Asymmetric synthesis using organoboranes. Relative effectiveness of the B-Halobis(terpenyl)boranes for the enantioselective halogenative cleavage of representative meso-epoxides

Article abstract of DOI:10.1071/CH07118

A comparative study of the relative effectiveness of various Ter ₂BX, such as ^dEap₂BX, ^lEap ₂BX, 2-^dIcr₂BX, 4-^dIcr ₂BX, and ^lCleap₂BX

Full text of DOI:10.1071/CH07118

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Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2007, 60, 835–842
Asymmetric Synthesis using Organoboranes. Relative
Effectiveness of the B-Halobis(terpenyl)boranes for
the Enantioselective Halogenative Cleavage
of Representative meso-Epoxides∗
Chandra D. RoyA,B,C and Herbert C. BrownA
ADepartment of Chemistry, Herbert C. Brown Center for Borane Research, Purdue University,
West Lafayette, IN 47907-2084, USA.
BPresent address: EMD Biosciences, Inc., 10394 Pacific Center Court, San Diego, CA 92121, USA.
CCorresponding author. Email: chandra0919@gmail.com
A comparative study of the relative effectiveness of various Ter2BX, such as dEap2BX, lEap2BX, 2-dIcr2BX, 4-dIcr2BX,
and lCleap2BX along with dIpc2BX for the asymmetric ring opening of three representative meso-epoxides (cyclohexene,
cyclopentene, and cis-2,3-butene oxides) is reported. Among all the reagents studied, 2-dIcr2BCl (78–80%) demonstrated
significant improvement in enantiomeric excess over a previously explored reagent, dIpc2BCl (41%), especially for
meso-cyclohexene oxide. Although all these three reagents, dIpc2BBr, dEap2BBr, and 2-dIcr2BBr provided comparable
enantiomerically enriched 2-bromocyclohexan-1-ol (76–86%) from meso-cyclohexene oxide, the carene-based reagent,
2-dIcr2BBr 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 previously reported reagent, dIpc2BBr (57 and 61%,
respectively). The enantioselectivity of the reaction was observed to be highly substrate dependent. The present study
represents a significant advance in asymmetric synthesis using the chiral organoborane chemistry.
Manuscript received: 20 April 2007.
Final version: 13 May 2007.
Introduction
using SiCl4 in the presence of a chiral phosphoramide Lewis
base. Later Fu and coworkers[14] and Nakajima et al.[15] pub-
lished the enantioselective cleavage of epoxides with SiCl4
using η5-C5Ar5-based planar-chiral pyridine N-oxides. These
catalytic methods (developed by the groups of Fu and Nakajima)
providedthebestresultsonlywithacyclicepoxides. Eventhecat-
alytic method of Denmark et al. appeared to be highly substrate
dependent (highly effective only with certain substrates, such as
stilbene oxide and benzyloxy-substituted 2,3-butene oxide). In
the past decades, several valuable chiral organoboron reagents
derived from the naturally occurring terpene-based chiral aux-
iliaries, especially the super chiral auxiliary, α-pinene, were
developed by Brown[16–18] and their synthetic applications were
successfully demonstrated in many asymmetric transformations,
such as hydroboration, reduction, homologation, allylboration,
enolboration, and ring opening of meso-epoxides (Fig. 1).
