6070 J . Org. Chem., Vol. 63, No. 17, 1998
Notes
N-(O,O-Dim eth ylp h osp h or yl)-(S)-r,r-d ip h en yl-2-p yr r o-
lid in em eth a n ol (2). Carbon tetrachloride (2.04 mL, 3.25 g,
21.1 mmol) was added dropwise to an ice-cold stirred solution
of (S)-(+)-R,R-diphenyl-2-pyrrolidinemethanol (2.14 g, 8.45 mmol),
dimethyl phosphite (930 mL, 1.12 g, 10.1 mmol), and triethyl-
amine (1.41 mL, 1.03 g, 10.1 mmol) in anhydrous CH2Cl2 (20
mL). The resulting solution was allowed to slowly warm to room
temperature and then stirred for a further 10 h. After this
period, the reaction was quenched with water and the organic
layer separated. The aqueous layer was extracted with CH2-
Cl2, the combined organic layers were washed with saturated
NH4Cl, water, and then brine and dried (MgSO4), and the solvent
was removed in vacuo. The resulting solid was recrystallized
from n-hexane-CH2Cl2 (4:1) to give 2 (2.13 g, 76%) as a white
solid: mp 118-120 °C (from n-hexane-CH2Cl2); [R]D -61.6 (c
0.5, CH2Cl2); υmax/cm-1 3405 (OH), 1233 (PdO); 1H NMR (250
MHz; CDCl3) δ 1.02-1.17 (1H, m), 1.46-1.63 (1H, m), 2.58-
2.70 (1H, m), 3.06-3.18 (1H, m), 3.58 (3H, d, J ) 11.0 Hz), 3.66
(3H, d, J ) 11.0 Hz), 4.72 (1H, dt, J ) 5.2, 8.4 Hz), 5.69 (1H, bs,
exchangeable), 7.20-7.33 (6H, m), 7.40-7.51 (4H, m); 13C NMR
(62.9 MHz; CDCl3) δ 24.9 (d, J ) 5.9 Hz), 30.8 (d, J ) 7.9 Hz),
53.1 (d, J ) 5.9 Hz), 67.6 (d, J ) 4.9 Hz), 80.5, 126.8, 126.9,
127.2, 127.4, 127.7, 128.1, 143.7, 146.1; m/z (CI) 344 (M+ - OH,
100), 183 (98); 31P NMR (162 MHz; CDCl3) δ 15.2. Anal. Calcd
for C19H24NO4P: C, 63.15; H, 6.69; N, 3.88. Found: C, 63.1; H,
6.7; N, 3.9.
N -(Di-p -An isylp h osp h or yl)-(S)-r,r-d ip h e n yl-2-p yr r o-
lid in em eth a n ol (1). p-Anisylmagnesium bromide 2 M in THF
(12.8 mL, 25.6 mmol) was added dropwise to a stirred solution
of N-(O,O-dimethylphosphoryl)-(S)-R,R-diphenyl-2-pyrrolidine-
methanol (2) (2.10 g, 5.81 mmol) in anhydrous THF (50 mL) at
-78 °C under a nitrogen atmosphere. The resulting mixture
was allowed to slowly warm to room temperature over a 3 h
period and then heated at 60 °C for a further 90 min whereupon
the reaction was complete as assayed by thin-layer chromatog-
raphy. The solution was allowed to cool to room temperature
and diluted with water and the THF removed in vacuo. The
residue was acidified with saturated NH4Cl and the aqueous
phase extracted with EtOAc. The combined organic layers were
washed with water and brine and dried (MgSO4), and the solvent
removed in vacuo. The residue was purified by column chro-
matography using EtOAc-CH2Cl2-NEt3 (2:98:0.1) and then
EtOAc-CH2Cl2-NEt3 (5:95:0.1) as the eluants. This gave 1
(2.09 g, 70%) as a white solid that was further purified by
recrystallization from n-hexane-CH2Cl2 (4:1). This gave the
pure product as white solid: mp 169-172 °C (from n-hexane-
CH2Cl2); [R]D -66.6 (c 0.5, CH2Cl2); υmax/cm-1 3230 (OH), 1255
(PdO); 1H NMR (250 MHz; CDCl3) δ 1.06-1.18 (1H, m), 1.25-
1.42 (1H, m), 1.69 (1H, bs, exchangeable), 2.00-2.11 (2H, m),
2.33 (1H, ddd, J ) 7.5, 10.3, 15.6 Hz), 2.64-2.94 (1H, m), 3.84
(3H, s), 3.88 (3H, s), 4.73 (1H, dt, J ) 5.5, 8.3 Hz), 6.87-7.02
(4H, m), 7.21-7.70 (14H, m); 13C NMR (62.9 MHz; CDCl3) δ 24.8
(d, J ) 4.9 Hz), 31.0 (d, J ) 4.9 Hz) 49.8 (d, J ) 4.9 Hz), 55.2,
67.2, 80.0, 113.8 (d, J ) 13.8 Hz), 114.1, 120.9, 121.9, 122.9,
124.0, 126.6, 126.8, 127.0, 127.7, 127.9, 128.7, 133.8 (d, J ) 10.8
Hz) 144.4, 146.1, 162.4 (d, J ) 2.0 Hz); m/z (CI) 514 (M + H+,
2), 236 (100); 31P NMR (162 MHz; CDCl3) δ 34.4. Anal. Calcd
for C31H32NO4P: C, 72.5; H, 6.28; N, 2.73. Found: C, 72.7; H,
6.3; N, 3.0.
