Diastereoselective synthesis of β-substituted α-hydroxyphosphinates through hydrophosphinylation of α-heteroatom-substituted aldehydes

Article abstract of DOI:10.1016/S0040-4020(02)01629-0

The diastereoselective synthesis of β-substituted α-hydroxyphosphinates was achieved by hydrophosphinylation of α-oxy aldehydes and α-amino aldehydes with ethyl allylphosphinate catalyzed by lithium phenoxide.

Full text of DOI:10.1016/S0040-4020(02)01629-0

Tetrahedron 59 (2003) 767–772
Diastereoselective synthesis of b-substituted
a-hydroxyphosphinates through hydrophosphinylation of
a-heteroatom-substituted aldehydes
Takehiro Yamagishi,a Takanori Kusano,a Babak Kaboudin,b Tsutomu Yokomatsu,a
Chiseko Sakumaa and Shiroshi Shibuyaa
,
*
aSchool of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
bDepartment of Chemistry, Institute for Advanced Studies in Basic Sciences, Gava Zang, Zanjan 45195-159, Iran
Received 11 November 2002; accepted 11 December 2002
Abstract—The diastereoselective synthesis of b-substituted a-hydroxyphosphinates was achieved by hydrophosphinylation of a-oxy
aldehydes and a-amino aldehydes with ethyl allylphosphinate catalyzed by lithium phenoxide. q 2003 Elsevier Science Ltd. All rights
reserved.
b-Heteroatom-substituted a-hydroxyphosphinic acids are
an interesting class of compounds from the viewpoint of
medicinal chemistry, since these compounds serve as
potentially useful components of a wide range of phosphinyl
peptides1 and phosphasugars.2 However, few investigations
have been taken on a chiral synthesis of these class of
compounds. Patel reported a stereoselective synthesis of
b-amino-a-hydroxyphosphinates, a chiral building block
for the phosphinyl peptide showing good inhibitory
activities against renin3 and HIV protease,4 through
elongation of b-amino-a-hydroxyphosphonates whose
stereochemistry was known.1 a,b-Dihydroxyphosphinates,
potentially useful compounds for the synthesis of phospha-
sugars of 2-deoxyglucose and 2-deoxyallose, were also
prepared stereoselectively by the reaction of a-oxygenated
aldehydes with isopropyl allylphosphinate in the presence
of tert-butyldimethylchlorosilane and triethylamine.2 We
have recently established the methodology for a stereo-
selective synthesis of b-amino-a-hydroxyphosphinates
through hydrophosphinylation of N,N-dibenzyl-a-amino
aldehydes by using AlLibis(binaphthoxide) (ALB)5 as the
catalyst.6 In our reaction, the new synthesis of syn- and anti-
b-amino-a-hydroxyphosphinate derivatives was achieved
by tuning the chirality of ALB.6a,b The excellent ability of
ALB for catalyzing diastereoselective hydrophosphinyl-
ation of a-amino aldehydes could be accounted for by
simultaneous activation of aldehydes with aluminum metal
as a Lewis acid, on the other hand, activation of phosphinic
nucleophile with the lithium binaphthoxide moiety as a
Brønsted base.5 We have successively investigated a
stereoselective hydrophosphinylation of a-heteroatom-sub-
stituted aldehydes to establish a new conventional methods
for the synthesis of b-heteroatom-substituted a-hydroxy-
phosphinates. In the hydrophosphinylation of a-oxygenated
aldehydes and a-amino derivatives, lithium phenoxide
(PhOLi) was expected to activate the ethyl allyl-
phosphinate7 by converting to the corresponding phos-
phonite form (I) as shown in Scheme 1. The activated
nucleophile would then react with aldehyde to give (II).
Proton exchange between lithium alkoxide and phenol leads
to the hydrophosphinylation product and regeneration of the
catalyst.
In this paper, we describe a utility of PhOLi as an efficient
catalyst for the hydrophosphinylation of a-heteroatom-
substituted aldehydes (Scheme 2).
We first attempted reactions of (S)-a-tert-butyldiphenyl-
silyloxy aldehydes 1a,8 1b9 and 1c10 with ethyl allyl-
phosphinate in the presence of PhOLi (20 mol%), generated
from n-BuLi and phenol, in THF at 2408C. As we expected,
the reaction of 1a–c proceeded catalytically affording syn-
2a–c and anti-2a–c in the yields shown in Scheme 3. The
ratio for syn- and anti-isomer could be determined by 31P
NMR (162 MHz, CDCl3) analysis of crude products. The
sterically less bulky substituent (R) in substrates enhanced
the diastereoselectivity, in the case of 1c (R¼Me), a
moderate anti-selectivity (syn/anti¼23:77) was obtained.
The observed selectivity favoring the formation of anti-
adduct was realized by considering a Felkin–Anh transition
state due to the absence of bidentate chelation with
a-silyloxy aldehydes and metallic reagents.11 The products
Keywords: diastereoselection; phosphinic acids and derivatives.