Although the α-pinene-based reagents, dIpc2BX (X = Br,
I) demonstrated good to excellent enantioselectivities in the
ARO reactions with most of the epoxides studied, the lower
enantiomeric excesses (ee’s) achieved with dIpc2BCl per-
suaded us to undertake the syntheses of structurally modified
terpene-based chiral boron reagents, Ter2BX, and test these
chiral reagents, in the hope of improving enantioselectivi-
ties. Earlier, Brown and coworkers[16–18] had succeeded in
finding improved steric and electronic matches between the
The desymmetrization of meso-epoxides by an enantio-
selective addition of nucleophiles is a very efficient strat-
egy in asymmetric synthesis since it creates and establishes
two contiguous stereogenic centers simultaneously.[1] Vic-
inal halohydrins are very important key intermediates in
the syntheses of many halogenated marine natural products
(e.g., aplysiapyranoid A, laurenyne, dactylyne, isodactylyne,
2-bromo-β-chamigrene) and pharmaceuticals (e.g., thien-
amycin, immunosuppressantsISP-1, cryptophycin1, epothilone,
antiviral nucleosides).[2] The asymmetric ring openings (AROs)
of meso- or racemic epoxides have been successfully achieved
with a variety of nucleophiles, such as aromatic amines,[3] car-
bon nucleophiles,[4] phenols,[5] thiols,[6] carboxylic acids,[7]
azides,[8] cyanides,[9] and halides.[10–13] Among the myriad of
nucleophiles studied, halides have drawn considerable atten-
tion. In 1988, the first general synthesis of optically active
β-halohydrins using stoichiometric amounts of chiral Lewis
acid halides, B-halodiisopinocampheylboranes (Ipc2BX) was
reported from this laboratory.[11] Nugent used the trimethyl-
silyl azide (TMSN3)/allyl halide in the presence of a zirconium
complex in the ARO of different epoxides to afford the cor-
responding vicinal halohydrins in high chemical and optical
yields.[12] Denmark et al.[13] reported the first catalytic ARO
of epoxides to provide enantiomerically enriched chlorohydrins
∗ This paper is dedicated to the memory of my mentor, the late Professor Herbert C. Brown (1912–2004). The work described herein was carried out at Purdue
University as a post-doctoral research associate.
© CSIRO 2007
10.1071/CH07118
0004-9425/07/110835

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RESEARCH FRONT
836
C. D. Roy and H. C. Brown
terpene-based reagent and the substrate, thereby achieving
higher enantioselectivity in many reactions. Hydroborating
agents (RapBH2)[16] and reducing agents (Rap2BCl),[17] derived
from these structurally modified terpenes as well as allylborat-
ing agent (2-dIcr2BAll),[18] prepared from (+)-ꢀ2-carene, have
shown considerable improvements in enantioselectivities over
α-pinene-based reagents. Consequently, we synthesized a series
of structurally modified chiral B-halobis(terpenyl)boranes that
can act as chiral Lewis acids bearing halides (as nucleophilic
units) and examined their effectiveness in the enantioselec-
tive desymmetrization of meso-epoxides. In a continuation
of our research work to develop new methods and reagents
for the regio-, chemo-, and enantioselective ring opening of
epoxides,[19] we recently communicated our preliminary results
on the ARO of meso-epoxides with special emphasis on
meso-cyclohexene oxide using structurally modified B-halobis
(terpenyl)boranes.[20] The success with 2-dIcr2BX prompted us
to extend our comprehensive study on the enantioselective halo-
genative cleavage of three representative meso-epoxides with
Ter2BX (X = Cl, Br) and the results of such study are described
herein.
Results and Discussion
Synthesis of C2-Symmetric Chiral
B-Halobis(terpenyl)borane Reagents
The C2-symmetric Ter2BX reagents were prepared by the
hydroboration of the corresponding olefins with suitable B-
haloboranes.[17] Both (−)-2-ethylapopinene (lEap, 92–93% ee)
and (−)-β-chloroethylapopinene (lCleap, 92–93% ee) were
prepared from the commercially available (R)-(−)-nopol (92–
93% ee). The (−)-nopol (92–93% ee) was refluxed with
Ph3P in CCl4 for 7 h to obtain (−)-β-chloroethylapopinene.
The (−)-2-ethylapopinene was obtained either by reducing
the (−)-β-chloroethylapopinene with LiEt3BH (Aldrich: Super
Hydride) or reducing the nopol tosylate (prepared from (−)-
nopol) with LiAlH4. The (+)-ethylapopinene (>99% ee)
was prepared by the metallation of (+)-α-pinene (>99%)
with tert-BuOK/n-BuLi, followed by alkylation with CH3I.
