A practical synthesis of syn- and anti-α,β-dihydroxyphosphinates via diastereoselective reduction of α-phosphinoyl ketones

Article abstract of DOI:10.1016/j.tetasy.2007.12.016

Reduction of β-keto-diphenylphosphine oxide (S)-4 derived from (S)-mandelic acid with NaBH₄ in methanol at -78 °C gave the anti-3-diphenylphosphinoyl-1,2-diol 6, whereas the reduction of (S)-4 with Zn(BH₄)₂ in THF at -78 °C afforded the syn-1,2-diol 5, both in high yield and excellent diastereoselectivity. This procedure represents a new approach to the diastereoselective synthesis of diphenylphosphinoyl diols and an example of highly diastereoselective 1,2-induction. A theoretical model to explain the direction and degree of asymmetric induction is proposed.

Full text of DOI:10.1016/j.tetasy.2007.12.016

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 161–166
A practical synthesis of syn- and anti-a,b-dihydroxyphosphinates
via diastereoselective reduction of a-phosphinoyl ketones
´
´
´
ˆ
Haydee Rojas-Cabrera, Julio M. Hernandez-Perez, Minhhuy Ho,
*
´
´
´
Eugenio Hernandez-Fernandez and Mario Ordonez
˜
Centro de Investigaciones Quı´micas, Universidad Auto´noma del Estado de Morelos, Av. Universidad No. 1001,
62009 Cuernavaca, Morelos, Mexico
Received 15 August 2007; accepted 19 December 2007
Abstract—Reduction of b-keto-diphenylphosphine oxide (S)-4 derived from (S)-mandelic acid with NaBH4 in methanol at À78 °C gave
the anti-3-diphenylphosphinoyl-1,2-diol 6, whereas the reduction of (S)-4 with Zn(BH4)2 in THF at À78 °C afforded the syn-1,2-diol 5,
both in high yield and excellent diastereoselectivity. This procedure represents a new approach to the diastereoselective synthesis of
diphenylphosphinoyl diols and an example of highly diastereoselective 1,2-induction. A theoretical model to explain the direction and
degree of asymmetric induction is proposed.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
and phosphine oxides, respectively.2,5 Herein, we report a
new methodology for the synthesis of syn- and anti-diphenyl-
phosphinoyl-1-phenyl propane-1,2-diols, which involved
the diastereoselective reduction of b-keto-diphenylphos-
phine oxide 4 derived from (S)-mandelic acid.8
Dihydroxyalkylphosphonates of type 1 and their deriva-
tives have attracted considerable attention in recent years
for their role in biologically relevant processes such as
the inhibition of imidazole glycerol phosphate (IGP).1
Additionally, dihydroxyphosphonates 1 have been used
in the stereoselective synthesis of c-amino-b-hydrox-
yphosphonates,2 which are key precursors for the prepara-
tion of phosphostatine and analogues.3 Diphenyl-
phosphinoyl diols 2 have also been established as useful
intermediates in the synthesis of enantiomerically pure
c-hydroxy vinyl phosphine oxides,4 allylic alcohols,5 cyclo-
propyl ketones,6 and as ligands.7
2. Results and discussion
The starting chiral b-keto-diphenylphosphine oxide (S)-4
was readily prepared from (S)-mandelic acid (Scheme 1).
O
O
Ph
Ph
1. SOCl2, MeOH
OH
OMe
O
O
OH
OH
2. TBSCl, imidazole
DMF, rt
OH
(S)-Mandelic acid
OTBS
R
P(OR')2
PPh2
R
3
88%
OH
OH
O
2
1
CH3PPh2, n-BuLi
THF, -78 oC
75%
Synthesis of optically active dihydroxy phosphonates syn-1
and diphenylphosphinoyl diols syn-2 has been achieved by
asymmetric dihydroxylation of the allylic phosphonates
O
O
PPh2
Ph
OTBS
(S)-4
*
Corresponding author. Tel./fax: +52 (777) 329 79 97; e-mail: palacios@
ciq.uaem.mx
Scheme 1.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.12.016

162
H. Rojas-Cabrera et al. / Tetrahedron: Asymmetry 19 (2008) 161–166
Esterification of (S)-mandelic acid with thionyl chloride in
methanol, followed by treatment with tert-butyldimethyl-
silyl chloride (TBSCl) in the presence of imidazole afforded
the corresponding methyl ester derivative (S)-3 in 88%
yield.9 Next, reaction of methyl ester (S)-3 with the lithium
salt of methyl diphenylphosphine oxide at À78 °C in THF
gave the b-keto-diphenylphosphine oxide (S)-4 in 75%
yield (Scheme 1).
