Asymmetric ring opening of meso-epoxides with B-halobis(2-isocaranyl)boranes 2-dIcr2BX

Article abstract of DOI:10.1016/j.tetasy.2006.06.044

Hydroboration of commercially available (+)-2-carene (96% ee) with either BH₂Cl·SMe₂ or BCl₃/Me₃SiH, provides chemically pure B-chlorobis(2-isocaranyl)borane (2-^dIcr₂BCl) whereas B-bromobis

Full text of DOI:10.1016/j.tetasy.2006.06.044

Tetrahedron: Asymmetry 17 (2006) 1931–1936
Asymmetric ring opening of meso-epoxides with
B-halobis(2-isocaranyl)boranes 2-dIcr2BX
Chandra D. Roy* and Herbert C. Brownz
Department of Chemistry, Herbert C. Brown Center for Borane Research, Purdue University, 560 Oval Drive,
West Lafayette, IN 47907-2084, USA
Received 5 June 2005; accepted 29 June 2006
Available online 25 July 2006
This paper is dedicated to Professor Herbert C. Brown
Abstract—Hydroboration of commercially available (+)-2-carene (96% ee) with either BH2ClÆSMe2 or BCl3/Me3SiH, provides chemi-
cally pure B-chlorobis(2-isocaranyl)borane (2-dIcr2BCl) whereas B-bromobis(2-isocaranyl)borane (2-dIcr2BBr) could only be prepared
by Matteson’s BBr3/Me3SiH procedure in high chemical yield and purity. The enantiomeric excess achieved with 2-dIcr2BCl (78%),
was significantly higher than those realized with the previously explored reagent, dIpc2BCl (41%), especially for meso-cyclohexene oxide.
The new reagent, 2-dIcr2BBr also showed considerable improvements in enantiomeric excesses, in the cases of meso-cyclopentene oxide
(67%) and meso-cis-2,3-butene oxide (78%) than those achieved with the previously reported reagent, dIpc2BBr (57% and 61%,
respectively).
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Although dIpc2BX succeeded in cleaving the meso-epoxides
enantioselectively, the moderate enantioselectivities
achieved in many cases, especially with dIpc2BCl and
dIpc2BBr, pressed the need for development of superior
reagents which could achieve enantioselectivities approach-
ing 100%. In the asymmetric allylboration, significant
improvements in enantioselectivity were realized with
B-allylbis(2-isocaranyl)borane (2-dIcr2BAll)14 over dIpc2BAll.
This persuaded us to synthesize and test these new chiral
reagents, B-chlorobis(2-isocaranyl)borane (2-dIcr2BCl) and
B-bromobis(2-isocaranyl)borane (2-dIcr2BBr) for the asym-
metric cleavage of meso-epoxides. Herein, we report our
results on the enantioselective cleavage of meso-epoxides
with 2-dIcr2BCl and 2-dIcr2BBr.15
Asymmetric synthesis starting from meso-compounds is an
effective and attractive approach to the synthesis of com-
plex optically active organic compounds of chemical and
biological interest.1 Vicinal halohydrins, are also very use-
ful synthetic intermediates for the synthesis of halogenated
marine natural products (laurenyne, isodactylyne), anti-
biotics (thienamycin), and immuno-suppressant ISP-1.2
Desymmetrization of either meso- or racemic-epoxides
has been successfully accomplished with a wide variety
of nucleophiles, such as, carbon nucleophiles,3 phenols,4
thiols,5 carboxylic acids,6 aromatic amines,7 azide,8 and
cyanide.9 Although halides have been extensively used as
nucleophiles10 in the enantioselective cleavage of epoxides,
including B-halodiisopinocampheylboranes (Ipc2BX)11
from our laboratory, there have only been a couple of
reports available in the literature by Denmark12 and
Buono13 which provide highly enantiomerically enriched
chlorohydrins utilizing chiral organophosphorus Lewis
base catalysts.
2. Results and discussion
At first, we decided to reexamine some of our earlier work
on the enantioselective ring opening of a few representa-
tive meso-epoxides with dIpc2BX. A slight variation in
the reaction conditions (little longer reaction time and slow
warming after addition of n-butyraldehyde) and quick
analysis of the halohydrins on Chiraldex-GTA analytical
column, 10–20% higher enantiomeric excess is realized
(Table 1).