Finally, Ter2BX 3–12 (X = Cl, Br) were obtained either by
direct hydroboration of the corresponding olefins with BH2X–
SMe2 or by Matteson’s BX3/Me3SiH methodology (Scheme 1,
Fig. 2). The hydroboration of (+)-ꢀ2-carene and (+)-ꢀ3-
carene (96% ee) with either commercially available BH2Cl–
SMe2 in CH2Cl2 or BCl3/Me3SiH in n-hexanes, afforded B-
chlorobis(2-isocaranyl)borane 9 (2-dIcr2BCl) (11B: δ 74.5) and
B-chlorobis(4-isocaranyl)borane 11 (4-dIcr2BCl) in high chem-
ical yield and purity. Hydroboration of (+)-ꢀ2-carene with
BH2Br–SMe2 in CH2Cl2 gave a mixtureof products (2-dIcr2BBr
and 2-dIcrBHBr). The bromination of 2-dIcr2BH (prepared by
the hydroboration of (+)-ꢀ2-carene with BH3) with Br2 in
CH2Cl2 also could not provide pure 2-dIcr2BBr. Only Matte-
son’s BBr3/Me3SiH procedure yielded 2-dIcr2BBr 10 (96% ee,
11B: δ 78) and 4-dIcr2BBr 12 in high chemical yield and purity.
Asymmetric
homologation
BR
O
O
)2BCrt
)2BOTf
Asymmetric
crotylboration
Asymmetric
enolboration
)2BAll
)2BCl
Asymmetric
allylboration
Asymmetric
reduction
)2BH
)2BX
Asymmetric
epoxide opening
Asymmetric
hydroboration
)BH2
Asymmetric
hydroboration
Fig. 1. α-Pinene, the super chiral auxiliary.
Cl
1. Ph3P/CCl4
Cl
OH
1. p-TsCl
BH2Br-SMe2 or
BBr3/Me3SiH
BH2Cl-SMe2 or
)2BCl
)2BBr
BCl3/Me3SiH
2. LiAlH4
7
6
BH2Cl-SMe2 or
BCl3/Me3SiH
BBr3/Me3SiH
Cl
)2BCl
)2BBr
8
5
Scheme 1. Synthesis of structurally modified terpenes and Ter2BX.
R
X
B
R
R
X
B
R
X
B
X
B
1 R ꢀ CH3, X ꢀ Cl
2 R ꢀ CH3, X ꢀ Br
3 R ꢀ C2H5, X ꢀ Cl
4 R ꢀ C2H5, X ꢀ Br
5 R ꢀ C2H5, X ꢀ Cl
6 R ꢀ C2H5, X ꢀ Br
7 R ꢀ C2H4Cl, X ꢀ Cl
8 R ꢀ C2H4Cl, X ꢀ Br
9 X ꢀ Cl
10 X ꢀ Br
11 X ꢀ Cl
12 X ꢀ Br
Fig. 2. Structurally modified chiral reagents, Ter2BX.

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RESEARCH FRONT
Asymmetric Synthesis using Organoboranes
837
ARO of meso-Cyclohexene Oxide 13 with Ter2BX
enriched 2-chlorocyclohexan-1-ol (41% ee, conf. 1R,2R),
whereas Ipc2BCl afforded 2-chlorocyclohexan-1-ol of 38.5%
l
For the comparative study, we chose to examine the enantio-
selective ring opening of three representative meso-epoxides,
e.g., meso-cyclohexene oxide 13, meso-cyclopentene oxide 14,
and cis-2,3-butene oxide 15 (Fig. 3), with Ter2BX. In order to
compare the relative effectiveness of these reagents, we selected
meso-cyclohexene oxide as a standard substrate, which was sub-
jected to ARO reactions with dEap2BCl 3 (97% ee), lEap2BCl
5 (91–92% ee), lCleap2BCl 7 (91–92% ee), 2-dIcr2BCl 9 (97%
ee), and 4-dIcr2BCl 11 (97%) along with the previously stud-
ee with opposite configuration (1S,2S). These ee values are
considerably higher than the previously reported values (22%)
(Table 1). These two experimental results were also highly infor-
mative to compare and establish the relative configurations of the
various product chlorohydrins.
