Toward effective chiral catalysts containing the N-P=O structural framework for the borane-mediated asymmetric reduction of prochiral ketones

Article abstract of DOI:10.1016/j.tetasy.2004.05.011

Representative chiral catalysts containing the N-P=O structural framework having (5S)-1,3-diaza-2-phospha-2-oxo-3-phenylbicyclo[3.3.0]octane moiety with amino groups of varying steric requirements on phosphorus, have been synthesized and their applications in the borane-mediated asymmetric reduction of prochiral ketones described.

Full text of DOI:10.1016/j.tetasy.2004.05.011

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1881–1888
Toward effective chiral catalysts containing the NAP@O
structural framework for the borane-mediated asymmetric
reduction of prochiral ketones
*
Deevi Basavaiah, Gone Jayapal Reddy and Kalapala Venkateswara Rao
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
Received 22 March 2004; accepted 11 May 2004
Abstract—Representative chiral catalysts containing the NAP@O structural framework having (5S)-1,3-diaza-2-phospha-2-oxo-3-
phenylbicyclo[3.3.0]octane moiety with amino groups of varying steric requirements on phosphorus, have been synthesized and their
applications in the borane-mediated asymmetric reduction of prochiral ketones described.
ꢀ
2004 Elsevier Ltd. All rights reserved.
1
. Introduction
development of novel different classes of chiral catalysts
containing the NAP@O structural framework for the
borane-mediated asymmetric reduction of prochiral
ketones with the aim of providing simple and conve-
nient methodologies for the synthesis of secondary
Since the ingenious introduction of chiral catalysts
containing the NAP@O structural framework by
9
1–8
Wills,
there has been an increasing interest in the
Ph
H
N
P
H C
3
N
O
O
H
N
OH
O
N
N
N
N
O
O
P
N
N
P
O
P
H
N
N
N
Ph
Cl
P
N
N
H
N
H
Ph
P
O
4
H C
Ph
Ph
3
N
2
3
H
Ph
1
O
N
H
3
C
O
O
P
N
N
N
O
P
H
N
N
H
N
P
N
H
P
H
H C
H
H
3
N
N
N
Ph
5
H C
3
H
Ph
Ph
5
A
Ph
5
C
5B
B
O
N
CH3
CH
3
H
O
P
O
P
N
H
P
N
N
N
H
H
N
N
H
N
H
Ph
N
Ph
Ph
5
D
5E
5C'
*
0
Corresponding author. Tel.: +91-40-23010221; fax: +91-40-23012460; e-mail: dbsc@uohyd.ernet.in
957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.05.011

1882
D. Basavaiah et al. / Tetrahedron: Asymmetry 15 (2004) 1881–1888
1
0–16
alcohols in high enantiomeric purities.
tion of our interest
In continua-
in the borane-mediated asym-
bicyclo[3.3.0]octane 5B and (5S)-1,3-diaza-2-(allyl-
amino)-2-phospha-2-oxo-3-phenylbicyclo[3.3.0]octane
5C. The desired chiral catalysts, 5A–C, were prepared
via the reaction of 4 with appropriate amine (benzyl-
amine, t-butylamine, and allylamine, respectively) (Eq.
1).
13;14;16
metric reduction of prochiral ketones, we herein report
the synthesis and applications of representative chiral
catalysts containing the NAP@O structural framework
thus providing a simple methodology for the synthesis
of secondary alcohols in up to 94% enantiomeric puri-
ties.
H
O
NEt , CH Cl
2
N
RNH2
+
3
2
N
H
RHN
P
2
. Results and discussion
Cl
P
N
N
Ph
O
Ph
We recently reported the synthesis and applications of
four chiral catalysts, (1R,2R)-1,2-bis[{(5S)-1,3-diaza-2-
phospha-2-oxo-3-phenylbicyclo[3.3.0]octan-2-yl}methyl-
amino]cyclohexane 1, 1,4-bis[(5S)-1,3-diaza-2-phospha-
4
5A-E
5
5-81%
RNH = benzylamine (18 h, rt), t-butylamine (12 h, reflux), allylamine (12 h, rt),
2
(
S)-1-phenylethylamine (2 d, rt), (R)-1-phenylethylamine (2 d, rt)
2
-oxo-3-phenylbicyclo[3.3.0]octan-2-yl]piperazine 2, (5S)-
-[(1R,2R,3S,5R)-2-hydroxy-2,6,6-trimethylbicyclo[3.1.1]-
heptan-3-yloxy]-1,3-diaza-2-phospha-2-oxo-3-phenyl-
ð1Þ
2
bicyclo[3.3.0]octane 3, and (2S,5S)-1,3-diaza-2-phospha-
2
We first examined the borane-mediated asymmetric
reduction of phenacyl bromide 6a under the influence of
the chiral molecule 5A with different catalytic amounts.
The best results were obtained when phenacyl bromide
6a (1 mM) was treated with borane-dimethyl sulfide
(1 mM) under the influence of 5A (5 mol %) in refluxing
toluene for 45 min, thus providing the desired alcohol
(S)-2-bromo-1-phenylethanol 7a with 89% enantiomeric
purity in 82% yield (Eq. 2, Table 1). Similarly, we have
also examined the potential of chiral molecule 5B as a
catalyst for the borane-mediated asymmetric reduction
of phenacyl bromide 6a. Thus, we have performed the
reduction of phenacyl bromide 6a in the presence of
chiral phosphoramide 5B (5 mol % and also 10 mol %) in
refluxing toluene for 45 min to provide the desired
alcohol (S)-2-bromo-1-phenylethanol 7a in 85% (with
5 mol %) and 84% (with 10 mol %) enantiomeric excess
(Eq. 2, Table 1).
-oxo-2-chloro-3-phenylbicyclo[3.3.0]octane 4 for the
borane-mediated asymmetric reduction of prochiral
ketones thus providing a simple methodology for the
synthesis of secondary alcohols in high enantiomeric
13;14;16
purities.
