Asymmetric synthesis of β-amino-α-hydroxyphosphinic acid derivatives through hydrophosphinylation of α-amino aldehydes

Article abstract of DOI:10.1016/S0040-4020(02)00136-9

The diastereoselective synthesis of β-amino-α-hydroxyphosphinates was achieved by hydrophosphinylation of N,N-dibenzyl-α-amino aldehydes with ethyl ethylphosphinate catalyzed by (S)-ALB. The hydrophosphinylation using ethyl phosphinate afforded both syn- and anti-β-amino-α-hydroxy-H-phosphinates with high diastereoselectivities by tuning the chirality of ALB.

Full text of DOI:10.1016/S0040-4020(02)00136-9

TETRAHEDRON
Pergamon
Tetrahedron 58 )2002) 2577±2583
Asymmetric synthesis of b-amino-a-hydroxyphosphinic acid
derivatives through hydrophosphinylation of a-amino aldehydes
Takehiro Yamagishi, Kenji Suemune, Tsutomu Yokomatsup and Shiroshi Shibuya
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 7 January 2002; accepted 4February 2002
AbstractÐThe diastereoselective synthesis of b-amino-a-hydroxyphosphinates was achieved by hydrophosphinylation of N,N-dibenzyl-a-
amino aldehydes with ethyl ethylphosphinate catalyzed by )S)-ALB. The hydrophosphinylation using ethyl phosphinate afforded both syn-
and anti-b-amino-a-hydroxy-H-phosphinates with high diastereoselectivities by tuning the chirality of ALB. q 2002 Elsevier Science Ltd.
All rights reserved.
The b-amino-a-hydroxyphosphinic acids 1 serve as the key
intermediates for the synthesis of potent inhibitors of human
renin and HIV protease )Fig. 1).1,2 Stereogenic carbon±
phosphorus bond formation processes are of great interest
in the stereoselective synthetic sequences of the b-amino
alcohol moiety by the reaction of a-amino aldehydes with
phosphinic nucleophiles, since the stereochemistry of
b-amino alcohol is known to be an important factor to get
potent inhibitory active compounds. Although b-amino-a-
hydroxyphosphinic acid derivatives were obtained by the
reaction of N-Boc-a-amino aldehydes with methyl ethyl-
phosphinate )HPO)OMe))Et)) in the presence of TMSCl
and an amine, diastereoselectivity was not observed.1 Our
special interest is in developing concise and highly dia-
stereoselective synthesis of both b-amino-a-hydroxy-
phosphinic acids )1/Xˆalkyl) and b-amino-a-hydroxy-H-
phosphinic acids )1/XˆH). We examined the chiral AlLi-
bis)binaphthoxide) )ALB)3-catalyzed hydrophosphinyl-
ayion of a-amino aldehydes employing two types of
phosphinic
nucleophile,
alkyl
alkylphosphinate
)HPO)OR))R)) and alkyl phosphinate )H2PO2R), in exten-
sion of our previous work on catalytic asymmetric hydro-
phosphinylation of aldehydes.4 The reaction of ethyl
ethylphosphinate5 with N,N-dibenzyl-a-amino aldehydes6
afforded anti-b-amino-a-hydroxyphosphinates in a highly
diastereoselective manner. Furthermore, chiral ALB-
catalyzed hydrophosphinylation employing ethyl phos-
phinate,7 generated from anhydrous phosphinic acid and
triethyl orthoformate in situ, proceeded with a high level
of diastereofacial selectivity. The stereochemical outcome
of the reaction can be controlled in either anti- or syn-
selective manner by tuning the chirality of ALB.8 We
wish to describe full details in this paper )Scheme 1).
First, we examined the hydrophosphinylation of N,N-
dibenzyl-a-amino aldehyde 2a with ethyl ethylphosphinate
in the presence of )R)-ALB )20 mol%), generated from
)R)-binaphthol, in THF at 2408C for 12 h )Table 1). The
reaction was found to be sluggish, giving adducts syn-3 and
anti-3 only in 4% yield )entry 1). The 31P NMR spectrum of
Figure 1.
Scheme 1.
Keywords: diastereoselection; phosphinic acids and derivatives.