Among the various Ter2BCl examined, 2-dIcr2BCl 9 was
demonstratedtobethemosteffectivereagentintheenantioselec-
tive ring opening of meso-cyclohexene oxide (78–80% ee with 9,
41% ee with 1) (Scheme 2, Fig. 3). By changing the –CH3 group
to the –C2H5 group at the C-2 position in the apopinene struc-
ture, only 32% ee was observed in the case of dEap2BCl 3. Both
4-dIcr2BCl 11 and lCleap2BCl 7 provided 2-chlorocyclohexan-
1-ol of 18 and 25% ee, respectively. It is also interesting to
note that 9 yielded 2-chlorocyclohexan-1-ol of opposite con-
figuration (1S,2S). No improvement in enantioselectivity was
observed when the reaction was conducted at −100◦C for 4 h.
The chemical yield of the 2-chlorocyclohexan-1-ol in all cases
ranged between 60 and 70%.
d
ied Ipc2BCl 1 (99% ee) (Fig. 2) at −78◦C. Previous studies
d
l
involving Eap2BCl[15] and Cleap2BCl[15] have demonstrated
their superiority over dIpc2BCl with certain carbonyl com-
pounds in asymmetric reduction. In the case of Ipc2BCl 1, a
d
minor change in reaction conditions (slightly longer reaction
time, slow elevation of the reaction temperature after addition
of an aldehyde) and quick analysis of the chlorohydrins on a
Chiraldex-GTA analytical column, provided enantiomerically
(R)
(R)
(R)
OH
OH
(R)
(R)
(S)
(S)
Although the ARO of representative meso-epoxides with 2
provided relatively higher enantiomerically enriched bromo-
hydrins (48–84% ee) in comparison with 1 (40–46% ee), there
remained considerable opportunity for further improvements
with many substrates. Consequently, we undertook the asym-
metric cleavage of meso-epoxides with Ter2BBr along with
previously examined 2 (for comparison). Except for lCleap2BBr
8, all the Ter2BBr provided trans-2-bromocyclohexan-1-ol of
comparable ee (76–86% ee, Table 1). In the case of α-pinene-
based reagents, the conversion of the borinate ester into the
boronate ester was observed to be relatively fast (<2 h). The
O
O
O
(S)
(S)
(S)
X
X
13
14
15
16a (X ꢀ Cl)
16b (X ꢀ Br)
17a (X ꢀ Cl)
17b (X ꢀ Br)
(R)
(S)
(S)
OH
OH
X
OH
OH
(R)
(S)
(S)
X
(R)
X
(R)
X
18a (X ꢀ Cl)
18b (X ꢀ Br)
21a (X ꢀ Cl)
21b (X ꢀ Br)
19a (X ꢀ Cl)
19b (X ꢀ Br)
20a (X ꢀ Cl)
20b (X ꢀ Br)
Fig. 3. Representative meso-epoxides and the chiral halohydrins.
Table 1. ARO of meso-cyclohexene oxide 13 with various Ter2BX (X = Cl, Br)
Entry
Ter2BCl
Reaction conditions
Halohydrin no. Yield [%]
16a 70
ee [%]
Conf.E
1
2
3
4
5
6
7
8
dIpc2BCl 1
−78◦C, 4 h
41A
1R,2R
1R,2R
1R,2R
1R,2R
1S,2S
1R,2R
1R,2R
1R,2R
1S,2S
1S,2S
1R,2R
1R,2R
dIpc2BBr 2
−100◦C, 4 h
−78◦C, 4 h
−100◦C, 4 h
−78◦C, 4 h
−100◦C, 4 h
−78◦C, 4 h
−100◦C, 4 h
−78◦C, 4 h
−100◦C, 4 h
−78◦C, 4 h
−100◦C, 4 h
16b 75
85–92A
32C
dEap2BCl 3
dEap2BBr 4
lEap2BCl 5
16a
16b
17a
17b
16a
16b
17a
17b
16a
16b
65
74
68
76
65
75
66
72
68
70
78B
28A
lEap2BBr 6
89–99A,D
25B
lCleap2BCl 7
lCleap2BBr 8
2-dIcr2BCl 9
2-dIcr2BBr 10
4-dIcr2BCl 11
4-dIcr2BBr 12
36A
9
78–80B,C
76B
10
11
12
18B
3B
AEnantiomeric excess values were determined by gas chromatographic analysis on a Chiraldex-GTA
column as trifluoroacetate derivative.