With a view to further understanding the role of bicyclic
framework [(5S)-1,3-diaza-2-phospha-2-oxo-3-phenyl-
bicyclo[3.3.0]octane moiety] 5 and the influence of
amino groups of varying steric requirements on the
phosphorus of this bicyclic framework 5 and also with a
view for developing better catalysts for borane-mediated
asymmetric reduction of prochiral ketones, we planned
to synthesize and study the applications of three repre-
sentative molecules (5S)-1,3-diaza-2-(benzylamino)-2-
phospha-2-oxo-3-phenylbicyclo[3.3.0]octane 5A, (5S)-
1
,3-diaza-2-(t-butylamino)-2-phospha-2-oxo-3-phenyl-
a
Table 1. Asymmetric reduction of phenacyl bromide 6a : a comparison of catalytic efficiency of 5A–E and 1:1 mixture of 5D and 5E
O
OH
Br 1.0 eq. BH .SMe2 / Catalyst
Br
3
0
ð2Þ
Toluene, 110 C, 45 min
6
a
7a
b
c
d
Catalyst
Mol %
5
Yield (%) 7a
Enantiomeric purity (%) 7a
Configuration
5A
82
87
85
86
83
84
82
86
85
81
82
80
82
89
86
81
85
84
81
83
89
88
88
89
85
86
S
S
S
S
S
S
S
S
S
S
S
S
S
1
0
0
5
0
5
0
5
0
5
0
5
2
5
5
5
5
5
B
1
1
1
1
C
D
E
D and 5E
(1:1)
10
a
3 2
All reactions were carried out on 1 mM scale of phenacyl bromide 6a with 1 mM of BH ÆSMe in the presence of catalyst in toluene for 45 min at
110 ꢁC.
b
c
Yields of alcohol after purification by column chromatography (silica gel, 5% ethyl acetate in hexanes).
Determined by HPLC analysis using the chiral column, Chiralcel-OD.
Absolute configuration was assigned by comparison of the sign of the specific rotation with that reported.
d
18

D. Basavaiah et al. / Tetrahedron: Asymmetry 15 (2004) 1881–1888
1883
a
Table 2. Asymmetric reduction of phenacyl chloride 6b : a comparison of catalytic potential of 5A–E and 1:1 mixture of 5D and 5E
O
OH
Cl 1.0 eq. BH .SMe / Catalyst
Cl
3
2
ð3Þ
o
Toluene, 110 C, 45 min
6b
7b
b
c
d
Catalyst
Mol %
Yield (%) 7b
Enantiomeric purity (%) 7b
Configuration
5
5
5
5
5
5
A
5
5
5
5
5
5
82
81
83
85
83
80
84
65
61
87
84
82
S
S
S
S
S
S
B
C
D
E
D and 5E
(
1:1)
All reactions were carried out on 1 mM scale of phenacyl chloride 6b with 1 mM of BH
10 ꢁC.
a
3
2
ÆSMe in the presence of catalyst in toluene for 45 min at
1
b
c
Yields of alcohol after purification by column chromatography (silica gel, 5% ethyl acetate in hexanes).
Determined by HPLC analysis using the chiral column, Chiralcel-OD.
Absolute configuration was assigned by comparison of the sign of the specific rotation with that reported.
d
18
We have next employed (5S)-1,3-diaza-2-(allylamino)-2-
phospha-2-oxo-3-phenylbicyclo[3.3.0]octane 5C con-
taining the allylamino group on phosphorus in the (5S)-
6a using 5 mol % and 10 mol % chiral phosphoramide 5E
in refluxing toluene for 45 min under the influence of
BH ÆSMe . In both cases the resulting secondary alcohol
3
2
1
moiety 5 with a view to examine the influence of borane
moiety 5C , which might have been formed due to the
hydroboration of the olefinic group in (5S)-1,3-diaza-2-
,3-diaza-2-phospha-2-oxo-3-phenylbicyclo(3.3.0)octane
(S)-2-bromo-1-phenylethanol 7a was obtained in similar
enantioselectivities (88% and 89% enantiomeric excess,
respectively) (Eq. 2, Table 1).
0
(
allylamino)-2-phospha-2-oxo-3-phenylbicyclo(3.3.0)oct-
With a view to examining the effect of combination of
both the catalysts (5S)-1,3-diaza-2-[(S)-1-phenylethyl-
amino]-2-phospha-2-oxo-3-phenylbicyclo[3.3.0]octane
5D and (5S)-1,3-diaza-2-[(R)-1-phenylethylamino]-2-
phospha-2-oxo-3-phenylbicyclo[3.3.0]octane 5E, we
carried out the reduction of phenacyl bromide 6a in the
presence of 1:1 mixture of chiral phosphoramides 5D
and 5E (2.5:2.5 mol % and 5:5 mol %) in refluxing tolu-
ene for 45 min under the influence of BH ÆSMe . In both
ane 5C. Thus, we have carried out the reduction of
phenacyl bromide 6a in the presence of chiral phos-
phoramide 5C (5 mol % and 10 mol %) in refluxing tol-
uene for 45 min to provide the desired alcohol (S)-2-
bromo-1-phenylethanol 7a in 81% (with 5 mol %) and
8
1
3% (with 10 mol %) enantiomeric excesses (Eq. 2, Table
).
3
2
Next, we directed our studies to investigate the role of
chiral amino group on phosphorus in the bicyclic moiety
cases the resulting secondary alcohol (S)-2-bromo-1-
phenylethanol 7a was obtained in similar enantioselec-
tivities that is, 85% (with 2.5 mol % 5Dþ2.5 mol % 5E)
and 86% (with 5 mol % 5Dþ5 mol % 5E) enantiomeric
excesses (Eq. 2, Table 1).
5
. In this direction, we have first selected (S)-1-phenyl-
ethylamine as a chiral amine for our study. The required
5S)-1,3-diaza-2-[(S)-1-phenylethylamino]-2-phospha-2-
(
oxo-3-phenylbicyclo[3.3.0]octane 5D was prepared via
the treatment of (2S,5S)-1,3-diaza-2-phospha-2-oxo-2-
chloro-3-phenylbicyclo[3.3.0]octane 4 with (S)-1-phen-
ylethylamine in the presence of triethylamine (Eq. 1).
