(2S,5S)-1,3-Diaza-2-phospha-2-oxo-2-chloro-3-phenylbicyclo[3.3.0]octane: A novel chiral source for borane-mediated catalytic chiral reductions

Article abstract of DOI:10.1016/S0957-4166(02)00263-X

(2S,5S)-1,3-Diaza-2-phospha-2-oxo-2-chloro-3-phenylbicyclo[3.3.0]octane has been successfully employed as a chiral catalytic source for the borane mediated asymmetric reductions of prochiral α-halo ketones to provide the desired (S)-secondary alcohols in 81-91% enantiomeric purities, thus for the first time demonstrating the potential of the N-P(=O)Cl structural framework to generate a recoverable, reusable and air stable catalyst for the asymmetric reduction processes.

Full text of DOI:10.1016/S0957-4166(02)00263-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1125–1128
(2S,5S)-1,3-Diaza-2-phospha-2-oxo-2-chloro-3-phenylbicyclo[3.3.0]
octane: a novel chiral source for borane-mediated catalytic chiral
reductions†
Deevi Basavaiah,* Gone Jayapal Reddy and Vanampally Chandrashekar
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
Received 27 May 2002; accepted 30 May 2002
Abstract—(2S,5S)-1,3-Diaza-2-phospha-2-oxo-2-chloro-3-phenylbicyclo[3.3.0]octane has been successfully employed as a chiral
catalytic source for the borane mediated asymmetric reductions of prochiral a-halo ketones to provide the desired (S)-secondary
alcohols in 81–91% enantiomeric purities, thus for the first time demonstrating the potential of the N-P(ꢀO)Cl structural
framework to generate a recoverable, reusable and air stable catalyst for the asymmetric reduction processes. © 2002 Elsevier
Science Ltd. All rights reserved.
ethanols with high enantiomeric purities. We felt that a
loading of 30 mol% catalyst was too large an amount,
rendering the methodology expensive. Thus, we decided
to develop new frameworks and/or molecules able to
catalyze the reaction even when used in very small
amounts. We also felt that it would be highly useful if
such molecules could be easily accessible in large
amounts. A literature survey revealed that (2S,5S)-1,3-
diaza-2-phospha-2-oxo-2-chloro-3-phenylbicyclo[3.3.0]-
octane 3, which is readily available in large quanti-
ties,16 has not been examined for catalytic chiral reduc-
tion processes. We envisaged that 3, containing the
N-P(ꢀO)Cl framework, might offer promise as a cataly-
tic chiral source for borane-mediated catalytic chiral
reductions. To this end, we now report the borane-
mediated reduction of prochiral a-halo ketones in the
presence of (2S,5S) - 1,3 - diaza - 2 - phospha - 2 - oxo - 2-
chloro-3-phenylbicyclo-(3.3.0)octane 3 (5 mol%) to
provide the resulting (S)-secondary alcohols with high
enantiomeric purities.
Brown’s outstanding contributions to chiral borane
chemistry and Corey’s elegant utilization of oxazaboro-
lidines as chemzymes for the asymmetric reduction of
prochiral ketones to afford secondary alcohols with
high enantiomeric purities have indeed provided a new
outlook and direction to synthetic processes in chiral
chemistry, particularly in chiral reduction methodolo-
gies.1–7 Recently Wills et al. have introduced an inge-
nious class of novel chiral catalysts containing the
N-PꢀO structural framework for borane-mediated
asymmetric reduction of prochiral ketones.8–14 Very
recently we have demonstrated the application of 1,4-
bis[(5S)-1,3-diaza-2-phospha-2-oxo-3-phenylbicyclo-
[3.3.0]octan-2-yl]piperazine 2 (derived from the chiral
diamine, (S)-2-anilinomethylpyrrolidine, 1) containing
the N-PꢀO structural framework, as a catalyst for the
borane-mediated asymmetric reduction of prochiral a-
halo ketones.15 This methodology requires 30 mol%
catalyst for reduction of prochiral a-halo ketones to
afford the resulting (S)-configured 2-halo-1-aryl-
* Corresponding author. E-mail: dbsc@uohyd.ernet.in.
† Dedicated to Professor Herbert C. Brown, an outstanding organic chemist, on the occasion of his 90th birthday.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00263-X