afforded the b-hydroxy derivatives syn-5 and anti-6 with
good chemical yield and excellent diastereoselectivity with
a predominance of the desired diastereoisomer syn-5 (Table
1, entry 6).
To unequivocally establish the configuration of the new
stereogenic center of diphenylphosphinoyl-1-phenylpro-
pane-1,2-diols syn-5 and anti-6, these were first trans-
formed into the corresponding dioxolanes anti-9 and syn-
10, respectively. Treatment of diastereoisomerically pure
syn-5 and anti-6 with n-tetrabutylammonium fluoride
(TBAF) in THF at 0 °C afforded the diols syn-7 and anti-
8 with 80% and 90% yield, respectively. Finally, reaction
of diol syn-7 with 2,2-dimethoxypropane in the presence
of p-toluenesulfonic acid (PTSA) in acetonitrile gave the
acetonide anti-9 with 84% yield. In a similar manner,
anti-8 gave the acetonide syn-10 with 84% yield (Scheme 2).
The b-keto-diphenylphosphine oxide (S)-4 was reduced
using NaBH4, DIBAL-H, catecholborane (CB), LiBH4,
and Zn(BH4)2, to obtain the syn-5 and anti-6 diphenyl-
phosphinoyl-1-phenylpropane-1,2-diols. Conditions,yields,
and diastereoisomeric ratios are summarized in Table 1.
Table 1. Reduction of (S)-4 with various reducing agents
O
O
OH
OH
-
H:
PPh2
PPh2
Ph
Ph
+
(S)-4
O
OH
O
OH
PPh2
OTBS
OTBS
Ph
PPh2
Ph
syn-5
anti-6
OTBS
syn-5
OTBS
anti-6
Entry
Conditions
NaBH4, MeOH, 0 °C
Yield (%)
syn-5:anti-6
1
2
3
4
5
6
99
95
99
90
92
90
35:65
05:95
50:50a
63:37
74:26
96:04
Bu4NF
THF, 0˚C
Bu4NF
THF, 0˚C
80%
NaBH4, MeOH, À78 °C
DIBAL-H, THF, À78 °C
CB, THF, À78 °C
90%
O
O
OH
OH
LiBH4, THF, À78 °C
Zn(BH4)2, THF, À78 °C
PPh2
PPh2
Ph
Ph
a Unprotected products syn-7 and anti-8 were obtained under these
OH
syn-7
OH
anti-8
conditions.
MeO OMe
MeO OMe
84%
84%
The reduction of b-keto-diphenylphosphine oxide (S)-4
with NaBH4 in methanol at 0 °C afforded the correspond-
ing hydroxy derivatives syn-5 and anti-6 with high yield
and diastereoisomeric ratio 35:65 in the favor of diastereo-
isomer anti-6 (Table 1, entry 1). A better diastereoselectiv-
ity was achieved when the reduction was carried out at
À78 °C, when the hydroxy derivatives syn-5 and anti-6
were obtained in 95% yield and diastereoisomeric ratio of
5:95 (Table 1, entry 2). The diastereoisomeric ratio of the
reduction of (S)-4 was determinated by means of 31P
NMR, with a chemical shift for the diastereoisomer syn-5
at 36.25 ppm and for diastereoisomer anti-6 at 36.60 ppm.
PTSA, CH3CN
O
PTSA, CH3CN
H
H
PPh2
H
Ph
H
PPh2
Ph
O
O
O
O
O
anti-9
syn-10
Scheme 2.