Then we have first carried out the reduction of phenacyl
bromide 6a in the presence of chiral phosphoramide 5D
We also examined the applications of all these catalysts
[5A–E, and 5D:5E (1:1)] for the reduction of phenacyl
17
chloride 6b under the influence of BH
3
2
ÆSMe with a view
to understand the selectivity when ‘Cl’ is present in the
substrate instead of ‘Br’. The desired secondary alcohol,
(S)-2-chloro-1-phenylethanol 7b was obtained in 61–
87% enantiomeric excess (Eq. 3, Table 2).
(
4
5 mol % as well as 10 mol %) in refluxing toluene for
5 min under the influence of BH ÆSMe . In both cases
the resulting secondary alcohol (S)-2-bromo-1-phenyl-
3
2
ethanol 7a was obtained in similar enantioselectivities
[89% (with 5 mol %) and 88% (with 10 mol %) enantio-
meric excesses] (Eq. 2, Table 1).
From Tables 1 and 2 it is quite clear that chiral phos-
phoramide (5S)-1,3-diaza-2-[(S)-1-phenylethylamino]-2-
phospha-2-oxo-3-phenylbicyclo[3.3.0]octane 5D pro-
vided better enantioselectivities in the borane-mediated
asymmetric reduction of phenacyl bromide 6a and
phenacyl chloride 6b than the other phosphoramides
5A–C and 5E and 1:1 mixture of 5D and 5E. We have,
therefore, employed the catalyst 5D for the reduction of
a representative class of prochiral a-halo ketones 6c–g to
provide the chiral secondary alcohols 7c–g in high
enantiomeric excesses (89–94%) (Eq. 4, Table 3).
Enantiomeric excesses of the chiral alcohols 7c and 7d
In order to examine the effect of (R)-1-phenylethylamino
group on phosphorus in the bicyclic moiety 5, we next
prepared (5S)-1,3-diaza-2-[(R)-1-phenylethylamino]-2-
phospha-2-oxo-3-phenylbicyclo[3.3.0]octane 5E via the
treatment of (2S,5S)-1,3-diaza-2-phospha-2-oxo-2-
chloro-3-phenylbicyclo[3.3.0]octane 4 with (R)-1-phen-
17
ylethylamine in the presence of triethylamine (Eq. 1).
We then carried out the reduction of phenacyl bromide

1884
D. Basavaiah et al. / Tetrahedron: Asymmetry 15 (2004) 1881–1888
a
Table 3. Asymmetric reduction of prochiral a-halo ketones using the catalyst 5D
O
OH
1
.0 eq. BH .SMe / 5D (5 mol%)
3 2
X
X
Ar
Ar
0
Toluene, 110 C, 45 min
80-87%
7
a-g
6
a-g
ð4Þ
8
7-94% ee
X = Br, Cl
Ar = phenyl, 4-methylphenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl
b
25
½aꢀD
c
d
Substrate Ar
X
Product
Yield (%)
Conf.
Ee (%)
Phenyl 6a
Phenyl 6b
Br
Cl
Br
Cl
Br
Br
Br
7a
7b
7c
7d
7e
7f
86
85
84
82
87
80
82
þ39.4 (c 1.0, CHCl
3
)
S
S
S
S
S
S
S
89
87
91
89
þ42.8 (c 1.5, C
H )
6 12
4-Methylphenyl 6c
4-Methylphenyl 6d
4-Chlorophenyl 6e
4-Bromophenyl 6f
4-Nitrophenyl 6g
þ38.9 (c 1.08, CHCl
3
)
þ44.9 (c 1.0, CHCl
þ39.9 (c 1.0, CHCl
þ32.2 (c 0.9, CHCl
þ32.1 (c 1.0, CHCl
3
3
3
3
)
e
)
)
)
90
94
e
e
7g
91
a
3 2
All reactions were carried out on 1 mM scale of a-halo ketone with 1 mM of BH ÆSMe in the presence of catalyst 5D (5 mol %) in toluene for 45 min
at 110 ꢁC.
b
c
Yields of alcohols after purification by column chromatography (silica gel, 5% ethyl acetate in hexanes).
Absolute configuration was assigned by comparison of the sign of the specific rotation with that reported.
Determined by HPLC analyses using the chiral column, Chiralcel-OD.
13;16;18;19
d
e
1
Enantiomeric excesses were determined by H NMR (200 MHz) spectral analyses of the acetates in the presence of the chiral shift reagent, Eu(hfc)
with reference to the corresponding racemic acetates.
3
,
were determined by HPLC analyses using the chiral
column, Chiralcel-OD with reference to the corre-
sponding racemic alcohols. Enantiomeric excesses of
alcohols 7e–g were determined by H NMR spectral
analyses of their acetates in the presence of chiral shift
3-diaza-2-[(S)-1-phenylethylamino]-2-phospha-2-oxo-3-
phenylbicyclo[3.3.0]octane 5D provided better enantio-
selectivity (72% ee) than the other catalysts.
1
We next employed the chiral phosphoramide 5D for the
reduction of representative class of aryl alkyl ketones 6i–
n with a view to understand the generality of the catalyst
3
reagent, Eu(hfc) , with reference to their corresponding
racemic acetates.
5
D. The resulting secondary alcohols 7i–n were obtained
With a view to have a better understanding of the chiral
directing potential of the catalysts 5A–E and 1:1 mixture
of 5D and 5E, we also performed the reduction of ace-
tophenone 6h under the influence of these catalysts (5A–
E and 1:1 mixture of 5D and 5E) (5 mol %) in the
presence of BH ÆSMe . The resulting alcohol 7h was
in 43–76% enantiomeric excess (Eqs. 6 and 7, Table 5).