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D. Basa6aiah et al. / Tetrahedron: Asymmetry 13 (2002) 1125–1128
1
5e–g were determined by H NMR spectral analysis of
their acetate derivatives in the presence of the chiral
shift reagent, Eu(hfc)3, with reference to their corre-
sponding racemic acetates.
The required catalyst (2S,5S)-1,3-diaza-2-phospha-2-
oxo-2-chloro-3-phenylbicyclo[3.3.0]octane 3 was syn-
thesized according to the procedure reported by Fiaud
and co-workers via the reaction of (S)-2-anilino-
methylpyrrolidine 1 (obtained from inexpensive and
commercially available (S)-glutamic acid following the
literature procedure17,18) with POCl3/NEt3 in THF (Eq.
In order to understand the nature of the catalyst we
treated the molecule 3 (0.2 mmol, 51.4 mg) with
BH3·SMe2 (0.3 mmol, 1.5 equiv.) in toluene for 10 min
under reflux (Eq. (3)). The excess borane was destroyed
by addition of methanol and the resulting solid was
filtered, washed with ether and dried under reduced
pressure to provide a light yellow solid A (41 mg).22 We
have carried out the reductions of phenacyl bromide 4a
(1 mmol) and phenacyl chloride 4b (1 mmol) in the
presence of catalytic amounts of this solid A (12.8 mg)
to provide the resulting secondary alcohols 5a and 5b
with enantiomeric purities of 82 and 81%, respectively
(determined by HPLC analysis using the chiral column,
Chiralcel-OD) (Eq. (4)). With a view to recovering and
reusing the chiral source we carried out the reduction of
phenacyl bromide on 4 mmol scale with borane–
dimethyl sulfide in the presence of 3 (5 mol%, 51.4 mg)
and recovered the chiral source (40 mg) as a solid B.23
With a view to understanding reusability of the recov-
ered chiral source B we performed the reductions of
phenacyl bromide 4a (1 mmol) and phenacyl chloride
4b (1 mmol) with borane–dimethyl sulfide in the pres-
ence of catalytic amounts of the recovered chiral source
B (12.8 mg). The resulting secondary alcohols 5a and
5b were obtained in enantiomeric purities of 85 and
78%, respectively (determined by HPLC analysis using
a Chiralcel-OD chiral column) (Eq. (4)). These results
clearly indicate that the solids A and B have almost the
same chiral directing efficiency as the original chiral
source i.e. molecule 3. Both the prepared (A) and
(1)).16,19
(1)
We first examined the borane-mediated asymmetric
reduction of phenacyl bromide in the presence of vary-
ing amounts of catalyst 3. The best results were
obtained when phenacyl bromide 4a (1 mmol) was
treated with borane–dimethyl sulfide (1 mmol) under
the influence of 3 (5 mol%, 12.8 mg) in refluxing
toluene for 45 min, thus providing the desired alcohol
(S)-2-bromo-1-phenylethanol 5a in 89% yield with
enantiomeric purity of 87% (after usual work-up and
purification by column chromatography).15 This was
indeed a very encouraging result. We then extended the
same reaction to a representative class of prochiral
a-halo ketones (aryl halomethyl ketones) 4b–g to
provide the resulting secondary alcohols 5b–g with high
enantiomeric purities (81–91%) (Eq. (2), Table 1). The
enantiomeric purities of the chiral alcohols 5a–d were
determined by HPLC analysis using a Chiralcel-OD
chiral column with reference to the corresponding
racemic alcohols. The enantiomeric purities of alcohols
Table 1. Asymmetric reduction of a-halo ketonesa
(2)
Substrate
Ar
X
Product
Yield (%)b
[h]2D5
Conf.c
E.e (%)d
4a
4b
4c
4d
4e
4f
Phenyl
Phenyl
Br
Cl
Br
Cl
Br
Br
Br
5a
5b
5c
5d
5e
5f
89
93
87
91
88
80
78
+39.0 (c 1.0, CHCl3)
+40.0 (c 1.0, cyclohexane)
+37.5 (c 1.0, CHCl3)
+42.0 (c 1.0, CHCl3)
+30.7 (c 2.4, CHCl3)
+37.9 (c 1.2, CHCl3)
+32 (c 1.0, CHCl3)
S21
S21
S15
S15
S20
S15
Sf
87
81
83
4-Methylphenyl
4-Methylphenyl
4-Bromophenyl
4-Chlorophenyl
4-Nitrophenyl
82
86e
88e
91e
4g
5g
a All reactions were carried out on 1 mmol scale with respect to a-halo ketone with BH3·SMe2 (1 mmol) in the presence of 3 (5 mol%) in toluene
for 45 min at 110°C.
b Yields of pure alcohol after purification by column chromatography (silica gel, 5% ethyl acetate in hexanes).
c Absolute configuration was assigned by comparison of the sign of the specific rotation with that of reported molecules.15,20,21
d Determined by HPLC analysis using the chiral column, Chiralcel-OD.
e Enantiomeric purities were determined by 1H NMR (200 MHz) spectral analysis of the acetates in the presence of the chiral shift reagent,
Eu(hfc)3, with reference to the corresponding racemic acetates.
f Absolute configuration was tentatively assigned by analogy with 5a–f.