1
To obtain the diastereoisomer syn-5 as the principal prod-
uct, we carried out the reduction of (S)-4 using different
reducing agents. Thus, the reduction of (S)-4 with DI-
BAL-H in THF at À78 °C gave syn-5 and anti-6 in quanti-
tative yield but with a poor diastereoselectivity (Table 1,
entry 3), additionally under these conditions cleavage of
the silyl ether also occurred.
The H NMR spectra of anti-8 and syn-10 show that the
vicinal coupling constants for protons at C2 and C3 are
8.0 and 6.4 Hz, respectively, confirming the relative stereo-
chemistry between these protons.10 Additionally, the abso-
lute configuration at C-2 for the acetonide anti-9 was
confirmed by X-ray crystal structure analysis (Fig. 1).11
Therefore, if the reduction of (S)-4 with NaBH4 indeed
took place under non-chelation control or a Felkin–Anh
model,12 where the OTBS (largest group) is perpendicular
to the plane of the carbonyl group and phenyl (medium
group) is gauche, then the approach of hydride should be
close to the hydrogen (smallest group) or Si face, yielding
diastereoisomer syn-5 (Fig. 2). However, experimental data
show that diastereoisomer anti-6 is preferentially obtained
under these conditions.
On the other hand, reduction of (S)-4 with catecholborane
in THF at À78 °C led to syn-5 and anti-6 with good chem-
ical yield and 63:37 diastereoisomeric ratio in favor of syn-5
(Table 1, entry 4). When LiBH4 was used at À78 °C the
corresponding b-hydroxy derivatives were obtained with
similar yield and moderate diastereoselectivity in favor of
syn-5 (Table 1, entry 5). Finally, the reduction of (S)-4 with
Zn(BH4)2 (obtained from LiBH4 and ZnCl2) at À78 °C

H. Rojas-Cabrera et al. / Tetrahedron: Asymmetry 19 (2008) 161–166
163
to the carbonyl plane. However, the smallest functional
group (H) finds itself in the gauche position with respect
to the carbonyl moiety (Fig. 3). The Felkin–Anh model, in-
stead, suggests that the phenyl group to be in this position.
Since the calculated energy difference among the three
geometries was only around 1 kcal/mol, even though the
reaction was carried out at a rather low temperature, all
three conformations are accessible thermally to the
molecule.
O
O
O
H
H
Ph
O
O
Ph
TBSO
2
Ph
PPh2
Ph
3
OTBS
H
OTBS
PPh2
PPh2
PPh2
O
OTBS
H
O
O
(S)-4
A
B
C
Figure 3. Stable conformers of (S)-4 obtained when the O–C(2)–C(3)–H
Figure 1. X-ray structure for the acetonide anti-9.
dihedral is varied.
Table 2 also shows that conformers B and C have larger
dipolar moment than conformer A, which suggests that
the former two should constitute a larger proportion in a
polar solvent such as methanol. Furthermore, upon exam-
ination of the orbital coefficients of the three conformers,
we observe that in the LUMO, which according to Fron-
tier Orbital Theory is prone to nucleophilic attack, con-
formers B and C show a noticeable contribution from
the carbonylic carbon, while conformer A shows only a
negligible contribution from the carbon atom (Fig. 4).
Thus, by adopting the gauche position for the phenyl
group as suggested by the Felkin–Anh model, conformer
A in fact provides a less than ideal condition for hydride
attack.
O
OH
O
Ph
H-
H
PPh2
PPh2
si
Ph
TBSO
OTBS
syn-5
O
(minor product)
Figure 2. Felkin–Anh model for the reduction of (S)-4 with NaBH4.
A molecular orbital model is proposed to explain the ste-
reochemical outcome in the reduction of (S)-4 with NaBH4
in methanol. We first explored the stability of the confor-
mations of (S)-4 by varying the positions of the relevant
OTBS, the phenyl, and the hydrogen groups. This potential
energy surface of (S)-4 was explored by ab initio calcula-
tions where the O–C(2)–C(3)–H dihedral angle was rotated
at 10° increments.
These analyses bode well for the model in which (S)-4 re-
acts with NaBH4 preferably with the H group being
eclipsed to the carbonyl group, which leads to the forma-
tion of diastereoisomer anti-6 (Fig. 5).