The enantiomeric excesses of alcohols 7i, 7j, and 7n were
determined by HPLC analyses using chiral column,
Chiralcel-OD with reference to corresponding racemic
alcohols. The enantiomeric excesses of alcohols 7k–m
were determined by HPLC analyses of their acetates
using chiral column, Chiralcel-OJ-H with reference to
corresponding racemic acetates.
3
2
obtained in 52–72% enantiomeric excess (Eq. 5, Table
4
). In this case also the chiral phosphoramide (5S)-1,
a
Table 4. Borane-mediated asymmetric reduction of acetophenone 6h : a comparison of catalytic potential of molecules 5A–E and 1:1 mixture of 5D
and 5E
O
OH
1
.0 eq. BH .SMe / catalyst (5 mol%)
3 2
ð5Þ
o
Toluene, 110 C, 45 min
6
h
7h
b
c
d
Catalyst
Yield (%) 7h
Enantiomeric excess (%) 7h
Configuration
5
5
5
5
5
5
A
74
84
82
87
85
72
62
60
52
72
70
64
R
R
R
R
R
R
B
C
D
E
D and 5E (1:1)
a
All reactions were carried out on 1 mM scale of acetophenone 6h with 1 mM of BH
at 110 ꢁC.
Yields of alcohol after purification by column chromatography (silica gel, 5% ethyl acetate in hexanes).
Determined by HPLC analysis using the chiral column, Chiralcel-OD.
Absolute configuration was assigned by comparison of the sign of the specific rotation with that reported.
3 2
ÆSMe in the presence of catalyst (5 mol %) in toluene for 45 min
b
c
d
20

D. Basavaiah et al. / Tetrahedron: Asymmetry 15 (2004) 1881–1888
1885
a
Table 5. Enantioselective reduction of aryl alkyl ketones using the catalyst 5D
O
OH
1
.0 eq. BH .SMe / 5D (5 mol%)
3 2
Ar
R
Ar
7h-m
7-76% ee
R
0
Toluene, 110 C, 45 min
4-90%
7
ð6Þ
6
h-m
4
R = Me, Et, Pr
Ar = phenyl, 4-methylphenyl, 4-chlorophenyl, 4-bromophenyl
OH
O
1
.0 eq. BH .SMe / 5D (5 mol%)
3 2
0
ð7Þ
Toluene, 110 C, 45 min
2%
7
7n
6n
4
3% ee
b
25
½aꢀD
c
d
Ketone
Product
Yield (%)
Ee (%)
Conf.
Acetophenone 6h
Propiophenone 6i
Butyrophenone 6j
7h
7i
87
81
80
77
74
90
72
þ32.6 (c 1.60, MeOH)
72
61
47
R
R
R
R
R
R
R
þ27.8 (c 0.79, CHCl
3
)
7j
þ21.95 (c 1.5, benzene)
þ22.9 (c 0.6, MeOH)
d
4-Methylacetophenone 6k
4-Chloroacetophenone 6l
4-Bromoacetophenone 6m
7k
7l
51
76
e
þ38.4 (c 1.25, Et
2
O)
e
7m
7n
þ30.0 (c 1.0, CHCl
3
)
74
43
a-Tetralone 6n
ꢁ10.6 (c 0.9, MeOH)
a
All reactions were carried out on 1 mM scale of prochiral ketone with 1 mM of BH
10 ꢁC.
Yields of alcohols after purification by column chromatography (silica gel, 5% ethyl acetate in hexanes).
Enantiomeric excesses were determined by HPLC analyses using the chiral column, Chiralcel-OD.
Absolute configuration was assigned by comparison of the sign of the specific rotation with that reported.
3 2
ÆSMe in the presence of 5D (5 mol %) in toluene for 45 min at
1
b
c
d
e
20–22
Enantiomeric excesses were determined by HPLC analyses of the corresponding acetates using the chiral column, Chiralcel-OJ-H.
3. Conclusion
recorded in deuterochloroform (CDCl ) on a Bruker-
3
AC-200 spectrometer using tetramethylsilane (TMS,
3
1
From these results it is quite evident that in the case of
phenacyl bromide 6a all the catalysts [5A–E, 5D, and 5E
(1:1)] offer similar enantioselectivities (81–89% ee). In
the case of phenacyl chloride 6b the catalysts 5A, 5D,
d ¼ 0) as internal standard. P NMR (81 MHz) spectra
were recorded on Bruker-AC-200 spectrometer using
85% H PO (d ¼ 0 ppm) as external standard. Elemental
3
4
analyses were recorded on Perkin–Elmer 240C-CHN
analyzer. Mass spectra were recorded on VG7070H and
AutoSpec mass spectrometer. HPLC analyses were
carried out on Shimadzu LC-10AD instrument using
chiral column (Chiralcel-OD or Chiralcel-OJ-H). Opti-
cal rotations were measured on Jasco DIP 370 digital
polarimeter.
5
8
E, and 5D and 5E (1:1) provide similar selectivities (82–
7% ee), while the catalysts 5B and 5C provide slightly
inferior selectivities (65%, 61% ee, respectively). But in
the case of acetophenone 6h the catalysts 5D and 5E
offer similar selectivities (72%, 70% ee, respectively),
while the catalysts 5A–C, and 5D and 5E (1:1) provide
slightly inferior selectivities (52–64% ee). In conclusion,
bicyclic [(5S)-1,3-diaza-2-phospha-2-oxo-3-phenylbicy-
clo[3.3.0]octane] moiety mostly controls the stereo-
chemical course of the reaction, while the groups on
phosphorus have little or no significant role in directing
the stereochemical course of the reaction. Studies are
under way to design and synthesize appropriate chiral
catalysts with the NAP@O structural framework with a
view to achieve higher enantioselectivities in the borane-
mediated reduction of prochiral ketones.
We have previously prepared 7a–j and 7n molecules and
reported the spectral data.
