A novel and effective chiral phosphoramide catalyst for the borane-mediated asymmetric reduction of prochiral α-halo ketones

Article abstract of DOI:10.1016/S0957-4166(01)00101-X

The novel chiral phosphoramide, 1,4-bis[(5S)-1,3-diaza-2-phospha-2-oxo-3-phenylbicyclo(3.3.0)octan-2-yl] piperazine, was synthesised and successfully employed as a catalyst in the borane-mediated asymmetric reductions of prochiral α-halo ketones, providing the corresponding α-halo alcohols in 90-95% enantiomeric purities.

Full text of DOI:10.1016/S0957-4166(01)00101-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 685–689
A novel and effective chiral phosphoramide catalyst for the
borane-mediated asymmetric reduction of prochiral a-halo
ketones
Deevi Basavaiah,* Gone Jayapal Reddy and Vanampally Chandrashekar
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
Received 9 February 2001; accepted 28 February 2001
Abstract—The novel chiral phosphoramide, 1,4-bis[(5S)-1,3-diaza-2-phospha-2-oxo-3-phenylbicyclo(3.3.0)octan-2-yl]piperazine,
was synthesised and successfully employed as a catalyst in the borane-mediated asymmetric reductions of prochiral a-halo
ketones, providing the corresponding a-halo alcohols in 90–95% enantiomeric purities. © 2001 Elsevier Science Ltd. All rights
reserved.
1. Introduction
phosphinamide catalysts for highly enantioselective
borane-mediated asymmetric reductions.11–13
The asymmetric reduction of prochiral ketones to
provide secondary alcohols in high enantiomeric purity
is a fundamental reaction in chiral chemistry and the
applications of various borane-based chiral reducing
agents in this reaction have been well documented.1–4
After the ingenious utilisation of proline-based oxaza-
borolidines as catalysts by Corey, for the borane-medi-
ated enantioselective reductions of prochiral ketones, a
plethora of oxazaborolidines and related catalysts
based on various chiral pool sources have been devel-
oped and their applications have been well studied.2–8
Wills et al. recently introduced a novel class of catalysts
containing the N-PꢀO structural framework for the
borane-mediated asymmetric reductions of prochiral
ketones9–15 and they also developed interesting chiral
Recently, we turned our attention to chiral phosphor-
amides as part of our ongoing research program and in
this direction we have synthesised the novel chiral
phosphoramides 1 and 2 from (S)-2-anilinomethyl-
pyrrolidine. The elegant work of Wills9–15 on catalysts
containing the N-PꢀO structural framework prompted
us to examine the possible applications of catalysts 1
and 2 in borane-mediated asymmetric reductions.
Herein, we report the reductions of a-halo ketones
under the catalytic influence of 1,4-bis[(5S)-1,3-diaza-2-
phospha-2-oxo-3-phenylbicyclo(3.3.0)octan-2-yl]pipera-
zine 2, thus providing a convenient methodology for
synthesis of 2-halo-1-arylethanols in 90–95% enan-
tiomeric purities.
Scheme 1.
* Corresponding author. E-mail: dbsc@uohyd.ernet.in
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00101-X

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D. Basa6aiah et al. / Tetrahedron: Asymmetry 12 (2001) 685–689
2. Results and discussion
examined under various conditions. The best results
were obtained when the reduction was carried out using
30 mol% of catalyst 1 in refluxing toluene, providing
the desired alcohol (S)-2-chloro-1-phenylethanol 4a
with 82% e.e. and in 94% yield.
The chiral phosphoramide (1R,2R)-1,2-bis[{(5S)-1,3-
diaza-2-phospha-2-oxo-3-phenylbicyclo(3.3.0)octan-2-
yl}methylamino]cyclohexane 1 was synthesised by the
reaction of (5S)-1,3-diaza-2-phospha-2-oxo-2-chloro-3-
phenylbicyclo(3.3.0)octane (obtained from (S)-2-anili-
nomethylpyrrolidine, which, in turn, was synthesised
from inexpensive and commercially available (S)-glu-
tamic acid according to the known procedure16–18) with
(1R,2R)-1,2-di(methylamino)cyclohexane in 76% yield.