Corresponding author. Tel.: 181-426-76-3251; fax: 181-426-763239; e-mail: yokomatu@ps.toyaku.ac.jp
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020)02) 00136-9

2578
T. Yamagishi et al. / Tetrahedron 58 .2002) 2577±2583
Table 1. Hydrophosphinylation of 2a with ethyl ethylphosphinate in the presence of ALB
Entrya
ALB
Temperature )8C)
syn/antib
Yield )%)c
1
2
3
)R)-ALB
)R)-ALB
)S)-ALB
240
0
0
43:57
43:57
11:89
4
55
51
a
All reactions were carried out for 12 h.
Determined by 31P NMR analysis of crude products.
Combined yields of syn- and anti-isomers.
b
c
the crude products revealed that the diastereoselectivity was
poor )syn/antiˆ43:57). When the reaction was carried out at
08C, the chemical yield was raised to 55%, but resulting in
the same diastereoselectivity )entry 2).9 On the other hand,
employing )S)-ALB gave adduct 3 with anti-selectivity
)syn/antiˆ11:89) in 51% yield )entry 3). These results
indicated that the combination of )S)-ALB and 2a was suit-
ably matched for inducing diastereofacial selectivity. The
hydrophosphinylation products syn-3 and anti-3 were
obtained as a 1:1 mixture of isomers arising from the
chirality of the phosphinate group, respectively. Only in
the case of syn-3, these diastereomers, syn-3-A and syn-3-
B, were separated by silica gel column chromatography.
was estimated to be anti by considering the Felkin±Anh
transition state.10
We next examined hydrophosphinylation of 2a,b employing
ethyl phosphinate for the synthesis of b-amino-a-hydroxy-
H-phosphinates in a highly diastereoselective manner
)Table 2). In these cases, ethyl phosphinate is expected to
be readily activated by ALB showing increased nucleo-
philicity due to the low pKa value in comparison with
ethyl ethylphosphinate.
As we expected, ethyl phosphinate could be activated by the
catalyst even at ±408C affording the corresponding hydro-
phosphinylation products in moderate yields.11 An
intriguing result was revealed upon analyzing the diastereo-
selectivities of the products. Performing the reaction of 2a in
the presence of )R)-ALB gave rise to high syn-selectivity
)syn-4a/anti-4aˆ87:13) )entry 1). On the other hand, the
reaction of 2a by the use of )S)-ALB instead of )R)-ALB
proceeded with inversed stereoselection to afford anti-4a in
a ratio of 6:94)entry 2). Also, when the reaction of 2b was
carried out with )R)- or )S)-ALB, either syn-4b or anti-4b
could be obtained in high stereoselectivity )entries 3 and 4).
In the above-mentioned cases, diastereofacial selectivity
was found to be controlled predominantly by the chirality
of the asymmetric catalyst rather than that of the a-amino
aldehydes. As observed in Table 2, the diastereoselectivity
In view of the level of selectivity, ALB-catalyzed hydro-
phosphinylation was con®rmed to be more advantageous
over the existing conventional method; that is, hydro-
phosphinylation of 2a using 1.5 equiv. of both Et3N and
TMSCl, followed by desilylation with Bu4NF afforded 3
with modest selectivity )syn/antiˆ30:70) in 55% yield
)Scheme 2). The stereochemistry of the major diastereomer
Scheme 2.
Table 2. Hydrophosphinylation of 2a,b with ethyl phosphinate in the presence of ALB
Entrya
Substrate
ALB
syn/anti
Yield )%)b
1
2
3
4
2a
2a
2b
2b
)R)-ALB
)S)-ALB
)R)-ALB
)S)-ALB
87:13
6:9456
94:6
66
54
71
2:98
a
All reactions were carried out for 12 h at 2408C.
Combined yields of syn- and anti-isomers.
b

T. Yamagishi et al. / Tetrahedron 58 .2002) 2577±2583
2579
Figure 2.
Scheme 3.
of the hydrophosphinylation with )S)-ALB is generally
higher than that with )R)-ALB.
analysis on a chiral phase )DAICEL CHIRALPAK OD
column, hexane/EtOHˆ20:1). Therefore, it was proved
that no racemization of N,N-dibenzyl-a-amino aldehydes
took place during the hydrophosphinylation.
