuum liquid chromatography on silica gel. R-Pinene
was eluted with pentane, and the recovered ketone was eluted
with pentane:EE (9:1), followed by elution of the alcohol with
pentane:EE (1:1). The ketone was further purified by pre-
(c) 2:1.3 Rea ction , w ith (+)-1. 4 (65.2 mmol, 11.09 g) was
treated with 13.6 g (42.4 mmol) of (+)-1 at rt. The reaction
was complete in 2 h. Workup as above provided 2.79 g (72%)
of the recovered keto ester and 5.84 g (80%) of the hydroxy
ester. The keto ester was analyzed to be of g99% ee in the
(S)-isomer. [R]22D ) +15.99 (c 4.2, CHCl3).28 1H NMR δ (ppm)
(CDCl3): 1.22-1.27 (t, 7.1 Hz), 1.31 (s), 1.82-2.58 (m), 4.12-
4.20 (m). 13C NMR δ (ppm) (CDCl3): 13.97, 19.30, 19.48, 36.13,
37.56, 55.81, 61.20, 172.27, 215.73. Anal. Calcd for C9H14O3:
C, 63.31; H, 8.30. Found: C, 63.49; H, 8.38.
The hydroxy ester has an isomeric composition of 5%
(1S,2S)-5, 81% (1R,2R)-5, and 14% (1S,2R)-5.
Kin etic Resolu tion of Eth yl 1-Meth yl-2-oxocycloh ex-
a n eca r boxyla te (6). (a ) 2:1 Rea ction . The keto ester was
prepared in 99% yield by the methylation of ethyl 2-oxocyclo-
hexanecarboxylate using NaH and iodomethane in THF, bp
74-75 °C/1.9 mmHg. 6 (23 mmol, 4.23 g) was treated with
11.5 mmol (3.69 g) of (-)-1 at rt as described in the general
procedure. The reaction was complete in 3 h. Workup and
chromatography provided 1.60 g (75%) of the product hydroxy
ester and 1.71 g (81%) of the recovered keto ester. Analysis
of the TFA derivative of the alcohol showed a composition of
84% (1S,2S)-7, 11% (1R,2R)-7, and 5% (1R,2S)-7. The recov-
ered keto ester was analyzed on a Chiraldex-GTA capillary
column which showed a composition of 86% of the (R)-isomer
parative GC on
a SE-30 column, and the rotation was
measured. The ee of the ketone was determined by analysis
on a gas chromatograph using a Chiraldex-GTA capillary
column (23 m). The cis/ trans or exo/ endo ratios of the alcohols
were determined by a GC comparison (SPB-5 capillary column)
with the product obtained from the reduction of the ketone
with NaBH4. The ee of the diastereomers were determined
by converting the alcohol to the MCF, MTPA, or TFA deriva-
tive and analysis on a GC using an appropriate capillary
column. The reactions of individual ketones are presented
below.
and 14% of the (S)-isomer. [R]25 ) -85.40 (c 5.85, CHCl3)
D
corresponds to an optical purity of g99% on the basis of the
maximum rotation, [R]D ) +66.1 (CHCl3), reported in the
literature for the (S)-isomer.4 The spectral data of the
recovered keto ester are identical to those of (()-6.
Kin etic Resolu tion of Meth yl 1-Meth yl-2-oxocyclop en -
ta n eca r boxyla te (2). (a ) 2:1 Rea ction . The keto ester was
prepared in 91% yield by the methylation of methyl 2-oxocy-
clopentanecarboxylate using NaH and iodomethane in THF,
bp 80 °C/3.7 mmHg. 2 (28 mmol, 4.37 g) was treated with 4.5
g (14 mmol) of (-)-1 at rt as described in the general procedure.
The reaction was complete in 2 h. Workup and chromatog-
raphy provided 1.62 g (73%) of the product hydroxy ester and
1.87 g (86%) of the recovered keto ester. Analysis of the TFA
derivative of the alcohol on a Chiraldex-GTA column showed
an isomeric composition of 95% (1S,2S)-3, 2% (1R,2R)-3, and
3% (1R,2S)-3. The recovered keto ester was analyzed on a
Chiraldex-GTA capillary column which showed a composition
of 95% of the (R)-isomer and 5% of the (S)-isomer. The spectral
data of the recovered keto ester are identical to those of (()-2.