This route is shown in Scheme 1.
We also examined the borane–dimethyl sulphide-medi-
ated reduction of phenacyl chloride using catalytic
phosphoramide 2 in toluene. Encouraging results were
obtained when we carried out the reduction using 30
mol% of catalyst 2 in toluene, thus providing the
desired 2-chloro-1-phenylethanol 4a in 90% e.e. with
(S)-configuration in 91% yield. Similarly the stereose-
lective borane–dimethyl sulphide reduction of phenacyl
bromide 3b in toluene with catalysts 1 and 2 was
examined. These reactions afforded (S)-2-bromo-1-
phenylethanol 4b in 89% e.e. (88% yield) and 94% e.e.
(92% yield), respectively.
Similarly the chiral phosphoramide, 1,4-bis[(5S)-1,3-
diaza-2-phospha-2-oxo-3-phenylbicyclo(3.3.0)octan-2-
yl]piperazine 2, was prepared by the reaction of (5S)-
1,3-diaza-2-phospha-2-oxo-2-chloro-3-phenylbicyclo-
(3.3.0)octane with piperazine as shown in Eq. (1).
(1)
We first directed our studies towards the possible appli-
cation of (1R,2R)-1,2-bis[{(5S)-1,3-diaza-2-phospha-
2-oxo-3-phenylbicyclo(3.3.0)octan-2-yl}methylamino]cy-
clohexane 1 as a catalyst in the borane-mediated asym-
metric reductions of a-halo ketones. The reduction of
phenacyl chloride 3a by borane–dimethyl sulphide
under the catalytic influence of molecule 1 was first
Since the phosphoramide 2 offered better selectivities in
these initial reductions than the catalyst 1, we extended
its use to the reductions of various prochiral a-halo
ketones. These reactions afforded a-halo alcohols in
high 76–96% yields and excellent e.e.s of 90–95% (Eq.
(2), Table 1). Enantiomeric purities of the chiral alco-
hols 4a–4e were determined by HPLC analysis using
(2)
Table 1. Asymmetric reduction of a-halo ketonesa
Substrate
Ar
X
Catalyst (30 mol%)
Product
Yield (%)b
[h]2D5
Conf.c
E.e. (%)d
3a
3b
3a
3b
3c
3d
3e
3f
Phenyl
Phenyl
Phenyl
Phenyl
4-Methylphenyl
4-Ethylphenyl
4-Methylphenyl
4-Chlorophenyl
4-Bromophenyl
Cl
Br
Cl
Br
Cl
Cl
Br
Br
Br
1
1
2
2
2
2
2
2
2
4a
4b
4a
4b
4c
4d
4e
4f
94
88
91
92
96
84
83
90
76
+39.7 (c 2.25)e
+39.4 (c 2.0)f
+43.5 (c 2.4)e
+42.45 (c 2.0)f
+47.2 (c 1.1)f
+41.0 (c 1.0)f
+41.8 (c 1.0)f
+38.6 (c 1.15)f
+32.75 (c 1.3)f
S
S
S
S
82
89
90
94
92
92
95
91h
93h
Sg
Sg
Sg
Sg
S
3g
4g
a All reactions were carried out on 0.5 mM scale of a-halo ketone with 0.5 mM of BH3·SMe2 in the presence of 30 mol% catalyst in toluene for
90 min at 110°C.
b Yield 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.19,20
d Determined by HPLC analysis using the chiral column, Chiralcel-OD.
e
Specific rotations were obtained in cyclohexane.
Specific rotations were obtained in chloroform.
f
g Absolute configuration was tentatively assigned in analogy with 4a, 4b and 4g.
h Enantiomeric purity was determined by 1H NMR (200 MHz) analysis of the corresponding acetate in the presence of the chiral shift reagent,
Eu(hfc)3, with reference to the corresponding racemic acetate.