*
Corresponding author. Tel./fax: þ81-426-76-3239;
e-mail: yokomatu@ps.toyaku.ac.jp
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01629-0

768
T. Yamagishi et al. / Tetrahedron 59 (2003) 767–772
Scheme 1.
Scheme 2.
Scheme 3.
Scheme 4.

T. Yamagishi et al. / Tetrahedron 59 (2003) 767–772
769
syn-2a–c and anti-2a–c were formed as mixtures of
isomers arising from the chirality of the phosphinate
group, respectively. Individual diastereomers of syn-2a
and anti-2a,c were separated by preparative HPLC. No
racemization took place during the hydrophosphinylation,
which was verified by 31P NMR analysis of MTPA esters
derived from one of isomer of anti-2c.
In general, addition reactions of a-alkoxy aldehydes in the
presence of Lewis acid are proceeded under chelation
control to give products involving syn relative configur-
ation.14 Although we also examined hydrophosphinylation
of a-benzyloxy aldehydes using Lewis acid (LiClO4, TiCl4,
ZnCl2 and Yb(OTf)3) with and without PhOLi, any desired
adduct was not obtained, most possibly due to a decompo-
sition of phosphinic nucleophile with Lewis acid.15
However, the reaction of a-silyloxy aldehyde 1a in the
presence of PhOLi (20 mol%) and Et3N (400 mol%) gave
products in 66% with high syn-selectivity (syn/anti¼93:7)
(Scheme 5).16 To achieve the high syn-diastereoselectivity,
premixing of 1a with Et3N was necessary before treating
with phosphinic nucleophile. A low diastereoselectivity was
observed without treatment of 1a with Et3N prior to the
hydrophosphinylation (syn-2a/anti-2a¼40:60). Reactions
of other a-silyloxy aldehydes 1b,c with ethyl allyl-
phosphinate under the same condition resulted in moderate
anti-selectivity (35% yield, syn/anti¼23:77 for 1b; 35%
yield, syn/anti¼30:70 for 1c). The exact role of Et3N is
under investigation.
The stereochemistry of one isomer of syn-2a,c and anti-2c
was confirmed after converting to their corresponding
dioxolanes 3a,c and 4c, respectively, through deprotection
of the silyl group by TBAF, followed by treatment with 2,2-
1
dimethoxypropane and TsOH (Scheme 4). In the H NMR
NOESY spectrum of 3c and 4c, the cross peak between H-5
and a proton at allylic position of 3c was observed, while the
no correlation was displayed between the corresponding
1
ring protons of 4c. Performing two-dimensional 31P, H
heteronuclear NOE (HOESY) experiments provided
important information concerning the relative stereo-
chemistry of dioxolane derivatives.12 In the HOESY
spectra, phosphorus atom and Me group at C-5 of 4c
correlated, but no correlation was observed for 3c. The
correlation between phosphorus atom and H-5 was
observed in the HOESY spectra of 3a. On the basis of
these results, 3a,c and 4c were assigned to be trans and cis,
respectively.13
The present methodology was applied to a hydro-
phosphinylation of N,N-dibenzyl-L-phenylalanal 5a and
N,N-dibenzyl-L-leucinal 5b (Scheme 6).17 Hydrophos-
phinylation of 5a and 5b employing 20 mol% of PhOLi at
2408C afforded adducts in 69 and 78% yield, respectively.
The ratio of syn-6a and anti-6a was determined to be 25:75.
The similar selectivity was shown in the reaction of 5b (syn/
anti¼24:76).18 Products syn-6a,b and anti-6a,b were
obtained as diastereomixture arising from the chirality of
phosphinate group, respectively. Our previous reports
revealed (S)-ALB-catalyzed reactions of 5a,b with ethyl
allylphosphinate at 08C showing high anti-selectivity (5a;
63% yield, syn/anti¼7:93, 5b; 51% yield, syn/anti¼5:95).6c
Although the above-mentioned reactions provided moderate
anti-selectivity compared to the case of ALB, PhOLi proved
to possess sufficient catalytic activity to promote the
reaction even at 2408C.
In view of the activity of catalysts, PhOLi was confirmed to
be superior to ALB; that is, hydrophosphinylation of 1a
using (R)- and (S)-ALB (20 mol%) gave adducts in poor
yields ((R)-ALB; 18% yield, syn/anti¼48:52, (S)-ALB;
37% yield, syn/anti¼54:46). The hydrophosphinylation of
1a using other Brønsted base (20 mol%) Et3N, n-BuLi and
sodium phenoxide (PhONa), prepared from phenol and
NaH, was also examined. It was found that only PhONa
could promote the reaction to afford syn-2a and anti-2a in
low yield (32%) in a ratio of 39:61. Above-mentioned
results indicated PhOLi was relatively suitable catalyst for
the hydrophosphinylation of a-silyloxy aldehydes.