BEnantiomeric ratios (er) were determined by HPLC analysis on a DAICEL Chiralcel OD-H column as
3,5-dintrobenzoate ester.
CEnantiomeric excess values were determined by HPLC analysis on a DAICEL Chiralcel OD-H column
as 1-naphthoate ester.
DRacemization of the 2-bromocyclohexan-1-ol trifluoroacetate was observed.
EThe absolute configurations of the major halohydrins (1S,2S) were assigned based on the results obtained
from dIpc2BX reactions.
OBTer2
OH
OB(OCH2R)Ter
NH(CH2CH2OH)2
Ter2BX
1. RCHO
O
2. BF3-OEt2
n-pentane
n-pentane
X
X
X
11B: d 53
11B: d 31
X ꢀ Cl, Br
13
Scheme 2. ARO of meso-cyclohexene oxide with Ter2BX.

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838
C. D. Roy and H. C. Brown
NO2
NO2
NO2
O
O
X
O
X
O
X
NO2
ꢁ
ꢁ
ꢁ
ꢁ
O
O
O
O
Cl
22a (X ꢀ Cl)
22b (X ꢀ Br)
23a
24a (X ꢀ Cl)
24b (X ꢀ Br)
25a (X ꢀ Cl)
25b (X ꢀ Br)
NO2
NO2
NO2
(S)
O
O
O
O
NO2
(S)
(S)
(S)
(S)
(S)
(S)
O
O
X
O
X
O
X
Cl
(S)
26a (X ꢀ Cl)
26b (X ꢀ Br)
27a
28a (X ꢀ Cl)
28b (X ꢀ Br)
29a (X ꢀ Cl)
29b (X ꢀ Br)
Fig. 4. Racemic and the chiral halohydrin derivatives.
slow conversion of the borinate ester (11B: δ 53–56) into the
boronate ester (11B: δ 31) with other chiral reagents could be
attributed to the steric nature of the chiral auxiliaries. Such
conversion was accelerated by the addition of a small amount
of BF3–OEt2. With meso-cyclohexene oxide, only 76% ee was
achieved when analyzed by chiral high performance liquid chro-
matography (HPLC) after transforming the hydroxy group of the
2-bromocyclohexan-1-ol into a UV sensitive ester.
Considering the labile nature of these halohydrins, it was
decided to analyze the crude bromohydrins obtained from
dIpc2BBr 2 and lEap2BBr 6 reactions. In the case of 2,
the gas chromatographic analyses of the TFA (trifluoroacetyl)
ester derivatives of both the crude and the purified 2-
bromocyclohexan-1-ol (on Chiraldex-GTA column) revealed
that the crude product had a slightly higher ee (92% ee) in com-
parisonwiththecolumn-purifiedproduct(86%ee). Uponcareful
analysis of the TFA ester of the crude 2-bromocyclohexan-1-ol
(obtained from reaction with 6), it was obvious that the TFA
derivative was undergoing slow racemization in solution (the ee
of the product dropped from 99 to 89% in 1.5 h). The derivatiza-
tion of halohydrins into UV sensitive esters (3,5-dinitrobenzoate
and 1-naphthoate) and their analyses by chiral HPLC provided
consistent and reproducible results (Fig. 4). It is believed that
the ee’s of the original β-bromohydrins are likely to be higher
than the observed values. Vicinal halohydrins obtained from
2-dIcr2BX have opposite configurations (1S,2S) in comparison
with dIpc2BX (1R,2R).
relative effectiveness of Ter2BX in the asymmetric halogenative
cleavage of meso-cyclopentene oxide.