The high diastereoselectivity of the hydrophosphinylation
catalyzed by ALB would be accounted for by the kinetically
controlled process: treatment of anti-4a with ethyl phos-
phinate in the presence of )R)-ALB at 2408C formed
none of syn-isomer that would be expected from a reversible
process. Although the exact reason for high selectivities in
)R)-ALB-catalyzed hydrophosphinylation using ethyl phos-
phinate in comparison with ethyl ethylphosphinate remains
unclear, it seems likely to be associated with a steric
disposition for phosphinic nucleophile.
Finally, the ethyl ester of anti-3 could be easily removed by
treatment with TMSBr followed by methanolysis to give
b-amino-a-hydroxyphosphinic acid
9 in 92% yield
)Scheme 4) The product 9 was obtained as a single product
due to the loss of asymmetric character of phosphorus atom
by the rapid transfer of the acidic proton between the
phosphoryl )PvO) and the acidic )P±OH) sites.13
In conclusion, we have developed a diastereoselective
synthesis of b-amino-a-hydroxyphosphinates through
hydrophosphinylation of N,N-dibenzyl-a-amino aldehydes
with ethyl ethylphosphinate catalyzed by )S)-ALB. More-
over, applying ethyl phosphinate to the hydrophosphinyl-
ation afforded both syn- and anti-b-amino-a-hydroxy-H-
phosphinates selectively by tuning the chirality of ALB.
The present methodology would be widely applicable to
the synthesis of protease inhibitors.
The products anti-4a,b and syn-4a,b were obtained as a 1:1
mixture of diastereoisomers arising from the chirality of the
phosphinate group. The diastereomerically pure anti-4a-A
)mp: 149±1508C) was isolated from the mixture )anti-4a-A
and anti-4a-B) upon recrystallization from ethyl acetate.12
The relative stereochemistry of anti-4a-A was con®rmed
unambiguously by X-ray crystallographic analysis )Fig. 2).
The stereochemistry of anti-4a,b was also con®rmed after
converting to b-amino-a-acetoxyphosphonate 6a,b through
sequential acetylation, oxidation,13 deesteri®cation14 and
1. Experimental
1
methyl esteri®cation )Scheme 3). The H NMR spectra of
6a,b were identical with those of the authentic specimens
derived from the known b-amino-a-hydroxyphosphonate
7a,b10,15 through acetylation and deesteri®cation followed
by methyl esteri®cation. The optical purity of 6a derived
from anti-4a was determined to be 99% ee by HPLC
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 either
a Bruker DPX400 NMR spectrometer operating or a Varian
Mercury-300BB instrument operating at 400 )or 300) MHz
1
for H, 100 )or 75.5) MHz for 13C, and 162 MHz for 31P.
1
The chemical shift data for each signal on H NMR are
given in units of d relative to CHCl3 )dˆ7.26) for CDCl3
Scheme 4.

2580
T. Yamagishi et al. / Tetrahedron 58 .2002) 2577±2583
1
solution or CH3OH )dˆ3.30) for CD3OD solution. For 13C
NMR spectra, the chemical shifts in CDCl3 or CD3OD are
reported relative to the CDCl3 resonance )dˆ77.0) and
CD3OD resonance )dˆ49.0), respectively. The chemical
shifts of 31P are recorded relative to external 85% H3PO4
)dˆ0) with broad-band 1H decoupling. The aldehydes 2a,b
were prepared in enantiomerically pure forms from the
corresponding l-amino acids according to the literature
methods and used without puri®cation.6 All reactions were
conducted under nitrogen.