Initial results show two conformations with lowest energy,
A and B. These were then used as starting geometries for
further full optimization (all calculations were done at
the B3LYP/6-31G* level using the G98 suite of program.13
Stationary points were confirmed by frequency character-
ization). For the lower energy conformation B, we also var-
ied the orientation of the OTBS group and further
optimization yielded conformation C. The results are
shown in Table 2.
For the reduction of (S)-4 with Zn(BH4)2 at À78 °C in
THF we propose that it took place under chelation control,
whereby the Zn(BH4)2 coordinates with both oxygen of the
carbonyl and the phosphinoyl groups, and hydride transfer
takes place intramolecularly in a more rigid structure (Si
face), obtaining the diastereoisomer syn-5 as the major
product (Fig. 6), as suggested by Oishi and Nakata.14
Table 2. Dihedral angle, energy difference (E(B) = 0.0) and dipolar
moment of stable conformers of (S)-4
3. Conclusion
Conformer
A
B
C
In conclusion, we have found a new methodology for the
preparation of anti- and syn-3-diphenylphosphinoyl-1,2-
diols with excellent diastereoselectivity via the reduction
of b-keto-diphenylphosphine oxide (S)-4 with NaBH4
and Zn(BH4)2, respectively. This procedure represents an
example of highly diastereoselective 1,2-induction. Theo-
retical analysis suggests that the nucleophilic attack takes
place preferably when the H group is gauche to the car-
bonyl group contrary to a Felkin–Anh model.
Dihedral angle
DE (kcal/mol)
Dipole (D)
104.963
1.00
2.9772
22.19
0.00
3.7451
22.67
1.26
4.2928
Among the three most stable conformations obtained when
the O–C(2)–C(3)–H dihedral is varied, we note that in con-
formers B and C, the OTBS group is almost perpendicular

164
H. Rojas-Cabrera et al. / Tetrahedron: Asymmetry 19 (2008) 161–166
Figure 4. LUMO orbitals of stable conformers of (S)-4.
with ethyl acetate (2 Â 60 mL). The combined organic ex-
tracts were dried over Na2SO4 and evaporated under re-
duced pressure. The crude product was purified by
column chromatography (hexane–ethyl acetate 2:1) to af-
ford 620 mg (75%) of (S)-4 as a colorless oil. [a]D =
+20.9 (c 2.5, CHCl3). 1H NMR (400 MHz, CDCl3): d
À0.08 (s, 3H, CH3Si), 0.03 (s, 3H, CH3Si), 0.87 (s, 9H,
(CH3)3CSi), 3.65 (dd, Jgem = JH/P = 15.2 Hz, 1H, CH2P),
3.73 (dd, Jgem = 15.2, JH/P = 13.4 Hz, 1H, CH2P), 5.27 (s,
1H, CHCO), 7.29–7.70 (m, 15H, Harom). 13C NMR
(100 MHz, CDCl3): d À4.72 (CH3Si), 0.26 (CH3Si), 18.5
(C(CH3)3), 26.0 ((CH3)3C), 40.2 (d, J = 62.2 Hz, CH2P),
81.7 (CHPh), 126.8, 128.4, 128.6 (d, J = 4.6 Hz), 128.7
(d, J = 4.6 Hz), 128.8, 131.0 (d, J = 9.1 Hz), 131.2 (d,
J = 9.1 Hz), 132.0, 137.8 (CO). 31P NMR (81 MHz,
CDCl3) d 28.32. HRMS (FAB+) Calcd for C27H34O3PSi
(MH+) 465.2015; found 465.2021.
O
OH
O
H
re
H-
Ph
PPh2
Ph
OTBS
PPh2
OTBS
anti-6
O
(major product)
Figure 5. Model for the reduction of (S)-4 with NaBH4.
H
H B
H
O
OH
H
Zn
H
PPh2
Ph
B H
H
H
O
Ph
O
Ph2P
OTBS
syn-5
(major product)
H
si
TBSO
Figure 6. Suggested mechanism for the reduction of (S)-4 with Zn(BH4)2.