(b) 2:1.3 Rea ction . 2 (53.6 mmol, 8.36 g) was treated with
11.17 g (34.8 mmol) of (-)-1 at rt. The reaction was complete
in 12 h. Workup as above provided 2.05 g (70%) of the
recovered keto ester and 3.74 g (68%) of the hydroxy ester.
The keto ester was analyzed to be of g99% ee in the (R)-isomer.
[R]22D ) -11.41 (c 4.98, CHCl3) corresponds to an optical purity
of g99% on the basis of the rotation reported in the literature.3
The hydroxy ester showed an isomeric composition of 80%
(1S,2S)-3, 4% (1R,2R)-3, and 16% (1R,2S)-3.
(b) 2:1.2 Rea ction . 6 (10.2 mmol, 1.88 g) was treated with
1.97 g (6.1 mmol) of (-)-1 at rt. The reaction was complete in
3 h. Workup as above provided 0.69 g (91%) of the recovered
keto ester and 0.96 g (85%) of the hydroxy ester. The keto
ester was analyzed to be of 91% ee in the (R)-isomer. [R]25
)
D
-105.86 (c 6.83, CHCl3) corresponds to an optical purity of
g99% on the basis of the maximum rotation, [R]D ) +66.1
(CHCl3), reported in the literature for the (S)-isomer.4 The
hydroxy ester showed a composition of 83% (1S,2S)-7, 14%
(1R,2R)-7, and 3% (1R,2S)-7.
Kin etic Resolu tion of 1-Meth yln or ca m p h or (8). (a ) 2:1
Rea ction . This bicyclic ketone was prepared in 56% yield
from norcamphor using a literature procedure, bp 60-63 °C/
11 mmHg.23 8 (15 mmol, 1.86 g) was treated with 2.41 g (7.5
mmol) of (-)-1 at rt as described in the general procedure. The
reaction was complete within 2 h. Workup and chromatog-
raphy provided 0.84 g (89%) of the product alcohol and 0.90 g
(97%) of the recovered ketone. Gas chromatographic analysis
of the alcohol showed a composition of 91% of the exo and 9%
of the endo product. Analysis of its MCF derivative on a SPB-5
capillary column showed a composition of 86% (1S) and 5%
(1R) of the exo product and 9% (1R) of the endo product. The
recovered ketone was analyzed on a Chiraldex-GTA capillary
column which showed an ee of 63% in the (1R)-isomer.
(b) 2:1.4 Rea ction . 8 (80.5 mmol, 9.98 g) was treated with
18.08 g (56.4 mmol) of (-)-1 at 0 °C. The reaction was
complete in 5 h. Workup as above provided 2.72 g (91%) of
the recovered ketone and 6.53 g (92%) of the alcohol. The
Kin etic Resolu tion of Eth yl 1-Meth yl-2-oxocyclop en -
ta n eca r boxyla te (4). (a ) 2:1 Rea ction . The keto ester was
prepared in 93% yield by the methylation of ethyl 2-oxocyclo-
pentanecarboxylate using NaH and iodomethane in THF, bp
76 °C/2.1 mmHg. 4 (22 mmol, 3.75 g) was treated with 3.54 g
(11 mmol) of (-)-1 at rt as described in the general procedure.
The reaction was complete in 2 h. Workup and chromatog-
raphy provided 1.37 g (72%) of the product hydroxy ester and
1.48 g (79%) of the recovered keto ester. Analysis of the TFA
derivative of the alcohol on a Chiraldex-GTA column showed
an isomeric composition of 91% (1S,2S)-5, 2% (1R,2R)-5, and
7% (1R,2S)-5. The recovered keto ester was analyzed on a
Chiraldex-GTA capillary column which showed a composition
of 87.5% of the (R)-isomer and 12.5% of the (S)-isomer. The
spectral data of the recovered keto ester are identical to those
of (()-4.
ketone was analyzed to be of g99% ee in the (1R)-isomer. [R]25
D
) -41.70 (c 3.18, EtOH). The optical rotation was noted in
CHCl3 also to compare with the calculated rotation reported
in the literature.23 [R]25 ) -45.49 (c 5.03, CHCl3). Upon
D
(28) A rotation of [R]D ) +1.7 (c 10.33, CHCl3) is reported in the
literature for 4 without any assignment of the configuration. Saigo,
K.; Koda, H.; Nohira, H. Bull. Chem. Soc. J pn. 1979, 52, 3119. On the
basis of the analogy with other resolutions, we believe that (R)-4 is
obtained after kinetic resolution.