Scheme 5.
Scheme 6.

770
T. Yamagishi et al. / Tetrahedron 59 (2003) 767–772
In conclusion, we have developed the procedure for the
preparation of anti-b-substituted a-hydroxyphosphinates
through hydrophosphinylation of a-oxy aldehydes and
a-amino aldehydes with ethyl allylphosphinate using
PhOLi as a catalyst. Applying Et3N to the PhOLi-catalyzed
hydrophosphinylation of a-oxy aldehydes afforded mono-
protected syn-a,b-dihydroxyphosphinates with high
selectivity. A further investigation to improve diastereo-
selectivity is under progress.
2.21–2.08 (2H, m), 1.06 (9H, s), 1.03–0.97 (3H, m); 13C
NMR (100 MHz, CDCl3) d 135.8, 129.9, 128.3, 127.9 (d,
JPC¼10.4 Hz), 119.8 (d, JPC¼12.2 Hz), 74.7 (d,
JPC¼9.6 Hz), 73.9 (d, JPC¼105.9 Hz), 60.7 (d, JPC
¼
7.0 Hz), 31.5 (d, JPC¼87.7 Hz), 27.0, 16.5 (d,
JPC¼5.5 Hz); 31P NMR (162 MHz, CDCl3) d 50.77; IR
(KBr) 3216, 1113, 1031 cm21; EIMS m/z 451 (Mþ2t-Bu).
HRMS calcd for C25H28O4PSi (Mþ2t-Bu): 451.1494.
Found: 451.1481.
1.1.2. Ethyl allyl((1S,2S)-2-{[tert-butyl(diphenyl)silyl]-
oxy}-1-hydroxy-2-phenylethyl)phosphinate
(syn-2a).
1. Experimental
Colorless oil; [a]D28¼þ66.4 (c 0.26, CHCl3); 1H NMR
(400 MHz, CDCl3) d 7.76–7.27 (15H, m), 5.75–5.70 (1H,
m), 5.21–5.13 (2H, m), 5.05 (1H, dd, J¼5.0, 14.5 Hz), 4.11
(1H, dd, J¼5.7, 8.0 Hz), 3.86–3.50 (2H, m), 2.51–2.31
(2H, m), 1.10 (9H, s), 1.03–0.99 (3H, m); 13C NMR
(100 MHz, CDCl3) d 133.2, 129.8, 128.2, 127.6 (d,
JPC¼19.3 Hz), 120.2 (d, JPC¼12.0 Hz), 75.7 (d,
JPC¼6.6 Hz), 74.3 (d, JPC¼107.6 Hz), 60.8, 33.3 (d,
JPC¼86.8 Hz), 27.0, 19.4, 16.2 (d, JPC¼5.7 Hz); 31P NMR
(162 MHz, CDCl3) d 48.27; IR (neat) 3241, 1110,
1038 cm21; EIMS m/z 451 (Mþ2t-Bu). HRMS calcd for
C25H28O4PSi (Mþ2t-Bu): 451.1494. Found: 451.1508.
All melting points were taken on a Yanagimoto micro-
melting point apparatus and are uncorrected. Optical
rotations were measured with a JASCO DIP-360 digital
polarimeter. IR spectra were recorded on a JASCO FTIR-
620. Mass spectra were measured on a Finnigan TSQ-700 or
a VG Auto Spec E. Elemental analysis were recorded on an
Elemental Vavio EL. NMR spectra were obtained on Bruker
1
DPX400 NMR spectrometer operating at 400 MHz for H,
100 MHz for 13C, and 162 MHz for 31P. The chemical shift
1
data for each signal on H NMR are given in units of d
relative to CHCl3 (d¼7.26) for CDCl3 solution. For 13C
NMR spectra, the chemical shifts in CDCl3 are reported
relative to the CDCl3 resonance (d¼77.0). The chemical
shifts of 31P are recorded relative to external 85% H3PO4
1.1.3. Ethyl allyl((1R,2S)-2-{[tert-butyl(diphenyl)silyl]-
oxy}-1-hydroxy-2-phenylethyl)phosphinate
(anti-2a).
White needles; mp 98–1038C; [a]2D8¼þ35.5 (c 0.72,
1
(d¼0) with broad-band H decoupling. Two-dimensional
1
31P, 1H HOESY spectra were recorded in CDCl3 at
300 K. The mixing time was set to 1.5 s. Preparative
HPLC was performed on JASCO HPLC systems consisting
of the following: pump, PU-986; detector, UV-975,
measured at 254 nm; column, GL Sciences Inertsil PREP
SIL; mobile phase, EtOAc; flow rate, 15.0 mL/min. The
aldehydes 1a,8 1b,9 1c10 and 5a,b17 were prepared by Swern
oxidation of corresponding chiral alcohols and used without
further purification.17 Reactions were carried under nitrogen
atmosphere.