4.2. Reduction of (S)-4
4. Experimental
4.2.1. Reduction with NaBH4 at 0 °C in MeOH. To a solu-
tion of (S)-4 (500 mg, 1.1 mmol) in methanol (40 mL)
sodium borohydride (203 mg, 5.4 mmol) was slowly added
at 0 °C. After 6 h the solvent was evaporated. The residue
was diluted with H2O and extracted with ethyl acetate
(3 Â 30 mL). The organic layer was dried over Na2SO4
and concentrated under reduced pressure to yield 500 mg
(99%) of syn-5 and anti-6 in a ratio 35:65, respectively.
Optical rotations were taken at 20 °C on a Perkin–Elmer
241 polarimeter in a 1 dm tube; concentrations are given
in g/100 mL. For the flash chromatography, silica gel 60
(230–400 mesh ASTM, Merck) was used. 1H NMR spectra
were registered on a Varian INOVA 400 (400 MHz), 13C
NMR (100 MHz) and 31P NMR on a Varian Mercury
200 (81 MHz). The spectra were recorded in CDCl3 solu-
tion using TMS as internal reference. Flasks, stirrings bars
and hypodermic needles used for the generation of organo-
metallic compounds were dried for ca. 12 h at 120 °C and
allowed to cool in a dessicator over anhydrous CaSO4.
Anhydrous solvents (ethers) were obtained by distillation
from benzophenone ketyl. HRMS spectra were recorded
on a JEOL JMS-700.
4.2.2. Reduction with NaBH4 at À78 °C in MeOH. To a
solution of (S)-4 (500 mg, 1.1 mmol) in methanol (40 mL)
sodium borohydride (203 mg, 5.4 mmol) was slowly added
at À78 °C. After 6 h the solvent was evaporated. The resi-
due was diluted with H2O and extracted with ethyl acetate
(3 Â 30 mL). The organic layer was dried over Na2SO4 and
concentrated under reduced pressure to yield 500 mg (99%)
of anti-6 and syn-5 in a ratio 95:5, respectively. The crude
product was purified by column chromatography (hex-
ane–ethyl acetate 1:1) obtaining 465 mg (93%) of anti-6
as a white solid.
4.1. (S)-1-[(tert-Butyldimethylsilyl)oxy]-3-(diphenylphos-
phinoyl)-1-phenylpropan-2-one (S)-4
To a solution of methyl diphenylphosphine oxide (690 mg,
3.2 mmol) in anhydrous THF (100 mL), n-BuLi 2.5 M in
hexanes (220 mg, 1.35 mL, 3.4 mmol) was added at
À78 °C. After 1 h this solution was slowly added to a flask
containing (S)-3 (500 mg, 1.78 mmol) in THF (60 mL) at
À78 °C. The reaction mixture was stirred for 12 h before
the addition of a saturated solution of NH4Cl. The organic
layer was separated and the aqueous layer was extracted
4.2.2.1. (1S,2S)-1-[(tert-Butyldimethylsilyl)oxy]-3-(diphen-
ylphos-phinoyl)-1-phenylpropan-2-ol
anti-6. Mp
78–
1
80 °C, [a]D = +49.7 (c 4.0, CHCl3). H NMR (400 MHz,
CDCl3): d À0.10 (s, 3H, CH3Si), 0.10 (s, 3H, CH3Si),
0.91 (s, 9H, (CH3)3Si), 2.44 (d, J = 9.5 Hz, 1H, CH2P),
2.45 (dd, J = 9.5, 4.4 Hz, 1H, CH2P), 3.59 (s, 1H, OH),
4.03–4.16 (m, 1H CHOH), 4.76 (d, J = 4.4 Hz, 1H, CHPh)

H. Rojas-Cabrera et al. / Tetrahedron: Asymmetry 19 (2008) 161–166
165
7.18–7.70 (m, 15H, Harom). 13C NMR (100 MHz, CDCl3):
d À4.5 (CH3Si), À4.5 (CH3Si), 18.5 ((CH3)3CSi), 26.1
((CH3)3CSi), 30.6 (d, J = 72.7 Hz, CH2P), 72.5 (d, J =
4.0 Hz, CHOH), 78.1 (CHPh), 126.7, 127.5, 128.2, 128.8
(d, J = 11.7 Hz), 130.5 (d, J = 9.5 Hz), 130.9 (d, J = 9.1),
131.9 (d, J = 9.1 Hz), 132.0 (d, J = 9.1 Hz), 141.4. 31P
NMR (81 MHz, CDCl3): d 36.60. HRMS (FAB+) Calcd
for C27H36O3PSi (MH+) 467.2171; found 467.2174.