First of all, we revisited the ring opening of meso-
cyclopentene oxide with dIpc2BX (X = Cl, Br). No significant
d
improvement was seen with Ipc2BCl 1 (46% ee). Among the
various structurally modified Ter2BCl studied, only lCleap2BCl
7 (entry 19) showed slightly improved results (49% ee). It was
interesting to note that the configuration of the product chloro-
hydrin obtained from lCleap2BCl was similar to the chlorohydrin
obtained from dIpc2BCl 1. It appears that the β-chloroethyl side
chain has a significant influence on the stereochemical outcome
of the reaction. Next, we investigated the asymmetric epoxide
opening reactions of meso-cyclopentene oxide 14 with Ter2BBr.
Upon reexamination of epoxide 14 with dIpc2BBr 2, a slightly
improved enantioselectivity (from 48 to 57% ee) was observed,
under slightly different reaction conditions (Table 2, entry 14).
Among all the reagents studied, only 2-dIcr2BBr showed an
encouraging result (67% ee, entry 22). The results are tabulated
in Table 2.
ARO of cis-2,3-Butene Oxide 15 with Ter2BX
After examining two representative cyclic epoxides 13 and
14, attention was turned to test the effectiveness of these
reagents with cis-2,3-butene oxide 15 and compare the results
with dIpc2BX. Considering the enantioselectivity achieved with
lCleap2BX and 4-dIcr2BX, only four reagents, dEap2BX and
2-dIcr2BX were examined. First we attempted to reproduce the
previous work with dIpc2BX. Although we obtained chloro-
hydrin of slightly improved enantiomeric excess (46% ee, lit.[11]
ARO of meso-Cyclopentene Oxide 14 with Ter2BX
d
d
38% ee) with Ipc2BCl 1, Ipc2BBr 2 provided bromohydrin
of 57% ee (lit.[11] 61% ee) in our hand. Gratifyingly, both
2-dIcr2BCl 9 and 2-dIcr2BBr 10 turned out to be the most
effective reagents (57 and 78% ee’s, respectively) in the series.
Interestingly, the acyclic epoxide, cis-2,3-butene oxide furnished
halohydrins of relatively higher ee’s than the results obtained
from meso-cyclopentene oxide. These results are summarized in
Table 3.
Earlier, we reported the asymmetric cleavage of meso-
cyclopentene oxide 14 with various dIpc2BX (X = Cl, Br, I).
Interestingly, the enantioselectivity observed for all three halo-
hydrins were very close (44% ee with dIpc2BCl 1, 48% ee
with dIpc2BBr 2, and 52% ee with dIpc2BI) which is in
marked contrast to the results obtained with meso-cyclohexene
oxide (22, 84, and 91% ee, respectively). During the catalytic
enantioselective ring opening of epoxides with SiCl4 in the pres-
ence of a chiral Lewis base (phosphoramide), Denmark and
coworkers[13] also observed very low enantioselectivity with
meso-cyclopentene oxide (2-chlorocyclopentan-1-ol, 7% ee),
whereas meso-cyclohexene oxide afforded 2-chlorocyclohexan-
1-ol (52% ee). It appears that meso-cyclopentene oxide is a
highly reactive substrate possibly because of the ring strain.
Therefore, it was of great interest to examine and compare the
A Proposed Reaction Mechanism
Jacobsen’s mechanistic studies on ARO reactions have revealed
that the reaction is second order with respect to metal reagent
(one metal center serves as a Lewis acid and the second metal
center delivers the nucleophile).[8] Shibasaki’s bimetallic cat-
alytic process also follows the similar reaction pathway.[5]