1
3;16
The present spectral data
1
13
(IR, H NMR, C NMR) of 7a–j, 7n are in agreement
with the earlier data. (R)-1-Acetoxy-1-(4-methylphen-
yl)ethane, (R)-1-acetoxy-1-(4-chlorophenyl)ethane, and
(R)-1-acetoxy-1-(4-bromophenyl)ethane were prepared
from the corresponding alcohols 7k–m according to the
13;18
reported procedure.
4
4
.1. Preparation of catalysts
4
. Experimental
.1.1. Representative procedure
4.1.1.1. (5S)-1,3-Diaza-2-(benzylamino)-2-phospha-2-
All melting points were recorded on a Superfit (India)
capillary melting point apparatus and were uncorrected.
IR spectra were recorded on Jasco-FT-IR model 5300 or
oxo-3-phenylbicyclo[3.3.0]octane 5A. To a stirred solu-
tion of (2S,5S)-1,3-diaza-2-phospha-2-oxo-2-chloro-3-
phenylbicyclo[3.3.0]octane 4
CH Cl (5 mL) were successively added triethylamine
1
Perkin Elmer model 1310 spectrometer. H NMR
(
(0.5 mM, 128 mg) in
13
200 MHz) and C NMR (50 MHz) spectra were
2
2

1886
D. Basavaiah et al. / Tetrahedron: Asymmetry 15 (2004) 1881–1888
3
1
(
1 mM, 101 mg) and benzylamine (0.5 mM, 53.5 mg) at
142.22 (d, J ¼ 5:6 Hz), 146.00; P NMR: d 17.88; mass
þ
room temperature. After 18 h (monitored by TLC) the
reaction mixture was diluted with water (5 mL). Organic
layer was separated and aqueous layer was extracted
(FAB) (m/z): 342 (M þ1); analysis calcd for
C H N OP: C, 66.85; H, 7.09; N, 12.31; Found: C,
3
19
24
66.70; H, 7.12; N, 12.25%.
with CH
was washed successively with water and brine and was
dried over anhydrous Na SO . The solvent was removed
under reduced pressure and the residue, thus obtained
was purified by column chromatography (silica gel, 25%
ethyl acetate in hexanes) to provide the desired (5S)-1,3-
diaza-2-(benzylamino)-2-phospha-2-oxo-3-phenylbicyclo-
2
Cl
2
(3 · 15 mL). The combined organic layer
4.1.1.5. (5S)-1,3-Diaza-2-[(R)-1-phenylethylamino]-2-
phospha-2-oxo-3-phenylbicyclo[3.3.0]octane 5E. Time:
2
4
25
2
days (rt); viscous liquid; yield: 81%; ½aꢀ ¼ ꢁ22:9 (c 1,
D
ꢁ
1 1
CHCl ); IR (neat): m 3211, 1601, 1201 cm ; H NMR: d
3
1
.40 (d, 3H, J ¼ 6.6 Hz), 1.51–2.18 (m, 4H), 2.83–3.42
(m, 4H), 3.56–3.88 (m, 2H), 4.16–4.38 (m, 1H), 6.80–
[
3.3.0]octane 5A as a crystalline solid (98 mg) in 60%
13
25
D
7.45 (m, 10H); C NMR: d 25.04 (d, J ¼ 8:1 Hz), 26.06,
32.33, 44.76, 47.76 (d, J ¼ 16:9 Hz), 51.70, 57.72 (d,
J ¼ 8:2 Hz), 116.28 (d, J ¼ 3:7 Hz), 120.50, 125.78,
yield; mp: 117–120 ꢁC; ½aꢀ ¼ ꢁ42:3 (c 1.05, CHCl );
3
ꢁ
1
1
IR (KBr): m 3190, 1599, 1207 cm ; H NMR: d 1.57–
2
3
9
.17 (m, 4H), 2.83–3.25 (m, 2H), 3.30–3.51 (m, 1H),
.65–4.16 (m, 5H), 6.92–7.06 (m, 1H), 7.09–7.46 (m,
H); C NMR: d 26.27, 32.23, 44.85, 45.06, 48.95 (d,
1
26.51, 127.91, 128.57, 141.66 (d, J ¼ 6:0 Hz), 144.53;
31
þ
13
P NMR: d 20.14; mass (m=z): 341 (M ); analysis calcd
24 3
for C19 H N OP: C, 66.85; H, 7.09; N, 12.31; Found:
C, 66.66; H, 7.15; N, 12.35%.
J ¼ 16:6 Hz), 57.86 (d, J ¼ 8:5 Hz), 116.41 (d,
J ¼ 4:2 Hz), 121.00, 126.94, 127.24, 128.26, 129.04,
3
1
1
39.81 (d, J ¼ 6:2 Hz), 141.88 (d, J ¼ 5:8 Hz);
P
þ
4.2. Application of catalyst 5D
NMR: d 21.16; mass (m=z): 327 (M ); analysis calcd for
C H N OP: C, 66.04; H, 6.77; N, 12.84; Found: C,
6
1
8
22
3
4
.2.1. Representative procedure using the catalyst 5D
.2.1.1. Asymmetric reduction of phenacyl bromide 6a:
6.29; H, 6.75; N, 12.75%.