NMR (81 MHz, CDCl3): d 37.43 HRMS (CI+) Calcd for
C21H22O3P (MH+) 353.1307; found 353.1321.
4.4. (1S,2R)-3-(Diphenylphosphinoyl)-1-phenylpropane-1,2-
diol syn-7
The procedure is the same as for anti-6, using the diastereo-
isomer syn-5 as a starting material (900 mg, 1.93 mmol),
obtaining 544 mg (80%) of syn-7 as a white solid. [a]D =
1
4.2.3. Reduction with Zn(BH4)2. To a solution of (S)-4
(1.0 g, 2.2 mmol) in anhydrous THF (80 mL) freshly pre-
pared15 Zn(BH4)2 0.14 M (410 mg, 30 mL, 4.3 mmol) was
slowly added at À78 °C. The reaction mixture was stirred
for 7 h before the addition of a saturated solution of
NH4Cl, and extracted with ethyl acetate (3 Â 40 mL).
The combined organic layers were dried over Na2SO4
and evaporated under reduced pressure to yield 1.0 g
(99%) of syn-5 and anti-6 in a ratio of 96:4, respectively.
The crude product was purified by column chromatogra-
phy (hexane–ethyl acetate 1:2) obtaining 900 mg (90%) of
syn-5 as a white solid.
À1.8 (c 0.7, CHCl3): lit.10 [a]D = À1.8 (c 0.7, CHCl3). H
NMR (400 MHz, CDCl3): d 2.3 (ddd, J = 15.0, 8.6,
2.4 Hz, 1H, CH2P), 2.45 (ddd, J = 15.0, 12.0, 10.0 Hz,
1H, CH2P), 4.11–4.19 (m, 1H, CHOH), 3.76 (b, 2H,
OH), 4.60 (d, J = 6.0 Hz, 1H, CHPh), 7.25–7.65 (m, 15H,
Harom). 13C NMR (100 MHz, CDCl3): d 32.7 (d, J =
69.8 Hz, CH2P), 71.6 (d, J = 3.0 Hz, CHOH), 78.0 (d,
J = 13.7 Hz, CHPh), 127.3, 128.2, 128.6, 128.9 (d, J =
12.1 Hz), 130.6 (d, J = 9.2 Hz), 130.9 (d, J = 9.1 Hz),
132.2, 140.0. 31P NMR (81 MHz, CDCl3): d 36.00. HRMS
(CI+) Calcd for C21H22O3P (MH+) 353.1307; found
353.1270.
4.2.3.1. (1S,2R)-1-[(tert-Butyldimethylsilyl)oxy]-3-(diphen-
140–
4.5. (4S,5S)-2,2-Dimethyl-4-phenyl-5-(diphenylphosphinoyl
methyl)-1,3-dioxolane syn-10
ylphos-phinoyl)-1-phenylpropan-2-ol
syn-5. Mp
1
142 °C, [a]D = +33.4 (c 2.5, CHCl3). H NMR (400 MHz,
CDCl3): d 0.08 (s, 3H, CH3Si), 0.14 (s, 3H, CH3Si), 0.97
(s, 9H, (CH3)3CSi), 2.13 (ddd, J = 15.0, 4.1 Hz, 1H,
CH2P), 2.56 (ddd, J = 15.0, 8.3, 1.6 Hz, 1H, CH2P), 4.27
(s, 1H, OH), 4.28–4.34 (m, 1H, CHOH), 4.93 (d, J =
4.8 Hz, 1H, CHPh), 7.40–7.88 (m, 15H, Harom). 13C
NMR (100 MHz, CDCl3): d À5.0 (CH3Si), À4.7 (CH3Si),
18.3 ((CH3)3CSi), 25.9 ((CH3)3CSi), 30.8 (d, J = 71.3 Hz,
CH2P), 71.4 (d, J = 4.6 Hz, CHOH), 76.7 (d, J =
13.7 Hz, CHPh), 127.4, 127.7, 128.0, 128.8 (d, J =
9.1 Hz), 128.9 (d, J = 10.6 Hz), 130.6 (d, J = 10.7 Hz),
131.2 (d, J = 9.1 Hz), 140.1. 31P NMR (81 MHz, CDCl3):
d 36.25. HRMS (FAB+) Calcd for C27H36O3PSi (MH+)
467.2171; found 467.2162.