*
Corresponding author. Tel.: +1 858 450 5618; fax: +1 858 453 3552;
e-mail: chandra61804@yahoo.com
z Deceased on December 19, 2004.
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.06.044

1932
C. D. Roy, H. C. Brown / Tetrahedron: Asymmetry 17 (2006) 1931–1936
Table 1. Asymmetric ring opening of representative meso-epoxides with dIpc2BX
Entry
1
Epoxide
Reagent, reaction conditions
Halohydrin
X
% Yield
% ee (Lit)a
Confb
OH
dIpc2BCl, n-C5H12, ꢀ78 °C, 4 h
dIpc2BBr, n-C5H12, ꢀ100 °C, 4 h
Cl
Br
60
65
46 (44)
58 (48)
1R,2R
1R,2R
O
X
OH
2
3
dIpc2BCl, n-C5H12, ꢀ78°C, 4 h
dIpc2BBr, n-C5H12, ꢀ100 °C, 4 h
Cl
Br
70
75
41 (22)
92 (84)
1R,2R
1R,2R
O
X
OH
dIpc2BCl, n-C5H12, ꢀ78 °C, 4 h
dIpc2BBr, n-C5H12, ꢀ100 °C, 4 h
Cl
Br
55
65
40 (27)
77 (63)
1R,2R
1R,2R
O
X
a Enantiomeric excess was determined on Chiraldex-GTA column as TFA derivatives.
b The absolute configurations of the halohydrins (1R,2R) were assigned based on the results obtained from previous Ipc2BX reactions from this laboratory.
The superscript ‘d’ indicates that the reagent is derived from (+)-a-pinene.
B-Chlorobis(2-isocaranyl)borane (2-dIcr2BCl) (96% ee)
(11B NMR: d 74.5 ppm in n-pentane) was successfully pre-
pared either by the hydroboration of 2-carene (96% ee)
with BH2ClÆSMe2 in CH2Cl2 for 12 h or by Matteson’s
BCl3/Me3SiH methodology in high yield and chemical pur-
ity (>95%) in n-hexanes.16 Unlike 2-dIcr2BCl, 2-dIcr2BBr
could not be synthesized in high chemical purity either by
direct hydroboration of 2-carene with BH2BrÆSMe2 in
CH2Cl2 or by the reaction of 2-dIcr2BH with Br2 in
CH2Cl2. Only Matteson’s BBr3/Me3SiH procedure
provided 2-dIcr2BBr (96% ee; 11B NMR: d 78 ppm in
n-pentane) in high chemical yield and purity (>95%) in
n-hexanes or n-heptane (Scheme 1).
ee; meso-cyclooctene oxide, >99% ee) very efficiently, fails
in the case of meso-cyclopentene oxide (23% ee).