4
synthesis of (S)-2-bromo-1-phenylethanol 7a. To a stirred
solution of (5S)-1,3-diaza-2-[(S)-1-phenylethylamino]-2-
phospha-2-oxo-3-phenylbicyclo[3.3.0]octane 5D (0.05
mM, 17.1 mg) in toluene (5 mL) was added borane–di-
methyl sulfide (1.0 mM, 76 mg) at room temperature and
the reaction mixture was heated to 110 ꢁC. Once the
temperature has stabilized at 110 ꢁC, phenacyl bromide
4.1.1.2. (5S)-1,3-Diaza-2-(t-butylamino)-2-phospha-2-
oxo-3-phenylbicyclo[3.3.0]octane 5B. Time: 12 h (re-
25
flux); yield: 55%; Mp: 129–132 ꢁC; ½aꢀ ¼ ꢁ36:8 (c 1.05,
D
ꢁ
1 1
CHCl ); IR (KBr): m 3171, 1601, 1224 cm ; H NMR: d
3
1
2
3
2
.13 (s, 9H), 1.57–2.19 (m, 4H), 2.66 (d, 1H, J ¼ 8:8 Hz),
.83–3.07 (m, 1H), 3.30–3.46 (m, 1H), 3.61–3.89 (m,
H), 6.88–6.98 (m, 1H), 7.12–7.38 (m, 4H); C NMR: d
6.15, 31.00 (d, J ¼ 4:9 Hz), 32.70, 44.44, 47.96 (d,
13
6
a (1.0 mM, 199 mg) in toluene (2 mL) was added
dropwise over 10 min and stirring continued for further
5 min (monitored by TLC). Then the reaction mixture
J ¼ 17:0 Hz), 50.75, 57.13 (d, J ¼ 7:3 Hz), 116.29 (d,
4
31
J ¼ 4:0 Hz), 120.61, 128.86, 142.05 (d, J ¼ 5:5 Hz);
P
was allowed to cool to room temperature and quenched
with methanol. The solvent was removed under reduced
pressure and the residue obtained was purified by col-
umn chromatography (silica gel, 5% ethyl acetate in
hexanes) to provide the desired (S)-2-bromo-1-phenyl-
ethanol 7a in 86% (173 mg) yield as a colorless oil;
þ
NMR: d 17.17; MS (m=z): 293 (M ); analysis calcd for
C
6
15
H
24
N
1.26; H, 8.30; N, 14.35%.
3
OP: C, 61.42; H, 8.25; N, 14.32; Found: C,
4
.1.1.3.
(5S)-1,3-Diaza-2-(allylamino)-2-phospha-2-
oxo-3-phenylbicyclo[3.3.0]octane 5C. Time: 12 h (rt);
2
D
5
17
25
D
½aꢀ ¼ þ39:4 (c 1.0, CHCl
3
) [lit. ½aꢀ ¼ ꢁ39:0 (c 8.00,
25
yield: 58%; Mp: 70–72 ꢁC; ½aꢀ ¼ ꢁ33:2 (c 1.1, CHCl
3
);
3
CHCl ), (R)-configuration, 93% ee] 89% ee, the enan-
D
ꢁ
1
1
IR (KBr): m 3190, 1599, 1201 cm ; H NMR: d 1.59–
tiomeric excess was determined by HPLC using a chiral
column [Chiralcel-OD, 90:10 hexanes–i-PrOH, 1.0 mL/
min, 254 nm, retention times: 8.04 min (S) and 9.65 min
(R)].
2
3
1
2
.18 (m, 4H), 2.72–3.09 (m, 2H), 3.22–3.51 (m, 3H),
.63–3.94 (m, 3H), 4.92–5.19 (m, 2H), 5.60–5.82 (m,
H), 6.90–7.01 (m, 1H), 7.14–7.37 (m, 4H); C NMR: d
6.17, 32.14, 43.53, 44.85, 48.95 (d, J ¼ 16:8 Hz), 57.73
13
(
1
d, J ¼ 8:4 Hz), 114.82, 116.28 (d, J ¼ 4:1 Hz), 120.81,
4
.2.1.2. (S)-2-Chloro-1-phenylethanol 7b. Colorless oil;
28.91, 136.48 (d, J ¼ 5:9 Hz), 141.88 (d, J ¼ 5:9 Hz);
25
D
18
31
þ
yield 85%; ½aꢀ ¼ þ42:8 (c 1.5, cyclohexane) [lit.
P NMR: d 21.38; mass (m=z): 277 (M ); analysis calcd
25
½
aꢀ ¼ ꢁ48:1 (c 1.73, cyclohexane), (R)-configuration,
for C14
6
H
0.84; H, 7.30; N, 15.18%.
20
N
3
OP: C, 60.64; H, 7.27; N, 15.15; Found: C,
D
00% ee] 87% ee, the enantiomeric excess was deter-
1
mined by HPLC using a chiral column [Chiralcel-OD,
0:10 hexanes–i-PrOH, 1.0 mL/min, 254 nm, retention
times: 8.08 min (S) and 9.58 min (R)].
9
4.1.1.4. (5S)-1,3-Diaza-2-[(S)-1-phenylethylamino]-2-
phospha-2-oxo-3-phenylbicyclo[3.3.0]octane 5D. Time:
2
D
5
2
days (rt); yield: 80%; Mp: 148–150 ꢁC; ½aꢀ ¼ ꢁ104:2
ꢁ
1 1
(
c 1.125, CHCl
3
); IR (KBr): m 3211, 1601, 1205 cm ; H
4.2.1.3. (S)-2-Bromo-1-(4-methylphenyl)ethanol 7c.
25
NMR: d 1.22 (d, 3H, J ¼ 6:6 Hz), 1.46–2.06 (m, 4H),
Colorless oil; yield: 84%; ½aꢀ ¼ þ38:9 (c 1.08, CHCl )
D
3
13
25
D
2
1
2
.48–2.69 (m, 1H), 3.24–3.83 (m, 5H), 3.97–4.18 (m,
H), 6.91–7.02 (m, 1H), 7.15–7.39 (m, 9H); C NMR: d
5.06 (d, J ¼ 7:9 Hz), 26.50, 32.25, 43.98, 49.33 (d,
[lit. ½aꢀ ¼ þ41:8 (c 1.0, CHCl
3
), (S)-configuration,
13
95% ee] 91% ee, the enantiomeric excess was determined
by HPLC using a chiral column [Chiralcel-OD, 97.5:2.5
hexanes–i-PrOH, 1 mL/min, 254 nm, retention times:
15.76 min (S) and 18.86 min (R)].
J ¼ 16:0 Hz), 51.19, 57.37 (d, J ¼ 9:5 Hz), 116.29 (d,
J ¼ 4:0 Hz), 120.83, 125.86, 126.64, 128.13, 129.07,

D. Basavaiah et al. / Tetrahedron: Asymmetry 15 (2004) 1881–1888
1887
4
.2.1.4. (S)-2-Chloro-1-(4-methylphenyl)ethanol 7d.