Mp 110±1138C; H NMR )400 MHz, CDCl3) d 7.30±7.06
)15H, m), 4.26±4.10 )1H, m), 4.09±3.98 )2H, m), 3.89 )1H,
d, Jˆ14.1 Hz), 3.83 )1H, d, Jˆ14.1 Hz), 3.70 )1H, d,
Jˆ14.1 Hz), 3.58 )1H, d, Jˆ14.1 Hz), 3.40±3.36 )1H, m),
3.12±3.07 )2H, m), 1.84±1.59 )2H, m), 1.23 )1.5H, t,
Jˆ7.0 Hz), 1.19 )1.5H, t, Jˆ7.0 Hz), 1.16 )1.5H, td,
Jˆ7.7, 17.4Hz), 1.06 )1.5H, td, Jˆ7.8, 17.4Hz); 31P
NMR )162 MHz, CDCl3) d 54.61, 54.39; IR )KBr) 3261,
1045 cm21; EIMS m/z 360 )M12CH2Ph). Anal. Calcd for
C27H34NO3P: C, 71.82; H, 7.59. Found: C, 71.41; H, 7.57.
1.2. The procedure for the hydrophosphinylation of 2a
with ethyl ethylphosphinate in the presence of TMSCl
and Et3N
1.1. The procedure for the hydrophosphinylation of 2a
with ethyl ethylphosphinate in the presence of &R)-ALB
To a solution of ethyl ethylphosphinate )732 mg, 6.0 mmol)
in THF )4mL) was added 0.1 M THF solution of ) R)-ALB
)8.0 mL, 0.8 mmol), prepared from )R)-BINOL )458 mg,
1.6 mmol) and LiAlH4 )30.4mg, 0.8 mmol) in situ accord-
ing to Shibasaki's method,3 and a solution of 2a )4.0 mmol)
in THF )8 mL) at 08C 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/EtOAcˆ1:1 to CHCl3/MeOHˆ20:1) to give
syn-3-A )142 mg, 8%), syn-3-B )338 mg, 19%) and anti-3
)513 mg, 28%).
To a solution of ethyl ethylphosphinate )732 mg, 6.0 mmol)
in CH2Cl2 )21 mL) was added TMSCl )0.76 mL, 6.0 mmol)
and Et3N )0.83 mL, 6.0 mmol) at 08C and the mixture was
stirred for 0.5 h at the same temperature. To this solution
was added a solution of 2a )4mmol) in THF )4mL) at 0 8C
and the mixture was stirred for 12 h at the same temperature.
The mixture was poured into cold H2O and extracted with
CHCl3. The combined extracts were washed with brine and
dried over MgSO4. Removal of the solvent gave a residue.
To a solution of the residue in THF )8 mL) was added 1 M
THF solution of Bu4NF )4.8 mL, 4.8 mmol) at 08C. After
stirring for 1 h at the same temperature, the mixture was
poured into cold 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/EtOAcˆ1:1 to
CHCl3/MeOHˆ20:1) to give a mixture of syn-3-A, syn-3-
B and anti-3 )992 mg, 55%).
1.1.1. Ethyl &1S,2S)-2-&dibenzylamino)-1-hydroxy-3-
23
phenylpropyl&ethyl)phosphinate &syn-3-A). Oil; [a]D
ˆ
1
124.2 )c 0.84, CHCl3); H NMR )300 MHz, CDCl3) d
7.42±7.04 )15H, m), 5.09 )1H, d, Jˆ15.8 Hz), 4.19±4.06
)2H, m), 3.77 )2H, d, Jˆ12.6 Hz), 3.66 )1H, dd, Jˆ5.4,
10.7 Hz), 3.50±3.33 )3H, m), 2.98 )1H, dd, Jˆ10.5,
14.4 Hz), 1.55±1.14 )2H, m), 1.35 )3H, t, Jˆ7.0 Hz), 0.87
)3H, td, Jˆ7.8, 17.3 Hz); 31P NMR )162 MHz, CDCl3) d
58.76; 13C NMR )75.5 MHz, CDCl3) d 140.0, 138.0, 129.6,
129.3, 128.6, 128.5, 127.4, 126.5, 66.4 )d, JPCˆ110.6 Hz),
60.3 )d, JPCˆ6.3 Hz), 58.6, 58.5, 53.3, 34.9, 16.5 )d,
JPCˆ93.9 Hz), 16.3 )d, JPCˆ5.2 Hz), 5.4)d, JPCˆ5.8 Hz);
IR )neat) 3240, 1029 cm21; EIMS m/z 360 )M12CH2Ph).