CHCl3); H NMR (400 MHz, CDCl3) d 7.67–7.32 (15H,
m), 5.67–5.62 (1H, m), 5.11–5.00 (2H, m), 4.97 (1H, dd,
J¼5.8, 8.0 Hz), 4.02 (1H, dd, J¼3.3, 8.0 Hz), 3.77–3.39
(2H, m), 2.47–2.17 (2H, m), 1.02 (9H, s), 0.94–0.91 (3H,
m); 13C NMR (100 MHz, CDCl3) d 136.0, 135.8, 133.4,
129.9, 129.7, 128.3, 128.1, 127.8, 127.6, 127.3 (d,
JPC¼22.8 Hz), 120.0 (d, JPC¼12.3 Hz), 75.5 (d, JPC
¼
71.6 Hz), 74.6 (d, JPC¼6.7 Hz), 61.6 (d, JPC¼6.9 Hz),
33.4 (d, JPC¼85.9 Hz), 27.0, 16.5 (d, JPC¼5.5 Hz); 31P
NMR (162 MHz, CDCl3) d 45.54; IR (KBr) 3239, 1112,
1052 cm21; EIMS m/z 451 (Mþ2t-Bu). HRMS calcd for
C25H28O4PSi (Mþ2t-Bu): 451.1494. Found: 451.1480.
1.1. The procedure for the hydrophosphinylation of 1a
with ethyl allylphosphinate in the presence of PhOLi
1.1.4. Ethyl allyl((1R,2S)-2-{[tert-butyl(diphenyl)silyl]-
oxy}-1-hydroxy-2-phenylethyl)phosphinate
(anti-2a).
A solution of phenol (37.6 mg, 0.4 mmol) in THF (8 mL)
was added 1.56 M hexane solution of n-BuLi (0.3 mL,
0.4 mmol) at 08C and stirred for 0.5 h at the same
temperature. To this solution was added a solution of
ethyl allylphosphinate (402 mg, 3.0 mmol) in THF (4 mL)
and a solution of 1a (2.0 mmol) in THF (4 mL) at 2408C.
After stirring for 12 h at the same temperature, the mixture
was diluted with H2O and extracted with CHCl3. The
combined extracts were washed with brine and dried over
MgSO4. Removal of the solvent gave a residue which was
chromatographed on silica gel (hexane/EtOAc¼2:1 to
AcOEt) to give a mixture of syn-2a and anti-2a (671 mg,
63%). The mixture was separated into two isomers of syn-2a
and two isomers of anti-2a by preparative HPLC.
Colorless oil; [a]D27¼þ37.4 (c 0.26, CHCl3); 1H NMR
(400 MHz, CDCl3) d 7.69–7.27 (15H, m), 5.49–5.46 (1H,
m), 5.17–4.98 (2H, m), 4.88–4.83 (1H, m), 4.08 (1H, d,
J¼10.3 Hz), 3.84–3.78 (2H, m), 2.72–2.12 (2H, m), 1.20–
1.10 (3H, m), 1.06–0.89 (9H, m); 13C NMR (100 MHz,
CDCl3) d 129.8, 128.2, 128.0, 127.7, 127.4 (d, JPC
¼
13.7 Hz), 120.1 (d, JPC¼12.3 Hz), 75.5 (d, JPC¼72.0 Hz),
74.6 (d, JPC¼6.6 Hz), 61.5 (d, JPC¼7.1 Hz), 33.4 (d,
JPC¼85.9 Hz), 27.0, 16.4 (d, JPC¼5.6 Hz); 31P NMR
(162 MHz, CDCl3) d 47.75; IR (neat) 3224, 1110,
1033 cm21; EIMS m/z 451 (Mþ2t-Bu). HRMS calcd for
C25H28O4PSi (Mþ2t-Bu): 451.1494. Found: 451.1485.
1.1.5. Ethyl allyl((1S,2S)- and (1R,2S)-2-{[tert-butyl(di-
phenyl)silyl]oxy}-1-hydroxy-3-phenylpropyl)phosphi-
nate (syn-2b and anti-2b). Compounds syn-2b and anti-2b
were prepared from 1b (2.0 mmol) in accordance with the
procedure described for 1a. Purification of the residue by
column chromatography (hexane/EtOAc¼2:1 to AcOEt) to
give a mixture of syn-2a and anti-2a (770 mg, 74%).
1.1.1. Ethyl allyl((1S,2S)-2-{[tert-butyl(diphenyl)silyl]-
oxy}-1-hydroxy-2-phenylethyl)phosphinate
(syn-2a).