HPLC analysis of its corresponding acetate with respect
to corresponding racemic acetate using a chiral column
[Chiralcel-OJ-H, 95:5 hexanes–i-PrOH, 1.0 mL/min,
254 nm, retention times: 7.66 min (R) and 10.82 min (S)];
25
Colorless oil; yield: 82%; ½aꢀ ¼ þ44:9 (c 1.0, CHCl
3
)
D
1
3
25
[
lit. ½aꢀ ¼ þ47:2 (c 1.1, CHCl ), (S)-configuration,
D
2% ee] 89% ee, the enantiomeric excess was determined
3
9
by HPLC using a chiral column [Chiralcel-OD, 97.5:2.5
ꢁ
1
1
IR (neat): m 3352 cm ; H NMR: d 1.48 (d, 3H,
J ¼ 6:6 Hz), 2.25 (bs, 1H), 2.37 (s, 3H), 4.84 (q, 1H,
J ¼ 6:6 Hz), 7.17 (d, 2H, J ¼ 8:0 Hz), 7.27 (d, 2H,
hexanes–i-PrOH, 1 mL/min, 254 nm, retention times:
1
4.06 min (S) and 16.20 min (R)].
13
J ¼ 8:0 Hz); C NMR: d 21.10, 25.08, 70.17, 125.40,
129.15, 137.06, 142.97.
4
.2.1.5. (S)-2-Bromo-1-(4-chlorophenyl)ethanol 7e.
25
Colorless oil; yield: 87%; ½aꢀ ¼ þ39:9 (c 1.0, CHCl )
D
3
1
3
25
[
lit. ½aꢀ ¼ þ38:6 (c 1.15, CHCl ), (S)-configuration,
D
1% ee] 90% ee, the enantiomeric purity was determined
3
4.2.1.12. (R)-1-Acetoxy-1-(4-methylphenyl)ethane.
ꢁ
1
1
9
by H NMR spectral analysis of the corresponding
Colorless oil; yield: 83%; IR (neat): m 1739 cm ; H
NMR: d 1.53 (d, 3H, J ¼ 6:8 Hz), 2.06 (s, 3H), 2.35 (s,
3H), 5.87 (q, 1H, J ¼ 6:8 Hz), 7.16 (d, 2H, J ¼ 8:2 Hz),
1
acetate in the presence of chiral shift reagent, Eu(hfc)3,
1
3
with reference to the racemic acetate.
7
2
.26 (d, 2H, J ¼ 8:2 Hz); C NMR: d 21.10, 21.32,
2.07, 72.22, 126.14, 129.16, 137.60, 138.77, 170.27.
4
Colorless solid; yield:
.2.1.6. (S)-2-Bromo-1-(4-bromophenyl)ethanol 7f.
80%; 25mp:
70–72 ꢁC;
4
.2.1.13. (R)-1-(4-Chlorophenyl)ethanol 7l. Colorless
25
19
½
aꢀ ¼ þ32:2 (c 0.9, CHCl
3
) [lit. ½aꢀ ¼ ꢁ31:0 (c 2.9,
25
D
22
D
CHCl
D
), (R)-configuration, 94% ee] 94% ee, the enan-
oil; yield: 74%; ½aꢀ ¼ þ38:4 (c 1.25, Et O) [lit.
2
25
aꢀ ¼ ꢁ49:0 (c 1.84, Et O), (S)-configuration, >99% ee]
3
½
D
6% ee, the enantiomeric excess was determined by
2
1
tiomeric excess was determined by H NMR spectral
analysis of the corresponding acetate in the presence of
chiral shift reagent, Eu(hfc)
racemic acetate.
7
HPLC analysis of its corresponding acetate with respect
to corresponding racemic acetate using a chiral column
Chiralcel-OJ-H, 95:5 hexanes–i-PrOH, 1.0 mL/min,
54 nm, retention times: 6.83 min (R) and 8.06 min (S)];
3
, with reference to the
[
2
4
.2.1.7. (S)-2-Bromo-1-(4-nitrophenyl)ethanol 257g.
ꢁ1
1
IR (neat): m 3352 cm ; H NMR: d 1.41 (d, 3H,
J ¼ 6:4 Hz), 2.81 (bs, 1H), 4.77 (q, 1H, J ¼ 6:4 Hz),
Light yellow solid; yield: 82%; mp: 80–81 ꢁC; ½aꢀ
¼
D
14
25
D
þ32:1 (c 1.0, CHCl
3
) [lit.
CHCl ), (S)-configuration, 91% ee] 91% ee, the enan-
½aꢀ ¼ þ32:0 (c 1.0,
13
7.13–7.33 (m, 4H); C NMR: d 25.13, 69.54, 126.78,
128.49, 132.92, 144.25.
3
1
tiomeric excess was determined by H NMR spectral
analysis of the corresponding acetate in the presence of
chiral shift reagent, Eu(hfc)
racemic acetate.
4.2.1.14.
(R)-1-Acetoxy-1-(4-chlorophenyl)ethane.
3
, with reference to the
ꢁ
1
1
Colorless oil; yield: 89%; IR (neat): m 1738 cm ; H
NMR: d 1.52 (d, 3H, J ¼ 6:8 Hz), 2.07 (s, 3H), 5.85 (q,
13
1
H, J ¼ 6:8 Hz), 7.25–7.38 (m, 4H); C NMR: d 21.31,
4
.2.1.8. (R)-1-Phenylethanol 7h. Colorless oil; yield:
25 25
22.18, 71.64, 127.59, 128.74, 133.71, 140.32, 170.21.