Although dIpc2BBr demonstrated its superiority over
dIpc2BCl in the asymmetric opening of meso-epoxides
(48–84% ee), there remained ample scope for further
improvements due to the moderate enantioselectivity with
many substrates. Therefore, it was of great interest to syn-
thesize and examine new reagents having different chiral
auxiliaries. Encouraged by the results obtained with
2-dIcr2BCl, we undertook the enantioselective ring opening
of meso-epoxides with 2-dIcr2BBr. We were delighted to
observe considerable improvements in enantiomeric ex-
cesses, especially with meso-cyclopentene- and meso-cis-2,3-
butene oxides (68% and 78%, respectively). The conversion
of the borinate ester to the boronate ester was observed to
be sluggish when the 2-carene chiral auxiliary was present
in comparison with the a-pinene. This problem was over-
come by the addition of a small amount of BF3ÆOEt2. With
meso-cyclohexene oxide, only a comparable result (78% ee)
was obtained. Considering the labile nature of the halohyd-
rins toward racemization, we emphasized on the rapid iso-
lation and quick analysis by chiral HPLC (with UV
detector) by converting the hydroxyl group of the halohyd-
rins into suitable UV sensitive esters (4-nitrobenzoate, 3,5-
dinitrobenzoate, and 1-naphthoate). It is important to note
that 2-dIcr2BX produces vicinal halohydrins of the oppo-
B-Chlorobis(2-isocaranyl)borane successfully cleaved rep-
resentative meso-epoxides at ꢀ78 °C to vicinal chlorohyd-
rins in reasonably good yields (Table 2); however, the
enantioselectivity of the reaction was highly substrate
dependent (Scheme 2). Only meso-cyclohexene oxide re-
acted with significant improved enantioselectivity.17 No
improvement in enantioselectivity was realised by lowering
the reaction temperature to ꢀ100 °C. An improved enan-
tiomeric excess achieved with 2-dIcr2BCl (78%) was far
superior to dIpc2BCl reported earlier by our research group
(22–41%) and also by others. In the case of meso-cis-2,3-
butene oxide also, 18–19% improvement was achieved in
comparison with dIpc2BCl. meso-Cyclopentene oxide ap-
peared to be a problematic substrate possibly due to ring
strain. It is quite evident from the literature that meso-
cyclopentene oxide yields chlorohydrin of relatively lower
enantiomeric excess. Even Buono’s catalytic method, which
appears to handle a wide variety of meso-epoxides (meso-
cyclohexene oxide, 84% ee; meso-cycloheptene oxide, 98%
d
site configuration (1S,2S) in contrast to Ipc2BX (1R,2R).
These results are summarized in Table 2.
Next, we decided to examine the enantioselective ring
opening of meso-cyclohexene oxide as a model reaction
d
with various Ter2BCl reagents, such as Eap2BCl (97% ee),
)2BCl
)2BBr
.
BBr3/2Me3SiH
2
BH2Cl SMe2
-78 oC to rt
CH2Cl2, rt
12 h
n-C6H14, 12 h
Scheme 1. Preparation of 2-dIcr2BCl and 2-dIcr2BBr.

C. D. Roy, H. C. Brown / Tetrahedron: Asymmetry 17 (2006) 1931–1936
Table 2. Asymmetric ring opening of representative meso-epoxides with 2-dIcr2BX
1933
Entry
Epoxide
Reagent, reaction conditions
Halohydrin
X
% Yield
% eea
Confb
OH
1
2-dIcr2BCl, n-C5H12, ꢀ78 °C, 4 h
2-dIcr2BBr, n-C5H12, ꢀ100 °C, 4 h
Cl
Br
66
72
78
78
1S,2S
1S,2S
O
X
OH
2
3
2-dIcr2BCl, n-C5H12, ꢀ78 °C, 4 h
2-dIcr2BBr, n-C5H12, ꢀ100 °C, 4 h
Cl
Br
60
69
12
68
1S,2S
1S,2S
O
X
OH
2-dIcr2BCl, n-C5H12, ꢀ78 °C, 4 h
2-dIcr2BBr, n-C5H12, ꢀ100 °C, 4 h
Cl
Br
58
70
57
78
1S,2S
1S,2S
O
X
a Enantiomeric excess values were determined by HPLC analysis on a Daicel Chiralcel OD-H column as aryl esters (4-nitrobenzoate, 3,5-dinitrobenzoate,
and 1-naphthoate).
b The absolute configurations of the halohydrins (1S,2S) were assigned based on the results obtained from Ipc2BX reactions. The superscript ‘d’ indicates
that the reagent is derived from (+)-2-carene.
OC4H9
OBdIcr
OBdIcr2
X
dIcr2BX
1. n-C3H7CHO
O
2. BF3.OEt2
n-Pentane
X
OH
HO
n-Pentane
N
H
dIcr
OH
X
O
O
B
+
N
H
X = Cl, Br
Scheme 2. Enantioselective ring opening of meso-cyclohexene oxide with 2-dIcr2BX.