White needles; mp 116–1218C; [a]2D8¼þ15.6 (c 0.37,
1
CHCl3); H NMR (400 MHz, CDCl3) d 7.72–7.27 (15H,
m), 5.54–5.40 (1H, m), 5.17–4.90 (2H, m), 4.89–4.82 (1H,
m), 4.12 (1H, dd, J¼7.2, 14.3 Hz), 4.01–3.74 (2H, m),

T. Yamagishi et al. / Tetrahedron 59 (2003) 767–772
771
1
Colorless oil; H NMR (400 MHz, CDCl3) d 7.88–6.85
one isomer of syn-2a (198 mg, 0.39 mmol) in THF (2.0 mL)
was added 1 M THF solution of TBAF (0.47 mL,
0.47 mmol) at 08C. After stirring for 1.5 h at the same
temperature, the mixture was poured into cold water and
extracted with CHCl3. The combined extracts were washed
with brine and dried over MgSO4. Removal of the solvent
gave a residue. A mixture of the residue, 2,2-dimethoxy-
propane (0.19 mL, 1.56 mmol) and p-toluenesulfonic acid
monohydrate (7.4 mg, 0.039 mmol) in benzene (2.0 mL)
was heated under reflux for 1.5 h. After being cooled, the
mixture was poured into sat. NaHCO3 solution and
extracted with Et2O. The combined extracts were washed
with brine and dried over MgSO4. Removal of the solvent
gave a residue which was chromatographed on silica gel
(hexane/EtOAc¼3:1 to 1:2) to give 3a (35 mg, 29%).
Colorless oil; [a]D27¼21.8 (c 0.65, CHCl3); 1H NMR
(400 MHz, CDCl3) d 7.50–7.29 (5H, m), 5.10–5.05 (2H,
m), 4.87 (1H, dd, J¼9.3, 11.4 Hz), 4.24–4.13 (3H, m),
2.57–2.31 (2H, m), 1.61–1.55 (6H, m), 1.36–1.29 (3H, m);
13C NMR (100 MHz, CDCl3) d 128.2, 127.8, 126.8 (d,
JPC¼10.7 Hz), 126.0, 120.0 (d, JPC¼11.9 Hz), 112.1 (d,
JPC¼3.9 Hz), 84.3 (d, JPC¼110.6 Hz), 71.5, 61.9
(d, JPC¼7.3 Hz), 31.0 (d, JPC¼87.2 Hz), 25.9, 25.7, 16.7
(d, JPC¼5.5 Hz); 31P NMR (162 MHz, CDCl3) d 47.84;
IR (neat) 1061, 1032 cm21; EIMS m/z 310 (Mþ). HRMS
calcd for C15H20O4P (Mþ2Me): 295.1099. Found:
295.1095.
(15H, m), 5.75–5.60 (1H, m), 5.29–4.93 (2H, m), 4.31–
3.97 (3H, m), 3.66–3.47 (1H, m), 3.00–2.51 (4H, m),
1.34–0.99 (12H, m); 31P NMR (162 MHz, CDCl3) d 49.90,
49.39, 48.82, 48.26; IR (neat) 3263, 1111, 1037 cm21
;
EIMS m/z 522 (Mþ). HRMS calcd for C30H39O4PSi (Mþ):
522.2355. Found: 522.2306.
1.1.6. Ethyl allyl((1S,2S)-2-{[tert-butyl(diphenyl)silyl]-
oxy}-1-hydroxypropyl)phosphinate (syn-2c). Compounds
syn-2c and anti-2c were prepared from 1c (10 mmol) in
accordance with the procedure described for 1a. Purification
of the residue by column chromatography (hexane/
EtOAc¼2:1 to AcOEt) to give a mixture of syn-2c and
anti-2c (3.03 g, 68%). The mixture was separated into a
mixture of two isomers of syn-2c and individual isomers of
anti-2c by preparative HPLC. This compound was obtained
as a mixture of diastereomers in a ratio of 1:3.8. Colorless
1
oil; H NMR (400 MHz, CDCl3) d 7.77–7.35 (10H, m),
5.78–5.72 (1H, m), 5.17–5.12 (2H, m), 4.29–4.21 (1H, m),
4.18–4.02 (2H, m), 3.97 (1H, d, J¼4.3 Hz), 2.75–2.59 (2H,
m), 1.29 (3H, t, J¼7.0 Hz), 1.17 (3H, d, J¼6.2 Hz), 1.08
(9H, s); 13C NMR (100 MHz, CDCl3) d 136.1, 135.7, 133.7,
132.8, 130.1, 129.9, 127.7, 127.2 (d, JPC¼9.8 Hz), 120.1 (d,
JPC¼12.1 Hz), 73.9 (d, JPC¼108.8 Hz), 69.3 (d, JPC
¼
5.9 Hz), 60.8 (d, JPC¼6.9 Hz), 32.2 (d, JPC¼85.9 Hz),
26.9, 19.5, 16.5 (d, JPC¼5.6 Hz); 31P NMR (162 MHz,
CDCl3) d 50.12, 49.29; IR (neat) 3289, 1110, 1037 cm21
;
EIMS m/z 389 (Mþ2t-Bu). HRMS calcd for C20H26O4PSi
(Mþ2t-Bu): 389.1338. Found: 389.1323.