20
8
7%; ½aꢀ ¼ þ32:6 (c 1.60, MeOH) [Lit. ½aꢀ ¼ þ44:1
D
D
(
enantiomeric excess was determined by HPLC using a
c 3.0, MeOH), (R)-configuration, 97% ee] 72% ee, the
4.2.1.15. (R)-1-(4-Bromophenyl)ethanol 7m. Colorless
2
5
22
oil; yield: 90%; ½aꢀ ¼ þ30:0 (c 1.0, CHCl
3
) [lit.
chiral column [Chiralcel-OD, 95:5 hexanes–i-PrOH,
1
D
25
½
aꢀ ¼ ꢁ37:9 (c 1.13, CHCl ), (S)-configuration, >99%
.0 mL/min, 254 nm, retention times: 9.08 min (R) and
0.90 min (S)].
D
3
ee] 74% ee, the enantiomeric excess was determined by
HPLC analysis of its acetate with respect to corre-
sponding racemic acetate using a chiral column [Chi-
ralcel-OJ-H, 95:5 hexanes–i-PrOH, 1.0 mL/min, 254 nm,
retention times: 7.13 min (R) and 8.38 min (S)]; IR
1
4
.2.1.9. (R)-1-Phenylpropan-1-ol 7i. Colorless oil;
25
20
yield: 81%; ½aꢀ ¼ þ27:8 (c 0.79, CHCl
3
) [lit.
D
25
½
aꢀ ¼ þ43:0 (c 5.1, CHCl ), (R)-configuration, 96% ee]
D
1% ee, the enantiomeric excess was determined by
3
ꢁ1
1
(
neat): m 3358 cm ; H NMR: d 1.47 (d, 3H,
6
HPLC using a chiral column [Chiralcel-OD, 95:5 hex-
J ¼ 6:8 Hz), 1.79 (d, 1H, J ¼ 4:0 Hz), 4.80–4.95 (m, 1H),
13
7
.25 (d, 2H, J ¼ 8:8 Hz), 7.47 (d, 2H, J ¼ 8.8 Hz);
C
anes–i-PrOH, 1.0 mL/min, 254 nm, retention times:
8
NMR: d 25.09, 69.51, 121.00, 127.13, 131.43, 144.75.
.11 min (R) and 9.86 min (S)].
4
.2.1.16.
(R)-1-Acetoxy-1-(4-bromophenyl)ethane.
4
.2.1.10. (R)-1-Phenylbutan-1-ol 7j. Colorless oil;
25
21
ꢁ1
1
Colorless oil; yield: 80%; IR (neat): m 1736 cm ; H
NMR: d 1.50 (d, 3H, J ¼ 6:6 Hz), 2.06 (s, 3H), 5.80 (q,
yield: 80%; ½aꢀ ¼ þ21:95 (c 1.5, benzene) [lit.
D
25
½
aꢀ ¼ ꢁ45:2 (c 4.81, benzene), (S)-configuration, 100%
D
1
H, J ¼ 6:6 Hz), 7.21 (d, 2H, J ¼ 8:3 Hz), 7.46 (d, 2H,
ee] 47% ee, the enantiomeric excess was determined by
HPLC using a chiral column [Chiralcel-OD, 95:5 hex-
anes–i-PrOH, 0.7 mL/min, 254 nm, retention times:
13
J ¼ 8:3 Hz); C NMR: d 21.15, 22.03, 71.54, 121.71,
1
27.83, 131.62, 140.82, 169.95.
1
1.27 min (R) and 12.78 min (S)].
4
.2.1.17. (R)-1,2,3,4-Tetrahydronaphth-1-ol 7n. Col-
25
D
20
4
.2.1.11. (R)-1-(4-Methylphenyl)ethanol 7k. Colorless
orless oil; yield: 72%; ½aꢀ ¼ ꢁ10:6 (c 0.9, MeOH) [lit.
25
22
25
½aꢀ ¼ ꢁ23:1 (c 1.3, MeOH), (R)-configuration, 94% ee]
oil; yield: 77%; ½aꢀ ¼ þ22:9 (c 0.6, MeOH) [lit.
D
D
25
½
aꢀ ¼ ꢁ43:5 (c 0.994, MeOH), (S)-configuration, >99%
43% ee, the enantiomeric excess was determined by
HPLC using a chiral column [Chiralcel-OD, 97.5:2.5
D
ee] 51% ee, the enantiomeric excess was determined by

1888
D. Basavaiah et al. / Tetrahedron: Asymmetry 15 (2004) 1881–1888
hexanes–i-PrOH, 0.4 mL/min, 254 nm, retention times
3
9. For borane-mediated asymmetric reductions of prochiral
ketones see reviews: (a) Brown, H. C.; Jadhav, P. K.;
Singaram, B. In Modern Synthetic Methods; Scheffold, R.,
Ed.; Springer: Heidelberg, 1986; Vol. 4, pp 307–356; (b)
Brown, H. C.; Ramachandran, P. V. Acc. Chem. Res.
6.25 min (S) and 41.08 min (R)].
Acknowledgements
1
992, 25, 16–24; (c) Corey, E. J.; Helal, C. J. Angew.
Chem., Int. Ed. 1998, 37, 1986–2012; (d) Singh, V. K.
Synthesis 1992, 605–617; (e) Deloux, L.; Srebnik, M.
Chem. Rev. 1993, 93, 763–784.
We thank CSIR (New Delhi) for funding this project.
We thank UGC (New Delhi) for recognizing our Uni-
versity of Hyderabad as ‘University with potential for
excellence (UPE)’ and providing some instrumental
facilities and also for the Special Assistance Program in
Organic Chemistry in the School of Chemistry, Uni-
versity of Hyderabad, Hyderabad. G.J.R. and K.V.R.
thank CSIR (New Delhi) for their research fellowships.
10. Chiodi, O.; Fotiadu, F.; Sylvestre, M.; Buono, G. Tetra-
hedron Lett. 1996, 37, 39–42.
1
1
1
1
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354.
2. Brunel, J. M.; Legrand, O.; Buono, G. Eur. J. Org. Chem.
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8
2
3. Basavaiah, D.; Jayapal Reddy, G.; Chandrashekar, V.
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4. Basavaiah, D.; Jayapal Reddy, G.; Chandrashekar, V.
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027–1038.
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7
8
1