High resolution MS calcd for C20H27NO3P )M12CH2Ph):
360.1728. Found: 360.1722.
1.3. General procedure for the hydrophosphinylation of
2a,b with ethyl phosphinate in the presence of &R)-ALB
A
mixture of anhydrous phosphinic acid )396 mg,
6.0 mmol) and triethyl orthoformate )3.0 mL, 18.0 mmol)
was stirred for 1.5 h at room temperature. To this solution
was added 4mL of THF and 0.1 M THF solution of
)R)-ALB )8.0 mL, 0.8 mmol), prepared from )R)-BINOL
)458 mg, 1.6 mmol) and LiAlH4 )30.4mg, 0.8 mmol) in
situ, and a solution of 2a,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/EtOAcˆ1:1 to AcOEt) to give syn-4a,b and anti-
4a,b.
1.1.2. Ethyl &1S,2S)-2-&dibenzylamino)-1-hydroxy-3-
phenylpropyl&ethyl)phosphinate &syn-3-B). Mp 102±
1048C; [a]D ˆ135.9 )c 0.93, CHCl3); 1H NMR
24
)300 MHz, CDCl3) d 7.41±7.04 )15H, m), 4.94 )1H, d,
Jˆ17.0 Hz), 3.82±3.66 )4H, m), 3.55±3.45 )3H, m),
3.34±3.30 )1H, m), 3.01 )1H, dd, Jˆ10.7, 14.8 Hz), 1.93±
1.71 )2H, m), 1.17 )3H, td, Jˆ7.8, 17.9 Hz), 1.03 )3H, t,
Jˆ7.0 Hz); 31P NMR )162 MHz, CDCl3) d 55.80; 13C NMR
)75.5 MHz, CDCl3) d 140.2, 138.1, 129.6, 129.3, 128.6,
128.4, 127.4, 126.5, 66.6 )d, JPCˆ111.7 Hz), 61.0 )d,
JPCˆ7.5 Hz), 58.4, 53.3 )2 carbons), 35.0, 19.4 )d,
JPCˆ91.6 Hz), 16.6 )d, JPCˆ5.8 Hz), 5.3 )d, JPCˆ5.2 Hz);
IR )KBr) 3167, 1029 cm21; EIMS m/z 452 )MH1). Anal.
Calcd for C27H34NO3P: C, 71.82; H, 7.59. Found: C, 71.68;
H, 7.59.
1.3.1. Ethyl &1S,2S)-&dibenzylamino)-1-hydroxy-3-phenyl-
propylphosphinate &syn-4a). This compound was obtained
as a mixture of diastereomers in a ratio of 1:1. One of the
diastereisomers is crystallized in another oily dia-
1
stereisomer. Yield )987 mg, 58%); H NMR )400 MHz,
CD3OD)
d
7.44±7.16 )15H, m), 7.15 )0.5H, d,
Jˆ561.7 Hz), 7.03 )0.5H, d, Jˆ560.3 Hz), 4.28±4.18 )2H,
m), 4.14±4.04 )2H, m), 3.89 )0.5H, m), 3.77±3.54 )3H, m),
3.42±3.36 )0.5H, m), 3.26±3.07 )1.5H, m), 2.88±2.83
)0.5H, m), 1.30 )3H, t, Jˆ7.0 Hz); 31P NMR )162 MHz,
1.1.3. Ethyl &1R,2S)-2-&dibenzylamino)-1-hydroxy-3-
phenylpropyl&ethyl)phosphinate &anti-3). This compound
was obtained as a mixture of diastereomers in a ratio of 1:1.
CD3OD) d 44.42, 40.09; IR )KBr) 3221, 1190 cm21
;

T. Yamagishi et al. / Tetrahedron 58 .2002) 2577±2583
2581
FABMS m/z 424 )MH1). Anal. Calcd for C25H30NO3P: C,
70.90; H, 7.14. Found: C, 71.08; H, 7.10.
JPCˆ5.9 Hz); IR )KBr) 3271, 1197 cm21; FABMS m/z
424 )MH1). Anal. Calcd for C25H30NO3P: C, 70.90; H,
7.14. Found: C, 70.91; H, 7.17.
1.3.2.
Ethyl
&1R,2S)-&dibenzylamino)-1-hydroxy-3-
phenylpropylphosphinate &anti-4a). This compound was
obtained as a mixture of diastereomers in a ratio of 1:1.