Chiral Synthesis via Organoboranes
J . Org. Chem., Vol. 61, No. 1, 1996 93
analysis as the MCF derivative on a SPB-5 capillary column,
the alcohol showed a composition of 80% (1S) and 4% (1R) of
the exo product and 16% (1R) of the endo product.
g (93%) of recovered ketone which was analyzed on a Chiral-
dex-GTA capillary column to show 96% ee in the (1R)-isomer.
(b) 2:1 Rea ction . 14 (16.2 mmol, 2.23 g) was treated with
2.60 g (8.1 mmol) of (-)-1 at rt. The reaction was complete in
2 h. Workup as above provided 1.03 g (92%) of the recovered
ketone and 1.03 g (91%) of the alcohol. The ketone was
(c) 2:1.4 Rea ction , w ith (+)-1. 8 (68.1 mmol, 8.45 g) was
treated with 15.3 g (47.7 mmol) of (+)-1 at 0 °C. The reaction
was complete in 5 h. Workup as above provided 2.30 g (91%)
of the recovered ketone and 5.58 g (93%) of the alcohol. [R]25
analyzed to be of 78% ee in the (1R)-isomer: [R]23 ) -55.97
D
D
) +45.91 (c 4.57, CHCl3). Upon analysis as the MCF deriva-
tive on a SPB-5 capillary column, the alcohol showed a
composition of 3% (1S) and 76% (1R) of the exo product and
21% (1S) of the endo product.
(c 2.58, EtOH) which corresponds to an optical purity of 79.5%
on the basis of the maximum rotation reported in the litera-
ture, [R]24 ) +70.4 for d-camphenilone.31 Analysis of the
D
MCF derivative of the alcochol on a SPB-5 capillary column
showed a composition of 92% (1R) and 2% (1S) of the endo
product and 6% (1S) of the exo product.
Kin etic Resolu tion of 1-Eth yln or ca m p h or (10). 2:1.2
Rea ction . This bicyclic ketone was prepared in 50% yield from
norcamphor using the same procedure used for the preparation
of 8, bp 71-73 °C/12 mmHg. This material showed identical
properties to 10 reported in the literature.29 10 (9.6 mmol,
1.33 g) was treated with 1.85 g (5.8 mmol) of (-)-1 at rt as
described in the general procedure. The reaction was complete
within 2 h. Workup and chromatography provided 0.68 g
(84%) of the product alcohol and 0.41 g (78%) of the recovered
ketone. Gas chromatographic analysis of the alcohol showed
a composition of 86% of the exo and 14% of the endo product.
Analysis of its MCF derivative on a SPB-5 capillary column
showed a composition of 84% (1S) and 2% (1R) of the exo
product and 14% (1R) of the endo product. The recovered
ketone was analyzed on a Chiraldex-GTA capillary column
which showed an ee of 92%. On the basis of analogy, we
believe that this corresponds to the (1R)-isomer: R25D ) -32.51
(neat). The spectral data of the recovered ketone are identical
to those of (()-10.
(c) 2:1.2 Rea ction , a t 0 °C. 14 (9.3 mmol, 1.29 g) was
treated with 1.80 g (5.6 mmol) of (-)-1 at rt. The reaction
was complete in 10 h. Workup as above provided 0.45 g (88%)
of the recovered ketone and 0.70 g (90%) of the alcohol. The
ketone was analyzed to be of g99% ee in the (1R)-isomer:
[R]25 ) -72.26 (c 5.21, EtOH).31 Analysis of the MCF
D
derivative of the alcohol on a SPB-5 capillary column showed
a composition of 90% (1S) and 1% (1R) of the endo product
and 6% (1R) and 3% (1S) of the exo product.