D. Basa6aiah et al. / Tetrahedron: Asymmetry 12 (2001) 685–689
687
Scheme 2.
the chiral column Chiralcel-OD with reference to
(200 MHz) and 13C NMR (50 MHz) spectra were
recorded in deuterochloroform (CDCl3) on a Bruker-
AC-200 spectrometer using tetramethylsilane (TMS,
l=0) as internal standard. 31P NMR (81 MHz) spectra
were recorded on a Bruker-AC-200 spectrometer using
85% H3PO4 (l=0 ppm) as external standard. Elemental
analyses were recorded on a Perkin–Elmer 240C-CHN
analyser. Liquid secondary ion mass spectrum of the
compound 1 was obtained using an Autospec-M
(Micromass, UK) mass spectrometer. Electrospray ioni-
sation mass spectrum (EIMS) of the compound 2 was
obtained using a Quattro-LC (Micromass, UK) mass
spectrometer. HPLC analyses of alcohols were carried
out on a Shimadzu LC-10AD instrument using the
chiral column, Chiralcel-OD. Optical rotations were
measured on a Jasco DIP 370 digital polarimeter. Start-
ing material (5S)-1,3-diaza-2-phospha-2-oxo-2-chloro-
3-phenylbicyclo(3.3.0)octane was prepared by the
reaction of (S)-2-anilinomethylpyrrolidine with POCl3
according to the literature procedure.18
racemic alcohols. Enantiomeric purities of alcohols 4f
1
and 4g were determined by H NMR spectral analysis
of the corresponding acetates in the presence of chiral
shift reagent, Eu(hfc)3, with reference to their racemic
acetates.
A possible mechanism of the asymmetric reduction
process is presented in Scheme 2. The first step of the
catalytic cycle might involve the coordination of the
phosphoramide oxygen to electron deficient boron,
thereby generating a partial negative charge on boron.
This renders the phosphoramide electron deficient,
allowing it to act as a Lewis acid for coordination to
the carbonyl functionality of the ketone. Subsequent
hydride transfer from borane to ketone would then lead
to the formation of an alkoxyborane, dissociation of
which would release the chiral phosphoramide for fur-
ther catalytic cycles (Scheme 2).
3. Conclusion
4.1. (1R,2R)-1,2-Bis[{(5S)-1,3-diaza-2-phospha-2-oxo-3-
phenylbicyclo(3.3.0)octan-2-yl}methylamino]cyclohexane 1
In conclusion, we have developed a new phosphor-
amide catalyst 1,4-bis[(5S)-1,3-diaza-2-phospha-2-oxo-
To a stirred solution of (5S)-1,3-diaza-2-phospha-2-
oxo-2-chloro-3-phenylbicyclo(3.3.0)octane (1.0 g, 3.92
mM) in CH2Cl2 (20 mL) were added triethylamine
(0.793 g, 7.84 mM) and (1R,2R)-1,2-di(methyl-
amino)cyclohexane (0.278 g, 1.96 mM) at room temper-
ature. After 20 h (monitored by TLC) the mixture was
diluted with water (10 mL). The organic layer was
separated and the aqueous layer extracted with CH2Cl2
(3×25 mL). The combined organic extract was washed
successively with water and brine and dried over anhy-
drous Na2SO4. The solvent was removed in vacuo and
the residue purified by column chromatography (silica
gel, 35% ethyl acetate in hexanes) to afford (1R,2R)-
3-phenylbicyclo(3.3.0)octan-2-yl]piperazine
2
for
borane-mediated reductions of prochiral a-halo
ketones, thus providing a simple methodology for the
highly enantioselective synthesis of a-halo alcohols.
4. Experimental
All melting points were recorded on a Superfit (India)
capillary melting point apparatus and are uncorrected.