1.1.10. Ethyl allyl[(4S,5S)-2,2,5-trimethyl-1,3-dioxolan-
4-yl]phosphinate (3c). The compound 3c was prepared
from a mixture of syn-2c (178 mg, 0.40 mmol) in an
analogous manner to that for preparation of 3a. Purification
of the residue by column chromatography (hexane/
EtOAc¼3:1 to 1:2) gave 3c (8.7 mg, 11%). Colorless oil;
[a]2D7¼þ4.0 (c 0.06, CHCl3); 1H NMR (400 MHz, CDCl3) d
5.86–5.83 (1H, m), 5.30–5.23 (2H, m), 4.43–4.11 (2H, m),
3.68 (1H, dd, J¼3.2, 9.3 Hz), 2.80–2.73 (2H, m), 1.43–1.40
(9H, m), 1.34 (3H, t, J¼7.0 Hz); 13C NMR (100 MHz,
CDCl3) d 126.8 (d, JPC¼9.7 Hz), 120.5 (d, JPC¼12.4 Hz),
110.4 (d, JPC¼9.9 Hz), 77.8 (d, JPC¼113.2 Hz), 72.6 (d,
JPC¼4.3 Hz), 61.1 (d, JPC¼6.9 Hz), 32.1 (d, JPC¼87.6 Hz),
P
1.1.7. Ethyl allyl((1R,2S)-2-{[tert-butyl(diphenyl)silyl]-
oxy}-1-hydroxypropyl)phosphinate (anti-2c). Colorless
oil; [a]2D8¼þ2.9 (c 0.21, CHCl3); 1H NMR (400 MHz,
CDCl3) d 7.70–7.38 (10H, m), 5.76–5.71 (1H, m), 5.26–
5.14 (2H, m), 4.25–4.19 (1H, m), 4.05–3.89 (2H, m), 3.83
(1H, dd, J¼3.2, 4.5 Hz), 2.75–2.61 (2H, m), 1.28 (3H, d,
J¼6.4 Hz), 1.20 (3H, t, J¼7.0 Hz), 1.08 (9H, s); 13C NMR
(100 MHz, CDCl3) d 135.8, 133.6, 129.9, 127.8, 127.2 (d,
JPC¼10.3 Hz), 120.3 (d, JPC¼12.0 Hz), 73.4 (d, JPC
¼
104.9 Hz), 69.7 (d, JPC¼5.8 Hz), 61.1 (d, JPC¼7.0 Hz),
33.3 (d, JPC¼85.2 Hz), 27.0, 19.2, 16.5 (d, JPC¼5.4 Hz); 31
P
26.8, 26.2, 18.3 (d, JPC¼1.8 Hz), 16.5 (d, JPC¼5.2 Hz); 31
NMR (162 MHz, CDCl3) d 48.73; IR (neat) 3278, 1110,
1037 cm21; EIMS m/z 389 (Mþ2t-Bu). HRMS calcd for
C24H35O4PSi (Mþ): 446.2042. Found: 446.2010.
NMR (162 MHz, CDCl3) d 46.76; IR (neat) 1088,
1032 cm21; EIMS m/z 249 (MHþ). HRMS calcd for
C11H21O4P (Mþ): 248.1177. Found: 248.1152.
1.1.8. Ethyl allyl((1R,2S)-2-{[tert-butyl(diphenyl)silyl]-
oxy}-1-hydroxypropyl)phosphinate (anti-2c). Colorless
oil; [a]2D8¼þ0.7 (c 1.08, CHCl3); 1H NMR (400 MHz,
CDCl3) d 7.71–7.37 (10H, m), 5.85–5.75 (1H, m), 5.29–
5.16 (2H, m), 4.35–4.18 (1H, m), 4.16–3.93 (2H, m), 3.75–
3.64 (1H, m), 2.71–2.62 (2H, m), 1.39–1.23 (6H, m), 1.08
(9H, s); 13C NMR (100 MHz, CDCl3) d 136.1, 135.7, 133.6,
129.9, 127.8, 127.6, 127.1 (d, JPC¼9.4 Hz), 120.4 (d,
JPC¼12.0 Hz), 73.7 (d, JPC¼107.1 Hz), 68.9, 61.3 (d,
JPC¼7.3 Hz), 33.0 (d, JPC¼84.9 Hz), 26.9, 19.2 (d,
JPC¼8.6 Hz), 16.4 (d, JPC¼5.3 Hz); 31P NMR (162 MHz,
CDCl3) d 48.74; IR (neat) 3278, 1110, 1036 cm21; EIMS
m/z 389 (Mþ2t-Bu). HRMS calcd for C20H26O4PSi
(Mþ2t-Bu): 389.1338. Found: 389.1328.