To a solution of anti-8 (500 mg, 1.42 mmol) in acetonitrile
(30 mL) p-toluenesulfonic acid (81 mg, 0.42 mmol) and 2,2-
dimethoxypropane (295 mg, 0.35 mL, 2.8 mmol) were
added at room temperature. After 12 h, triethylamine
(43 mg, 0.1 mL, 0.42 mmol) was added. The volatiles were
eliminated under reduced pressure and the residue was
purified by column chromatography (ethyl acetate–hexane
1:1) to afford 466 mg (84%) of syn-10 as a white solid. Mp
137–139 °C. [a]D = +66.6 (c 1.5, CHCl3). 1H NMR
(400 MHz, CDCl3): d 1.32 (s, 3H, CH3), 1.33 (s, 3H,
CH3), 1.85 (ddd, J = 15.4, 3.0 Hz, 1H, CH2P), 2.19 (ddd,
J = 15.4, 9.4, 5.8 Hz, 1H, CH2P), 4.89–4.96 (m, 1H,
CHCH2P), 5.29 (d, J = 6.4 Hz, CHPh), 7.28–7.75 (m,
15H, Harom). 13C NMR (100 MHz, CDCl3): d 25.1
(CH3), 27.2 (CH3), 33.0 (d, J = 71.3 Hz, CH2P), 73.5 (d,
J = 4.5 Hz, CHCH2P), 80.2 (d, J = 10.6 Hz, CHPh),
108.8 (C(CH3)2), 126.9, 128.1, 128.2 (d, J = 12.1 Hz),
128.5 (d, J = 12.1 Hz), 128.6, 130.7 (d, J = 9.1 Hz), 131.4
(d, J = 10.6 Hz), 131.6 (d, J = 12.1 Hz), 137.4. 31P NMR
(81 MHz, CDCl3): d 31.56. HRMS (FAB+) Calcd for
C24H26O3P (MH+) 393.1620; found 393.1633.
4.3. (1S,2S)-3-(Diphenylphosphinoyl)-1-phenylpropane-1,2-
diol anti-8
To a solution of anti-6 (800 mg, 1.7 mmol) in anhydrous
THF (40 mL) n-tetrabutylammonium fluoride 1.0 M
(896 mg, 3.4 mL, 3.4 mmol) was added at 0 °C. The reac-
tion mixture was stirred for 4 h before the addition of a sat-
urated solution of NH4Cl. The organic layer was separated
and the aqueous layer was extracted with ethyl acetate
(3 Â 25 mL). The combined organic extracts were dried
over Na2SO4 and evaporated under reduced pressure.
The crude product was purified by column chromatogra-
phy (ethyl acetate–hexane 3:1) to afford 544 mg (90%) of
anti-8 as a white solid. Mp 164–165 °C, [a]D = +45.7 (c
4.6. (4S,5R)-2,2-Dimethyl-4-phenyl-5-(diphenylphosphinoyl
methyl)-1,3-dioxolane anti-9
The procedure is the same as for syn-10, using the diaste-
reoisomer syn-7 as starting material, obtaining 466 mg
(84%) of anti-9 as a white solid. Mp 144–145 °C.