F igu r e 3. Stereochemical control in the asymmetric reduc-
tion.
F igu r e 4. Oxazaphospholidine oxide catalysts.
ensures effective catalyst turnover.13a,b In the absence
of an effective turnover the slower uncatalyzed pathway
will dominate, resulting in lower overall yields and
enantioselectivity. An alternative explanation is that an
unproductive species, perhaps a dimer, predominates at
lower temperature.7
Oxazaphospholidine oxides have been reported to be
effective reagents for the asymmetric reduction of ketones
by borane.8 In view of the obvious similarity of these
reagents to our own, we investigated the synthesis and
reactivity of 21 and 22 (Figure 4).8b These were prepared
in a 7:1 diastereoisomeric mixture from the reaction
between diphenylprolinol and phenylphosphonic dichlo-
ride in 70% yield. The configuration of the phosphorus
atom in the major diastereoisomer 21 was confirmed by
single-crystal X-ray analysis.13 Using the individual
isomers 21 and 22, we found that the former was a
superior catalyst in terms of asymmetric induction, giving
a product of 95% ee in the acetophenone reduction (10
mol % catalyst) compared to 75% ee for the latter. In
contrast to 1 the best results for 21 and 22 were achieved
at room temperature in THF solvent. Furthermore, the
oxazaphospholidine oxides were not recoverable after the
reaction. Buono has suggested that these compounds are
ring-opened by cleavage of the P-O bond to give a
catalytic species analogous to 20 (the P-N bond is
retained), which is stable for the lifetime of the reaction
but decomposes upon quenching and workup. It is
therefore clear that the P-O bond cleavage must be
streospecific and that the configuration at the phosphorus
atom contributes to the asymmetric induction in some
manner.3e We are presently investigating modified cata-
lysts based on 1 that contain chiral phosphorus atoms
and that may therefore give improved enantioselectivi-
ties.
Sta n d a r d Op tim ized P r oced u r e for th e Ca ta lytic Asym -
m etr ic Red u ction of P r och ir a l Keton es w ith N-(Di-p-
a n isylp h osp h or yl)-(S)-r,r-d ip h en yl-2-p yr r olid in em et h a -
n ol (1). N-(Di-p-anisylphosphoryl)-(S)-R,R-diphenyl-2-pyrrol-
idinemethanol (1) (359 mg, 0.70 mmol) was azetroped in situ
under a nitrogen atmosphere with anhydrous toluene (3 × 4 mL).
The catalyst was then dissolved in anhydrous toluene (14 mL)
to which was added borane-methyl sulfide (2 M in toluene, 3.67
mL, 7.34 mmol), and the mixture was heated to 110 °C. At
approximately 80 °C, a white precipitate forms, which does not
affect the reduction. Once the temperature had stabilized at
110 °C, chloroacetophenone (1.08 g, 6.99 mmol) in anhydrous
toluene (14 mL) was added dropwise via a syringe pump at a
flow rate of 0.5 mL/min. Once all the ketone had been added,
stirring was continued for a further 20 min, whereupon the
reaction was complete as assayed by thin-layer chromatography.
The mixture was allowed to cool to room temperature and
quenched with water. This was acidified with saturated NH4-
In conclusion, we have demonstrated that phosphina-
mide 1 is a readily available, robust, versatile, and
recoverable reagent for the asymmetric catalysis of the
reduction of ketones by borane.
Exp er im en ta l Section
General reagents and conditions have been described in a
previous paper.14
(13) Alcock, N.; Gamble, M. P.; Wills, M. Unpublished results (see
the Supporting Information).
(14) Palmer, M.; Walsgrove, T.; Wills, M. J . Org. Chem. 1997, 62,
5226.