1.1.11. Ethyl allyl[(4R,5S)-2,2,5-trimethyl-1,3-dioxolan-
4-yl]phosphinate (4c). The compound 4c was prepared
from one isomer of anti-2c (548 mg, 1.23 mmol) in an
analogous manner to that for preparation of 3a. Purification
of the residue by column chromatography (hexane/
EtOAc¼3:1 to 1:2) gave 4c (30 mg, 10%). Colorless oil;
[a]2D7¼þ14.0 (c 0.17, CHCl3); 1H NMR (400 MHz, CDCl3)
d 5.91–5.82 (1H, m), 5.31–5.23 (2H, m), 4.42–4.11 (3H,
m), 3.74 (1H, dd, J¼8.5, 9.0 Hz), 2.79–2.67 (2H, m), 1.43–
1.40 (9H, m), 1.34 (3H, t, J¼3.5 Hz); 13C NMR (100 MHz,
CDCl3) d 127.4 (d, JPC¼9.2 Hz), 120.4 (d, JPC¼12.1 Hz),
109.8 (d, JPC¼4.4 Hz), 74.9 (d, JPC¼114.0 Hz), 73.2, 61.4
(d, JPC¼7.3 Hz), 34.1 (d, JPC¼85.8 Hz), 27.0, 25.1, 18.7,
16.6 (d, JPC¼5.6 Hz); 31P NMR (162 MHz, CDCl3) d 45.52;
IR (neat) 1087, 1031 cm21; EIMS m/z 219 (Mþ2Et).
HRMS calcd for C10H18O4P (Mþ2Me): 233.0942. Found:
233.0937.
1.1.9. Ethyl allyl[(4S,5S)-2,2-dimethyl-5-phenyl-1,3-
dioxolan-4-yl]phosphinate (3a). To a stirred solution of

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T. Yamagishi et al. / Tetrahedron 59 (2003) 767–772
1.2. The procedure for the hydrophosphinylation of 1a
with ethyl allylphosphinate in the presence of PhOLi and
Et3N
References
1. Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E. Tetrahedron
Lett. 1990, 31, 5591.
To a solution of PhOLi (0.4 mmol) in THF (4 mL), prepared
from phenol (37.6 mg, 0.4 mmol) and 1.56 M hexane
solution of n-BuLi (0.26 mL, 0.4 mmol), was added a
solution of ethyl allylphosphinate (402 mg, 3.0 mmol) in
THF (4 mL) and a solution of 1a (2.0 mmol) and Et3N
(1.1 mL, 8.0 mmol) in THF (8 mL), which were mixed at
room temperature before 2 h in prior to use, at 2408C under
stirring. After stirring for 12 h at the same temperature, the
mixture was diluted with H2O and extracted with CHCl3.
The combined extracts were washed with brine and dried
over MgSO4. Removal of the solvent gave a residue which
was chromatographed on silica gel (hexane/EtOAc¼5:1 to
EtOAc) to give a mixture of syn-2a and anti-2a (670 mg,
66%).
2. Gallagher, M. J.; Ranasinghe, M. G.; Jenkins, I. D. J. Org.
Chem. 1996, 61, 436.
3. Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E.; Free, C. A.;
Rogers, W. L.; Smith, S. A.; DeForrest, J. M.; Oehl, R. S.;
Petrillo, Jr. E. W. J. Med. Chem. 1995, 38, 4557.
4. Stowasser, B.; Budt, K.-H.; Jian-Qi, L.; Peyman, A.; Ruppert,
D. Tetrahedron Lett. 1992, 33, 6625.
5. (a) Arai, T.; Bougauchi, M.; Sasai, H.; Shibasaki, M. J. Org.
Chem. 1996, 61, 2926. (b) Arai, T.; Sasai, H.; Aoe, K.;
Okamura, K.; Date, T.; Shibasaki, M. Angew. Chem. Int. Ed.
Engl. 1996, 35, 104. (c) Yamada, K.; Arai, T.; Sasai, H.;
Shibasaki, M. J. Org. Chem. 1998, 63, 3666. (d) Xu, Y.; Ohori,
K.; Ohshima, T.; Shibasaki, M. Tetrahedron 2002, 58, 2585.
6. (a) Yamagishi, T.; Suemune, K.; Yokomatsu, T.; Shibuya, S.
Tetrahedron Lett. 2001, 42, 5033. (b) Yamagishi, T.;
Suemune, K.; Yokomatsu, T.; Shibuya, S. Tetrahedron
2002, 58, 2577. (c) Yamagishi, T.; Kusano, T.; Yokomatsu,
T.; Shibuya, S. Synlett 2002, 1471. (d) For a catalytic
asymmetric hydrophosphinylation of prochiral aldehydes,
see: Yamagishi, T.; Suemune, K.; Yokomatsu, T.; Shibuya,
S. Tetrahedron 1999, 55, 12125.
1.3. General procedure for the hydrophosphinylation of
5a,b with ethyl allylphosphinate in the presence of
PhOLi
To a solution of PhOLi (0.8 mmol) in THF (8 mL), prepared
from phenol (75 mg, 0.8 mmol) and 0.98 M hexane solution
of n-BuLi (0.82 mL, 0.8 mmol), was added a solution of
ethyl allylphosphinate (804 mg, 6.0 mmol) in THF (4 mL)
and a solution of 5a,b (4.0 mmol) in THF (8 mL) at 2408C
under stirring. After stirring for 12 h at the same
temperature, the mixture was diluted with H2O and
extracted with CHCl3. The combined extracts were washed
with brine and dried over MgSO4. Removal of the solvent
gave a residue which was chromatographed on silica gel
(hexane/EtOAc¼2:1 to EtOAc) to give syn-6a,b and anti-
6a,b.