Precipitate
Cl
)2BX
)2BX
)2BX
)2BX
)2BX
dIpc2BX
lIpc2BX
dEap2BX
)2BX
lEap2BX
)2BX
lCleap2BX
2-dIcr2BX
4-dIcr2BX
Figure 1. Various structurally modified chiral reagents, Ter2BX.
l
l
lEap2BCl (91% ee), 4-dIcr2BCl (97% ee), Cleap2BCl (91%
ee), along with previously studied dIpc2BCl (99% ee)
(Fig. 1). These chiral Ter2BCl reagents were prepared by
the hydroboration of the corresponding olefins with
BH2ClÆSMe2 in CH2Cl2 for 12–48 h. Two of these reagents,
dEap2BCl18 and Cleap2BCl19 showed significant improve-
ments in enantioselectivities with certain carbonyl com-
pounds in asymmetric reduction over Ipc2BCl. In order
to compare the relative configurations of the product halo-
hydrins, we reexamined the asymmetric ring opening of
d

1934
C. D. Roy, H. C. Brown / Tetrahedron: Asymmetry 17 (2006) 1931–1936
Table 3. Asymmetric ring opening of meso-cyclohexene oxide with various Ter2BCl
Entry
Ter2BCl
Reaction conditions
Yield %
% eea
Confb
1
2
3
4
5
6
7
dIpc2BCl
lIpc2BCl
dEap2BCl
lEap2BCl
2-dIcr2BCl
4-dIcr2BCl
lCleap2BCl
n-Pentane, ꢀ78 °C, 4 h
n-Pentane, ꢀ78 °C, 4 h
n-Pentane, ꢀ78 °C, 4 h
n-Pentane, ꢀ78 °C, 4 h
n-Pentane, ꢀ78 °C, 4 h
n-Pentane, ꢀ78 °C, 4 h
n-Pentane, ꢀ78 °C, 4 h
70
66
65
68
66
68
65
41
39
32
28
78
19
15
1R,2R
1S,2S
1R,2R
1S,2S
1S,2S
1R,2R
1R,2R
a Enantiomeric excess values were determined by HPLC analysis on a Daicel Chiralcel OD-H column as aryl esters (3,5-dinitrobenzoate and
1-naphthoate).
b The absolute configurations of the halohydrins (1S,2S) were assigned based on the results obtained from Ipc2BX reactions.
meso-cyclohexene oxide with both commercially available
meric excess (86%) (in comparison with the crude
bromohydrin). Except for lCleap2BBr, all the four reagents,
d
l
reagents, Ipc2BCl and Ipc2BCl. Among various Ter2BCl
examined, 2-dIcr2BCl proved to be the best reagent of
choice for the meso-cyclohexene oxide. The results are sum-
marized in Table 3.
l
dIpc2BBr, dEap2BBr, Eap2BBr, and 2-dIcr2BBr showed
comparable results for the meso-cyclohexene oxide (78–
86% ee). The results are summarized in Table 4.
meso-Cyclopentene oxide appears to be a problematic sub-
strate, possibly due to ring strain. It is quite evident from
the literature that meso-cyclopentene oxide yields chlorohy-
drin of relatively lower enantiomeric excess. Even Buono’s
catalytic method, which handles a wide variety of
meso-epoxides very efficiently, fails in the case of meso-
cyclopentene oxide. It might be possible that either meso-
cyclopentene oxide undergoes rapid cleavage even at lower
temperatures or that the product could be undergoing
comparatively rapid racemization under the reaction con-
ditions considering the labile nature of halohydrins.20
While determining the enantiomeric excess of the 2-bromo-
1-trifluoroacetoxycyclohexane (obtained from lEap2BBr
reaction) by an analytical GC on a Chiraldex-GTA
column, we observed the racemization of the product
TFA ester.20 The HPLC analysis of various derivatives of
b-bromohydrins either with 4-nitrobenzoyl chloride or 3,5-
dinitrobenzoyl chloride or 1-naphthoyl chloride in CH2Cl2
in the presence of Et3N provided consistent enantio-
meric excess (ee). We believe that the enantiomeric excess
values of the original b-bromohydrins must be higher than
the observed ee values, considering the labile nature of the
halohydrins (quick analysis of the TFA derivative of
the crude product showed higher enantiomeric excess than
the purified product, especially for the bromohydrin de-