(d ) 2:1.3 Rea ction , a t r t. 14 (10.4 mmol, 1.43 g) was
treated with 2.16 g (6.7 mmol) of (-)-1 at rt. The reaction
was complete in 2 h. Workup as above provided 0.46 g (90%)
of the recovered ketone and 0.82 g (87%) of the alcohol. The
ketone was analyzed to be of g99% ee in the (1R)-isomer:
[R]25 ) -72.19 (c 3.01, EtOH).31 Analysis of the MCF
D
derivative of the alcohol on a SPB-5 capillary column showed
a composition of 80% (1S) and 2% (1R) of the endo product
and 14% (1R) and 4% (1S) of the exo product.
Kin etic Resolu tion of Ca m p h or (12). (a ) 2:1 Rea ction .
12 (17.2 mmol, 2.61 g) was treated with 2.76 g (8.6 mmol) of
(-)-1 at rt as described in the general procedure. The reaction
was complete within 1 h. Workup and chromatography
provided 1.25 g (94%) of the product alcohol and 1.16 g (89%)
of the recovered ketone. Gas chromatographic analysis of the
alcohol showed a composition of 99% of the exo and 1% of the
endo product. Analysis of its MCF derivative on a SPB-5
capillary column showed a composition of 96% (1S) and 3%
(1R) of the exo product and 1% of the (1R) endo product. The
recovered ketone was analyzed on a Chiraldex-GTA capillary
column which showed an ee of 66% in the (1R)-isomer.
(b) 2:1.2 Rea ction . 12 (8.9 mmol, 1.36 g) was treated with
1.72 g (5.4 mmol) of (-)-1 at rt. The reaction was complete in
2 h. Workup as above provided 0.51 g (94%) of the recovered
ketone and 0.78 g (94%) of the alcohol (exo:endo 97:3). Analysis
of the MCF derivative of the alcohol on a SPB-5 capillary
column showed a composition of 93% (1S) and 4% (1R) of the
exo product and 3% (1R) of the endo product. The ketone was
(e) P r ep a r a tive Sca le Kin etic Resolu tion of 14. 14 (0.5
mol, 69 g) was treated with 96 g (0.3 mol) of (+)-1, under neat
conditions, at 0 °C. The reaction was complete in 10 h. Ethyl
ether (200 mL) was added to the flask, followed by 20 mL of
acetaldehyde (1.2 equiv) at 0 °C. The mixture was warmed
to rt and stirred for 5 h. The 11B NMR spectrum of a
methanolzed aliquot (δ 18) showed complete elimination of
R-pinene. The reaction mixture was then treated with 100
mL of 6 N NaOH and stirred for 1 h. The organics were
extracted with EE, washed with brine, dried (MgSO4), and
concentrated. Flash chromatography on silica gel provided
77.5 g (95%) of R-pinene, 39.9 g (95%) of 15, and 27.0 g (98%)
of 14. The ketone was analyzed to be of g99% ee in the (1S)-
isomer: [R]25D ) +72.17 (c 3.5, EtOH).31 Analysis of the MCF
derivative of the alcohol on a SPB-5 capillary column showed
a composition of 90% (1R) and 1% (1S) of the endo product
and 6% (1S) and 3% (1R) of the exo product.
Kin et ic R esolu t ion of Dih yd r osp ir o[b icyclo[3.2.1]-
octa n e-2,2′(3′H)-fu r a n ]-3-on e (16). (a ) 2:1.2 Rea ction . This
bicyclic spiro ketone was prepared in 85% yield from norcam-
phor using a literature procedure.24 16 (17.7 mmol, 3.19 g)
was treated with 3.42 g (10.7 mmol) of (-)-1 at rt as described
in the general procedure. The reaction was complete within
12 h. Workup and chromatography provided 1.52 g (78%) of
the product alcohol and 1.02 g (81%) of the recovered ketone.