7. Baylis, E. K. Tetrahedron Lett. 1995, 36, 9385.
8. Raczko, J. Tetrahedrom: Asymmetry 1997, 8, 3821.
9. Palomo, C.; Aizpurua, J. M.; Urchegui, R.; Garcıa, J. M.
´
J. Org. Chem. 1993, 58, 1646.
10. (a) Mulzer, J.; Berger, M. Tetrahedron Lett. 1998, 39, 803.
´
(b) Gonzalez, A.; Aiguade, J.; Urpi, F.; Vilarrasa, J.
´
´
Tetrahedron Lett. 1996, 37, 8949.
11. (a) Keck, G. E.; Boden, E. P. Tetrahedron Lett. 1984, 25, 265.
(b) Kahn, S. D.; Keck, G. E.; Hehre, W. J. Tetrahedron Lett.
1987, 28, 279. (c) Keck, G. E.; Castellino, S. Tetrahedron Lett.
1987, 28, 281.
1.3.1. Ethyl allyl[(1S,2S)-2-(dibenzylamino)1-hydroxy-3-
phenylpropyl]phosphinate (syn-6a). This compound was
obtained as a mixture of diastereomers in a ratio of 1:2.0.
12. Yu, C.; Levy, G. C. J. Am. Chem. Soc. 1984, 106, 6533.
13. The stereochemistry of phosphinate group in 3a,c and 4c has
remained undetermined.
1
Yield (333 mg, 18%); white plates; mp 83–858C. The H
and 31P NMR spectra were identical to those of the authentic
sample reported in the literature.6c
14. For a review, see: Reetz, M. T. Angew. Chem. Int. Ed. Engl.
1984, 23, 556.
15. Contrary to this observation, the related hydrophosphonylation
of a-benzyloxy aldehydes with silyl phosphite using TiCl4
proceeded with high syn-diastereoselectivity via chelation
transition state. See: Yokomatsu, T.; Yoshida, Y.; Shibuya, S.
J. Org. Chem. 1994, 59, 7930.
1.3.2. Ethyl allyl[(1R,2S)-2-(dibenzylamino)1-hydroxy-
3-phenylpropyl]phosphinate (anti-6a). This compound
was obtained as a mixture of diastereomers in a ratio of
1:1.5. Yield (945 mg, 51%); white plates; mp 130–1338C.
The 1H and 31P NMR spectra were identical to those of the
authentic sample reported in the literature.6c
16. (a) The related hydrophosphonylation of a-silyloxy aldehydes
with silylphosphite showed high syn-selectivity. See: Bongini,
A.; Panunzio, M.; Bandini, E.; Martelli, G.; Spunta, G. Synlett
1995, 461. (b) Bandini, E.; Martelli, G.; Spunta, G.; Panunzio,
M. Tetrahedron: Asymmetry 1995, 6, 2127. (c) Bongini, A.;
Camerini, R.; Panunzio, M.; Bandini, E.; Martelli, G.; Spunta,
G. Tetrahedron: Asymmetry 1996, 7, 3485.
1.3.3. Ethyl allyl[(1S,2S)-2-(dibenzylamino)1-hydroxy-4-
methylpentyl]phosphinate (syn-6b). This compound was
obtained as a mixture of diastereomers in a ratio of 1:1.2.
1
Yield (326 mg, 19%); colorless oil. The H and 31P NMR
spectra were identical to those of the authentic sample
reported in the literature.6c
17. Reetz, M. T. Angew. Chem. Int. Ed. Engl. 1991, 30, 1531.
18. Although the hydrophosphinylation of 5a,b in the presence of
PhOLi (20 mol%) and Et3N (400 mol%) were examined, the
diastereoselectivity were analogous to those of PhOLi-
catalyzed reactions (33% yield, syn/anti¼23:77 for 5a; 81%
yield, syn/anti¼36:64 for 5b).
1.3.4. Ethyl allyl[(1R,2S)-2-(dibenzylamino)1-hydroxy-
4-methylpentyl]phosphinate (anti-6b). This compound
was obtained as a mixture of diastereomers in a ratio of
1:1.5. Yield (1.01 g, 59%); white plates; mp 141–1438C.
The 1H and 31P NMR spectra were identical to those of the
authentic sample reported in the literature.6c