rived from meso-cyclohexene oxide). Buono et al. reported
a drop in the specific rotation (a) of 2-chlorocyclohexan-
1-ol from ꢀ30 to ꢀ20 after 4 h in CH2Cl2.13
Next, we decided to examine the enantioselective ring
opening of meso-cyclohexene oxide as a model reaction
with various Ter2BBr, such as dEap2BBr (97% ee),
l
lEap2BBr (91% ee), Cleap2BBr (91% ee), along with previ-
ously studied dIpc2BBr (99% ee) (Fig. 1). The reagents,
l
dEap2BBr and Eap2BBr were successfully prepared either
d
by the hydroboration with BH2BrÆSMe2 or by Matteson’s
Me3SiH/BBr3 procedure whereas lCleap2BBr (91% ee)
could only be prepared by the hydroboration of 2-(b-chlo-
roethyl)apopinene using the Me3SiH/BBr3 method. In
order to compare the results, we reexamined the
asymmetric ring opening of meso-cyclohexene oxide with
the commercially available dIpc2BBr. A slight modification
in the reaction conditions (a longer reaction time with slow
warming after addition of an aldehyde) followed by quick
analysis of the bromohydrin on the GC (Chiraldex-GTA),
achieved slightly higher enantiomeric excess (92%) (Table
1). It is important to note that the column purified
2-bromocyclohexan-1-ol showed slightly lower enantio-
In the case of Ipc2BX, experimental and stereochemical
results supported an SN20-type reaction pathway involving
a four-centered transition state, preceded by the complexa-
tion of boron with a lone pair on oxygen, and resulting in
the selective cleavage of the enantiotopic S C–O bond in an
antiperiplanar manner (Scheme 3). We believe that
2-dIcr2BX also follows a similar reaction pathway, as
d
previously proposed for the Ipc2BX reaction, but on the
opposite enantiotopic R C–O bond resulting in the
enantiomer of an opposite configuration. Presumably,
steric factors are involved in the transition state as
observed in the asymmetric hydroboration of cis-alkenes
d
with Ipc2BH.21
Table 4. Asymmetric ring opening of meso-cyclohexene oxide with various Ter2BBr
Entry
Ter2BBr
Reaction conditions
% Yield
% eea
Confb
1
2
3
4
5
dIpc2BBr
n-Pentane, ꢀ100 °C, 4 h
n-Pentane, ꢀ100 °C, 4 h
n-Pentane, ꢀ100 °C, 4 h
n-Pentane, ꢀ100 °C, 4 h
n-Pentane, ꢀ100 °C, 4 h
75
74
76
72
75
86
78
78
78
36
1R,2R
1R,2R
1S,2S
1S,2S
1R,2R
dEap2BBr
lEap2BBr
2-dIcr2BBr
lCleap2BBr
a Enantiomeric excess values were determined by HPLC analysis on a Daicel Chiralcel OD-H column as aryl esters (3,5-dinitrobenzoate and
1-naphthoate).
b The absolute configurations of the bromohydrins (1S,2S) were assigned based on the results obtained from Ipc2BX reactions.

C. D. Roy, H. C. Brown / Tetrahedron: Asymmetry 17 (2006) 1931–1936
1935
OBdIcr2
X
O
O
BdIcr2
BdIcr2
X
X
Transition state
Scheme 3. Four-centered transition state for the cleavage of meso-cyclohexene oxide with 2-dIcr2BX.
Jacobsen, E. N. J. Org. Chem. 1997, 62, 4197; (c) Annis, A.
D.; Helluin, O.; Jacobsen, E. N. Angew. Chem., Int. Ed. 1998,
37, 1907; (d) Jacobsen, E. N. Acc. Chem. Res. 2000, 33,
421.
3. Conclusions
In conclusion, we have synthesized two chiral reagents,
2-dIcr2BCl and 2-dIcr2BBr and tested them in the asymmet-
ric cleavage of three representative meso-epoxides.
B-Chlorobis(2-isocaranyl)-borane (dIcr2BCl) has significantly
improved the enantiomeric excess of 2-chlorocyclohexan-1-
ol from 41% to 78–79%. In the case of meso-cis-2,3-butene
oxide also, 18–19% improvement was achieved in compar-
9. (a) Cole, B. M.; Shimizu, K. D.; Kruegar, C. A.; Harrity, J. P.