One of the diastereisomers is crystallized in another oily
1.4. Crystal data for compound anti-4a-A
X-Ray crystal data of anti-4a-A were collected by Mac-
Science MXC18 diffractometer. The structure was solved
by a direct method using SIR9216 and re®ned with a full
matrix least-squares method. Molecular formulaˆC25H30-
NO3P, Mrˆ423.50, Orthorhombic, space groupˆP212121,
1
diastereisomer. Yield )131 mg, 8%); H NMR )400 MHz,
CD3OD)
d
7.27±7.08 )15H, m), 6.68 )0.5H, d,
Jˆ549.5 Hz), 6.53 )0.5H, d, Jˆ558.0 Hz), 4.42±4.34 )1H,
m), 4.28±3.95 )2H, m), 3.91 )1H, d, Jˆ12.3 Hz), 3.86 )1H,
d, Jˆ14.0 Hz), 3.78±3.70 )0.5 H, m), 3.60 )1H, d,
Jˆ14.3 Hz), 3.52 )1H, d, Jˆ14.1 Hz), 3.49±3.44 )0.5H,
m), 3.20±3.11 )1.5H, m), 2.99 )0.5H, dd, Jˆ4.6, 14.3 Hz),
1.28 )1.5H, t, Jˆ7.1 Hz), 1.18 )1.5H, t, Jˆ7.0 Hz); 31P
NMR )162 MHz, CD3OD) d 40.66, 38.40; IR )KBr) 3267,
1197 cm21; FABMS m/z 424 )MH1). Anal. Calcd for
C25H30NO3P: C, 70.90; H, 7.14. Found: C, 70.83; H, 7.12.
Ê
Ê 3
Ê
Ê
23
aˆ16.725 )4) A, bˆ12.170 )2) A, cˆ11.434 )3) A,
Vˆ2327.2 )9) A , Tˆ298 K, Zˆ4, Dxˆ1.208 mg m
,
)Mo Ka)ˆ0.71073 A, mˆ1.375 mm21
,
Rˆ0.083 over
Ê
2658 independent re¯ections. Crystallographic data
)excluding structure factors) for the X-ray crystal structure
analysis reported in this paper have been deposited with the
Cambridge Crystallographic Data Center )CCDC) as
supplementary publication No. CCDC-160271. Copies of
the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
144)0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
1.3.3. Ethyl &1S,2S)-&dibenzylamino)-1-hydroxy-4-methyl-
pentylphosphinate &syn-4b). This compound was obtained
as a mixture of diastereomers in a ratio of 1:1. Yield
1
)788 mg, 51%); An oil; H NMR )400 MHz, CD3OD) d
7.39±7.24)10H, m), 7.12 )0.5H, d, Jˆ558.6 Hz), 7.03
)0.5H, d, Jˆ555.5 Hz), 4.27±4.17 )1H, m), 4.15±4.01
)2H, m), 3.79±3.53 )4H, m), 3.31±3.25 )0.5H, m), 3.17±
3.12 )0.5H, m), 1.80±1.60 )2H, m), 1.39 )1.5H, t,
Jˆ7.1 Hz), 1.29 )1.5H, t, Jˆ7.0 Hz), 1.23±1.19 )1H, m),
0.93 )1.5H, t, Jˆ6.6 Hz), 0.85 )1.5H, d, Jˆ6.5 Hz), 0.82
)1.5H, d, Jˆ6.1 Hz), 0.79 )1.5H, d, Jˆ6.5 Hz); 31P NMR
)162 MHz, CD3OD) d 43.64, 41.92; IR )neat) 3255,
1189 cm21; EIMS m/z 296 )M12HP)O)OEt). High resolu-
tion MS calcd for C20H26NO )M12HP)O)OEt): 296.2014.
Found: 296.2002.