1
1
2.4, CHCl3). H NMR (400 MHz, CDCl3): d 2.19 (ddd,
[a]D = +5.5 (c 1.5, CHCl3). H NMR (400 MHz, CDCl3):
J = 15.4, 8.2, 1.8 Hz, 1H, CH2P), 2.57 (ddd, J = 15.4,
12.0, 10.4 Hz, 1H, CH2P), 4.19–4.25 (m, 1H, CHOH),
4.42 (s, 2H, OH), 4.93 (d, J = 2.8 Hz, 1H, CHPh), 7.28–
7.60 (m, 15H, Harom). 13C NMR (100 MHz, CDCl3): d
29.5 (d, J = 72.1 Hz, CH2P), 71.6 (d, J = 4.6 Hz, CHOH),
76.2 (d, J = 12.2 Hz, CHPh), 126.1, 127.5, 128.4, 128.7 (d,
J = 3.8 Hz), 128.8 (d, J = 3.0 Hz), 130.5 (d, J = 9.8 Hz),
130.9 (d, J = 9.1 Hz), 132.0 (d, J = 2.3 Hz), 140.0. 31P
d 1.36 (s, 3H, CH3), 1.42 (s, 3H, CH3), 2.52 (ddd,
J = 14.8, 2.8 Hz, 1H, CH2P), 2.65 (ddd, J = 14.8, 9.2 Hz,
1H, CH2P), 4.08–4.15 (m, 1H, CHCH2P), 4.76 (d,
J = 8.0 Hz, CHPh), 7.31–7.71 (m, 15H, Harom). 13C
NMR (100 MHz, CDCl3): d 27.1 (CH3), 27.3 (CH3), 32.5
(d, J = 71.3 Hz, CH2P), 77.8 (d, J = 5.3 Hz, CHCH2P),
84.2 (d, J = 12.9 Hz, CHPh), 109.6 (C(CH3)2), 127.1,
128.3 (d, J = 11.4 Hz), 128.6 (d, J = 12.1 Hz), 128.7,

166
H. Rojas-Cabrera et al. / Tetrahedron: Asymmetry 19 (2008) 161–166
8. For diastereoselective reduction of c-amino-b-ketophospho-
128.8, 130.9 (d, J = 9.1 Hz), 131.2 (d, J = 9.9 Hz), 131.8 (d,
J = 9.9 Hz), 136.4. 31P NMR (81 MHz, CDCl3): d 30.76.
HRMS (FAB+) Calcd for C24H26O3P (MH+) 393.1620;
found 393.1624.
´
nates, see: (a) Ordonez, M.; De la Cruz-Cordero, R.;
˜
´
´
Fernandez-Zertuche, M.; Munoz-Hernandez, M. A.; Gar-
´
cıa-Barradas, O. Tetrahedron: Asymmetry 2004, 15, 3035–
´
´
˜
3043; (b) Ordonez, M.; De la Cruz-Cordero, R.; Quinonez,
˜
´
C.; Gonzalez-Morales, A. Chem. Commun. 2004, 672–673; (c)
´
´
´
Ordonez, M.; Gonzalez-Morales, A.; Salazar-Fernandez, H.
˜
´
Tetrahedron: Asymmetry 2004, 15, 2719–2725; (d) Ordonez,
˜
Acknowledgments
´
M.; De la Cruz-Cordero, R.; Fernandez-Zertuche, M.;
´
Munoz-Hernandez, M. A. Tetrahedron: Asymmetry 2002,
13, 559–562.
˜
We gratefully acknowledge CONACYT-Mexico for finan-
cial support via Grant 41657-Q and 62271-Q and graduate
fellowship by H.R.C. (170296). We also thank the valuable
technical help of Victoria Labastida for carrying out all MS
9. (a) Huszthy, P.; Bradshaw, J. S.; Zhu, C. Y.; Izatt, R. M. J.
Org. Chem. 1991, 56, 3330–3336; (b) de Vries, E. F. J.; Brusse,
J.; van der Gen, A. J. Org. Chem. 1994, 59, 7133–7137; (c)
Kobayashi, Y.; Takemoto, Y.; Kamijo, T.; Harada, H.; Ito,
Y.; Terashima, S. Tetrahedron 1992, 48, 1853–1868.
10. 1H NMR spectrum for diol (S,R)-7 or syn-7 was identical to
that reported by Nelson, A. and Warren, S. See Ref. 5.
11. X-ray crystal data of anti-9 were collected at 298 K using a
Bruker APEX CCD instrument (Mo Ka radiation
´
spectra and M. A. Munoz-Hernandez for the X-ray crystal-
˜
lographic analysis.
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