A.; Snapper, M. L.; Hoveyda, A. H. Angew. Chem., Int. Ed.
1996, 35, 1668; (b) Schaus, S. E.; Jacobsen, E. N. Org. Lett.
2000, 2, 1001.
10. (a) Naruse, Y.; Esaki, T.; Yamamoto, H. Tetrahedron 1988,
44, 4747; (b) Bonini, C.; Righi, G. Synthesis 1994, 225, and
references cited therein; (c) Nugent, W. A. J. Am. Chem. Soc.
1998, 120, 7139.26; (d) Nugent, W. A.; Licini, G.; Boncio, M.;
Bortolini, O.; Finn, M. G.; McCleland, W. Pure Appl. Chem.
1998, 70, 1041; (e) Bruns, S.; Haufe, G. Tetrahedron:
Asymmetry 1999, 10, 1563.
11. (a) Joshi, N. N.; Srebnik, M.; Brown, H. C. J. Am. Chem.
Soc. 1988, 110, 6246; (b) Srebnik, M.; Joshi, N. N.; Brown,
H. C. Israel J. Chem. 1989, 29, 229.
12. Denmark, S. E.; Barsanti, P. A.; Wong, K. T.; Stavenger, R.
A. J. Org. Chem. 1998, 63, 2428.
d
ison with Ipc2BCl. Unfortunately, this reagent is highly
substrate dependent and fails to afford highly enantiomerically
enriched 2-chlorocyclopentan-1-ol with meso-cyclopentene
oxide. In the case of B-bromobis(2-isocaranyl)borane
(dIcr2BBr), considerable improvements in enantiomeric
excesses were realized with both meso-cyclopentene oxide
(58–68%) and meso-cis-2,3-butene oxides (61–78%)
whereas meso-cyclohexene oxide showed only comparable
enantioselectivity (78%).
13. (a) Brunel, J. M.; Legrand, O.; Reymond, S.; Buono, G.
Angew. Chem., Int. Ed. 2000, 39, 2554; (b) Reymond, S.;
Brunel, J. M.; Buono, G. Tetrahedron: Asymmetry 2000, 11,
1273; (c) Reymond, S.; Brunel, J. M.; Buono, G. Tetrahedron:
Asymmetry 2000, 11, 4441; (d) Reymond, S.; Legrand, O.;
Brunel, J. M.; Buono, G. Eur. J. Org. Chem. 2001, 2819; (e)
Denmark, S. E.; Wynn, T.; Jellerichs, B. G. Angew. Chem.,
Int. Ed. 2001, 40, 2255; (f) Buono, G. Angew. Chem., Int. Ed.
2001, 40, 4536; (g) Buono, G. Eur. J. Org. Chem. 2002, 218.
14. Brown, H. C.; Randad, R. S.; Bhat, K. S.; Zaidlewicz, M.;
Racherla, U. S. J. Am. Chem. Soc. 1990, 112, 2389.
15. Roy, C. D.; Brown, H. C. Presented in H. C. Brown Lectures
in Chemistry (1999), Purdue University, IN, USA.
Acknowledgments
This work was supported by grants from the Office of
Naval Research and the Purdue Borane Research Fund.
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meso-cyclohexene oxide with 2-dIcr2BCl: All operations are
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(5 mmol, 0.5 mL) was slowly added dropwise with stirring.
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(10 mmol) was added followed by BF3ÆOEt2 (20 ll) and the
reaction mixture was allowed to warm up slowly overnight.
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with diethanolamine (5 mmol) to retrieve the 2-chlorocyclo-
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by HPLC analysis on a Daicel Chiralcel OD-H column after
transforming the 2-chlorocyclohexan-1-ol into both 3,5-dini-
trobenzoyl- and 1-naphthoyl esters. Enatiomeric excess: 78%
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20. We had earlier noticed the racemization of the trifluoro-
acetate derivative of the 2-bromocyclohexan-1-ol while
determining the enantiomeric excess by the analytical GC
on a Chiraldex-GTA column. Buono and co-workers had
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while recording the optical rotation in CH2Cl2 (Paper
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