Gas chromatographic analysis of the alcohol showed a com-
position of g99% of the endo product. Analysis of its TFA
derivative on a Chiraldex-GTA capillary column showed a
composition of 77% of (1S)-endo and 23% of (1R)-endo. The
recovered ketone was analyzed on a Chiraldex-GTA capillary
column which showed an ee of 89% in the (1R, 2S)-isomer.
analyzed to be of 98% ee in the (1R)-isomer. [R]25 ) +43.39
D
(c 4.48, EtOH) corresponds to an optical purity of 99.5% on
the basis of the rotation of [R]20D ) +43.6 (c 5, EtOH) reported
in the literature.30
Kin et ic R esolu t ion of Ca m p h en ilon e (14). (a ) 2:0.9
Rea ction . 14 (79.9 mmol, 11.02 g) was treated with 11.53 g
(35.9 mmol) of (-)-1 at rt as described in the general procedure.
The reaction was complete within 2 h. Workup and chroma-
tography provided 4.63 g (92%) of the product alcohol and 5.15
g (85%) of the recovered ketone. Gas chromatographic analysis
of the alcohol showed a composition of 5% of exo and 95% of
endo product. Analysis of the MCF derivative of the alcohol
on a SPB-5 capillary column showed a composition of 94% (1S)
and 1% (1R) of the endo product and 3% (1R) and 2% (1S) of
the exo product. The recovered ketone was analyzed on a
Chiraldex-GTA capillary column which showed an ee of 70%
in the (1R)-isomer.
[R]25 ) -16.52 (c 6.0, CHCl3). The spectral data of the
D
recovered ketone are identical to those of (()-16.
(b) 2:1.45 Rea ction . 16 (35.2 mmol, 6.33 g) was treated
with 8.17 g (25.5 mmol) of (-)-1 at 0 °C as described in the
general procedure. The reaction was complete in 5 d. Workup
and chromatography provided 4.17 g (90%) of the product
alcohol and 1.68 g (96%) of the recovered ketone. Gas
chromatographic analysis of the alcohol showed a composition
of g99% of the endo product. Analysis of its TFA derivative
on a Chiraldex-GTA capillary column showed a composition
of 71% of (1S)-endo and 29% of (1R)-endo. The recovered
The recovered ketone from the above reaction (1.9 g, 13.8
mmol) was treated with 0.88 g (2.8 mmol, 0.2 equiv) of (-)-1.
The reaction was complete in 6 h, and workup provided 1.41
(29) (a) Belikova, N. A.; Bobyleva, A. A.; Kalinichenko, A. N.; Plate´,
A. F.; Pekhk, T. I.; Lippmaa, E. T. Zh. Org. Khim. 1974, 10, 239. (b)
Lippmaa, E. T.; Pekhk, T. I.; Belikova, N. A.; Bobyleva, A. A.;
Kalinichenko, A. N.; Ordubadi, M. D.; Plate´, A. F. Org. Magn. Reson.
1976, 8, 74.
(30) Poe, C. F.; Plein, E. M. J . Phys. Chem. 1934, 38, 883.
(31) Huckel, W. Ann. 1941, 549, 186.

94 J . Org. Chem., Vol. 61, No. 1, 1996
Ramachandran et al.
ketone was analyzed on a Chiraldex-GTA capillary column
is gratefully acknowledged. We thank Dr. Phillip E.
Fanwick of our department for X-ray crystallography.
which showed an ee of g99% in the (1R,2S)-isomer: [R]25
-18.55 (c 12.76, CHCl3).
)
D
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C NMR of
(1S)-4 and ORTEP diagram of compound 18 (3 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
A sample of optically pure 16 prepared as above was reduced
with (+)-1 when the reaction was complete in 2 h, and a
diethanolamine workup provided the product alcohol in 90%
yield. This was then converted to its 3,5-dinitrobenzoate (18)
using a standard procedure. The oily product obtained was
crystallized from ethanol-water (mp 121-122 °C) and ana-
lyzed using X-ray crystallography. The details of the experi-
mental procedures of X-ray data collection are provided in the
supporting information.32
J O951206Z
(32) The author has deposited atomic coordinates for structure 18
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.
Ack n ow led gm en t . Financial support from the
United States Army Research Office (DAAH-94-G-0313)