IR spectra were recorded on a Jasco-FT-IR model 5300
1
or a Perkin–Elmer model 1310 spectrometer. H NMR

688
D. Basa6aiah et al. / Tetrahedron: Asymmetry 12 (2001) 685–689
1,2-bis[{(5S)-1,3-diaza-2-phospha-2-oxo-3-phenylbi-
determined by HPLC using a chiral column [Chiralcel-
OD, 95:5 hexanes:i-PrOH, 0.5 mL/min, 254 nm, reten-
tion times: 20.90 min (S) and 23.63 min (R)]; IR (neat):
3408 cm−1; 1H NMR: l 2.63 (d, 1H, J=3.0 Hz),
3.59–3.82 (m, 2H), 4.88–4.96 (m, 1H), 7.28–7.49 (m,
5H); 13C NMR: l 50.77, 74.11, 126.11, 128.45, 128.67,
140.10.
cyclo(3.3.0)octan-2-yl}methylamino]cyclohexane as
a
crystalline solid (0.863 g, 76%); mp 260–262°C; [h]2D5=
+35.0 (c 1.40, CHCl3); IR (KBr): 2934, 1601, 1502,
1
1305, 1215 cm−1; H NMR: l 1.12–2.19 (m, 16H), 2.30
(s, 3H), 2.35 (s, 3H), 2.75–3.03 (m, 2H), 3.30–3.51 (m,
2H), 3.54–4.04 (m, 8H), 6.92–7.39 (m, 10H); 13C NMR:
l 25.52, 26.00, 30.62, 32.47, 45.43, 48.88 (d, J=16.3
Hz), 55.66, 58.07 (d, J=8.0 Hz), 117.47 (d, J=3.4 Hz),
121.27, 128.68, 141.64 (d, J=5.7 Hz); 31P NMR: l
23.37; MS (FAB) (m/z): 583 (M+H)+. Anal. calcd for
C30H44N6O2P2: C, 61.84; H, 7.61; N, 14.42. Found: C,
61.75; H, 7.64; N, 14.52%.
4.4. (S)-2-Bromo-1-phenylethanol 4b
Colourless oil; yield: 92%; [h]2D5=+42.45 (c 2.0, CHCl3)
[Lit.19 [h]D25=−39 (c 8.00, CHCl3), (R)-configuration,
93% e.e.]; 94% e.e., the enantiomeric purity was deter-
mined by HPLC using a chiral column [Chiralcel-OD,
95:5 hexanes:i-PrOH, 0.5 mL/min, 254 nm, retention
times: 20.48 min (S) and 23.91 min (R)]; IR (neat):
3387 cm−1; 1H NMR: l 2.62 (d, 1H, J=3.8 Hz),
3.50–3.71 (m, 2H), 4.87–5.03 (m, 1H), 7.32–7.51 (m,
5H); 13C NMR: l 40.08, 73.84, 126.03, 128.47, 128.70,
140.43.
4.2. 1,4-Bis[(5S)-1,3-diaza-2-phospha-2-oxo-3-phenylbi-
cyclo(3.3.0)octan-2-yl]piperazine 2
Compound 2 was prepared by reaction of (5S)-1,3-
diaza - 2 - phospha - 2 - oxo - 2 - chloro - 3 - phenylbicyclo-
(3.3.0)octane (1 g, 3.92 mM) with piperazine (0.169 g,
1.96 mM) at room temperature for 20 h following the
procedure for (1R,2R)-1,2-bis[{(5S)-1,3-diaza-2-phos-
pha-2-oxo-3-phenylbicyclo(3.3.0)octan-2-yl}methylam-
ino]cyclohexane 1, as a crystalline solid (0.91 g, 88%)
(after purification by column chromatography, silica
gel, 1% methanol in ethyl acetate); mp 260°C (dec.);
[h]2D5=−59.4 (c 1.4, CHCl3); IR (KBr): 2957, 1602,
4.5. (S)-2-Chloro-1-(4-methylphenyl)ethanol 4c
Colourless oil; yield: 96%; [h]2D5=+47.2 (c 1.10, CHCl3);
92% e.e., the enantiomeric purity was determined by
HPLC using a chiral column [Chiralcel-OD, 95:5 hex-
anes:i-PrOH, 0.5 mL/min, 254 nm, retention times:
21.49 min (S) and 23.54 min (R)]; IR (neat): 3414 cm−1;
1H NMR: l 2.36 (s, 3H), 2.62 (b, 1H), 3.58–3.80 (m,
2H), 4.87 (1H, dd, J=8.2, 3.8 Hz), 7.19 (d, 2H, J=7.8
Hz), 7.28 (d, 2H, J=7.8 Hz); 13C NMR: l 21.14, 50.74,
73.94, 126.02, 129.32, 137.11, 138.20.