D. Basa6aiah et al. / Tetrahedron: Asymmetry 13 (2002) 1125–1128
1127
recovered (B) catalysts are air stable, recoverable and
considerable effect on the stereodirection in comparison
with that of the chiral diamine 1.
1
reusable. A comparison of H and 13C NMR spectral
studies of the original chiral source 3 with that of A and
B clearly indicates that they may have similar structural
organization (the chiral diamine moiety is intact).19,22
The IR, 1H, 13C and 31P NMR spectral studies of A and
B indicate that these solids may have the same structure
(while determining the melting points we also found
that both A and B decompose at 126–129°C).22
(5)
In conclusion, we have successfully carried out the
borane-mediated asymmetric reduction of prochiral a-
halo ketones using (2S,5S)-1,3-diaza-2-phospha-2-oxo-
(3)
2-chloro-3-phenylbicyclo[3.3.0]octane 3 as a chiral
catalytic source. Although the exact structure of the
catalyst is not known at the moment, this work demon-
strates for the first time, the potential of N-P(ꢀO)Cl
framework as a chiral source to generate a recoverable,
reusable and air stable catalyst for the borane-mediated
enantioselective reduction processes. Further work in
the development of new chiral molecules based on the
N-P(ꢀO)Cl framework with a view to understanding
the actual structure of the catalyst and the mechanism
of this catalytic reduction process is now in progress in
our laboratory.
The most striking difference between the chiral source 3
and the solids A and B is their solubility profile (the
solids A and B are insoluble in most organic solvents
including hexanes, ether, chloroform, dichloromethane,
ethyl acetate, THF, methanol and water, while the
original chiral source 3 is soluble in ether, chloroform
and dichloromethane etc.). In both cases (solids A and
B), the 11B NMR spectrum shows a very weak broad
signal at l 2.80 indicating that the actual catalyst
(solids A or B), may not contain any boron species.
This weak signal may be attributed to the presence of
minor amounts of some boron species in the actual
catalysts (A or B). On the basis of these preliminary
studies, we assume that the catalyst (A or B) may not
be monomeric in nature.
Acknowledgements
We thank CSIR (New Delhi) for funding this research
project. We also thank the UGC (New Delhi) for the
Special Assistance Program in Organic Chemistry in the
School of Chemistry, University of Hyderabad, Hyder-
abad. G.J.R and V.C. thank CSIR (New Delhi) for
their research fellowships.
It is worth mentioning here the interesting work of
Asami and co-workers24 who reported the use of chiral
b-diamines as catalysts for borane-mediated chiral
reductions of prochiral ketones. During this study they
reported that the reduction of acetophenone with
BH3·THF in the presence of (S)-2-anilinomethylpyrro-
lidine 1 (10 mol%) provided the desired secondary
alcohol in 14% enantiomeric purity. With a view to
understanding the mechanism and examining other
applications of the NP(ꢀO)Cl framework we performed
the borane-mediated reduction of acetophenone in the
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