1
1500, 1300, 1224 cm−1; H NMR: l 1.51–2.12 (m, 8H),
2.73–3.85 (m, 18H), 6.83–7.29 (m, 10H); 13C NMR: l
26.06, 32.07, 44.37, 44.97, 48.86 (d, J=16.6 Hz), 57.88
(d, J=8.0 Hz), 116.23 (d, J=3.7 Hz), 121.04, 128.93,
141.57 (d, J=5.4 Hz); 31P NMR: l 20.51; MS (ES)
(m/z): 527 (M+H)+. Anal. calcd for C26H36N6O2P2: C,
59.30; H, 6.89; N, 15.96. Found: C, 59.42; H, 6.91; N,
15.85%.
4.6. (S)-2-Chloro-1-(4-ethylphenyl)ethanol 4d
Colourless oil; yield: 84%; [h]2D5=+41.0 (c 1.0, CHCl3);
92% e.e., the enantiomeric purity was determined by
HPLC using a chiral column [Chiralcel-OD, 95:5 hex-
anes:i-PrOH, 0.5 mL/min, 254 nm, retention times:
19.00 min (S) and 20.88 min (R)]; IR (neat): 3408 cm−1;
1H NMR: l 1.23 (t, 3H, J=7.8 Hz), 2.58–2.70 (m, 3H),
3.59–3.80 (m, 2H), 4.84–4.93 (m, 1H), 7.20 (d, 2H,
J=8.2 Hz), 7.30 (d, 2H, J=8.2 Hz); 13C NMR: l 15.48,
28.58, 50.76, 74.00, 126.11, 128.14, 137.35, 144.58.
4.3. General procedure for the asymmetric reduction of
phenacyl chloride: synthesis of (S)-2-chloro-1-phenyl-
ethanol 4a
1,4-Bis[(5S)-1,3-diaza-2-phospha-2-oxo-3-phenylbicy-
clo(3.3.0)octan-2-yl]piperazine 2 (0.15 mM, 79 mg) was
first dried by azeotropic drying with anhydrous toluene
(2×3 mL) under nitrogen. The phosphoramide was then
diluted with toluene (5 mL) and to this stirred solution
borane–dimethyl sulphide (0.5 mM, 38 mg) was added
and the reaction mixture heated to 110°C. Once the
temperature was stable at 110°C, phenacyl chloride (0.5
mM, 77 mg) in toluene (1 mL) was added dropwise.
After completion of the addition, the mixture was
stirred for a further 90 min (monitored by TLC). The
reaction mixture was allowed to cool to room tempera-
ture and quenched with saturated NH4Cl solution. The
organic layer was separated and the aqueous layer were
extracted with ether (3×10 mL). The combined organic
layers were dried over anhydrous Na2SO4, and the
solvent was removed under reduced pressure. The
residue was purified by column chromatography (silica
gel, 5% ethyl acetate in hexanes) to obtain the desired
(S)-2-chloro-1-phenylethanol 4a in 91% yield (71 mg),
as a colourless oil. [h]D25=+43.5 (c 2.4, cyclohexane)
[Lit.19 [h]2D5=−48.1 (c 1.73, cyclohexane), (R)-configura-
tion, 100% e.e.]; 90% e.e., the enantiomeric purity was
4.7. (S)-2-Bromo-1-(4-methylphenyl)ethanol 4e
Colourless oil; yield: 83%; [h]2D5=+41.8 (c 1.0, CHCl3);
95% e.e., the enantiomeric purity was determined by
HPLC using a chiral column [Chiralcel-OD, 95:5 hex-
anes:i-PrOH, 0.5 mL/min, 254 nm, retention times:
26.05 min (S) and 28.58 min (R)]; IR (neat): 3375 cm−1;
1H NMR: l 2.35 (s, 3H), 2.54 (b, 1H), 3.49–3.68 (m,
2H), 4.90 (1H, dd, J=8.6, 3.8 Hz), 7.18 (d, 2H, J=8.0
Hz), 7.27 (d, 2H, J=8.0 Hz); 13C NMR: l 21.19, 40.14,
73.70, 125.93, 129.36, 137.46, 138.25.
4.8. (S)-2-Bromo-1-(4-chlorophenyl)ethanol 4f
Colourless oil; yield: 90%; [h]2D5=+38.6 (c 1.15,
CHCl3); 91% e.e., the enantiomeric purity was deter-
1
mined by H NMR spectral analysis of the correspond-
ing acetate in the presence of the chiral shift reagent,

D. Basa6aiah et al. / Tetrahedron: Asymmetry 12 (2001) 685–689
689
Eu(hfc)3, with reference to the racemic acetate; IR
Acknowledgements
1
(neat): 3242 cm−1; H NMR: l 2.64 (bs, 1H), 3.43–3.68
(m, 2H), 4.91 (1H, dd, J=8.6, 3.6 Hz), 7.22–7.47 (m,
4H); 13C NMR: l 39.64, 73.05, 127.39, 128.81, 134.15,
138.86.
We thank the CSIR (New Delhi) for funding this
research project. We thank the UGC (New Delhi) for
Special Assistance Program in Organic Chemistry in the
School of Chemistry, University of Hyderabad, Hyder-
abad. G.J.R. and V.C. thank the CSIR (New Delhi) for
their research fellowships.
4.9. (S)-2-Bromo-1-(4-bromophenyl)ethanol 4g
White solid; yield: 76%; mp: 70–72°C; [h]2D5=+32.75 (c
1.3, CHCl3) [Lit.20 [h]D25=−31 (c 2.9, CHCl3), R-con-
figuration, 94% e.e.]; 93% e.e., the enantiomeric purity
1
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mL) and the reaction mixture was extracted with ether
(3×20 mL). The combined organic layers were washed
successively with aqueous 5% HCl and 10% sodium
bicarbonate solution and the organic layer was dried
over anhydrous Na2SO4. The solvent was removed
under reduced pressure and the residue obtained was
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acetate in hexanes) to provide the desired (S)-1-acet-
oxy-2-bromo-1-(4-bromophenyl)ethane (76 mg) in 70%
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1
(neat): 1743 cm−1; H NMR: l 2.13 (s, 3H), 3.50–3.69
(m, 2H), 5.86–5.98 (m, 1H), 7.23 (d, 2H, J=8.4 Hz),
7.51 (d, 2H, J=8.4 Hz); 13C NMR: l 20.95, 33.83,
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4.11. (S)-1-Acetoxy-2-bromo-1-(4-chlorophenyl)ethane
Colourless oil; yield: 80%; [h]2D5=+54.1 (c 1.35, CHCl3);
18. Peyronel, J. F.; Samuel, O.; Fiaud, J. C. J. Org. Chem.
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1
IR (neat): 1745 cm−1; H NMR: l 2.13 (s, 3H), 3.53–
3.69 (m, 2H), 5.90–5.99 (m, 1H), 7.23–7.40 (m, 4H); 13
C
NMR: l 20.89, 33.88, 74.10, 128.06, 128.93, 134.73,
136.22, 169.69.
20. Hiratake, J.; Inagaki, M.; Nishioka, T.; Oda, J. J. Org.
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.
.