1.4.1. &1R,2S)-2-&Dibenzylamino)-1-[ethoxy&oxido)phos-
phino]-3-phenylpropyl acetate &5a). To a stirred solution
of anti-4a )701 mg, 1.5 mmol) in CH2Cl2 )4.5 mL) was
added Ac2O )0.50 mL, 4.5 mmol), pyridine )0.38 mL,
4.7 mmol) and DMAP )18 mg, 0.15 mmol) at 08C and the
mixture was stirred for 3 h at room 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 which was chromatographed on silica gel )hexane/
EtOAcˆ3:1 to 1:1) to give 5a )650 mg, 93%). This
compound was obtained as a mixture of diastereomer in a
1
1.3.4. Ethyl &1R,2S)-&dibenzylamino)-1-hydroxy-4-methyl-
pentylphosphinate &anti-4b). This compound was obtained
as a mixture of diastereomer in a ratio of 1:1. Yield )44 mg,
ratio of 1:1. An oil; H NMR )400 MHz, CD3OD) d 7.25±
7.13 )15H, m), 6.86 )0.5H, d with small splits, Jˆ583.7 Hz),
6.70 )0.5H, d with small splits, Jˆ579.8 Hz), 5.53±5.51
)1H, m), 4.08±3.97 )2H, m), 3.76 )1H, d, Jˆ13.7 Hz),
3.75 )1H, d, Jˆ13.7 Hz), 3.72±3.60 )1H, m), 3.56 )1H, d,
Jˆ13.7 Hz), 3.52 )1H, d, Jˆ13.7 Hz), 3.25±3.18 )1H, m),
2.99±2.88 )1H, m), 2.03 )1.5H, s), 1.98 )1.5H, s), 1.21
)1.5H, t, Jˆ7.0 Hz), 1.20 )1.5H, t, Jˆ7.1 Hz); 31P NMR
)162 MHz, CD3OD) d 33.12, 32.96; IR )neat) 1748,
1219 cm21; EIMS m/z 374)M 12CH2Ph). High resolution
MS calcd for C20H25NO4P )M12CH2Ph): 374.1521. Found:
374.1529.
1
3%); An oil; H NMR )400 MHz, CD3OD) d 7.38±7.24
)10H, m), 6.97 )0.5H, d with small splits, Jˆ540.3 Hz),
6.94)0.5H, d, Jˆ542.3 Hz), 4.45±4.38 )1H, m), 4.24±
4.10 )2H, m), 3.95 )2H, d, Jˆ13.6 Hz), 3.47 )2H, d,
Jˆ13.6 Hz), 3.22±3.16 )1H, m), 1.97±1.88 )2H, m), 1.39
)1.5H, t, Jˆ7.0 Hz), 1.33 )1.5H, t, Jˆ7.0 Hz), 1.29±1.24
)1H, m), 0.94)3H, d,
Jˆ6.7 Hz), 0.53 )1.5H, d,
Jˆ6.2 Hz), 0.51 )1.5H, d, Jˆ6.3 Hz); 31P NMR
)162 MHz, CD3OD) d 40.32, 39.00; IR )neat) 3277,
1203 cm21; FABMS m/z 390 )MH1). High resolution MS
calcd for C22H32NO3P )MH1): 390.2198. Found: 390.2175.
1.4.2. &1R,2S)-2-&Dibenzylamino)-1-[ethoxy&oxido)phos-
phino]-4-methylpentyl acetate &5b). The compound 5b
was prepared from 4b )1.56 g, 4.0 mmol) in an analogous
manner to that for preparation of 5a. Puri®cation of the
residue by column chromatography )hexane/EtOAcˆ3:1
to 1:1) gave 5b )1.64g, 95%). This compound was obtained
1.3.5. Ethyl &1R,2S)-&dibenzylamino)-1-hydroxy-3-phenyl-
propylphosphinate &anti-4a-A). This compound was
obtained by recrystallization of anti-4a from EtOAc. Mp
25
149±1508C; [a]D ˆ113.7 )c 0.80, MeOH); 1H NMR
1
)400 MHz, CD3OD) d 7.17±7.08 )15H, m), 6.68 )1H, d,
Jˆ549.5 Hz), 4.38±4.32 )1H, m), 4.11±3.98 )2H, m), 3.86
)2H, d, Jˆ14.0 Hz), 3.52 )2H, d, Jˆ14.1 Hz), 3.49±3.44
)1H, m), 3.12 )1H, dd, Jˆ9.7, 14.3 Hz), 2.99 )1H, dd,
Jˆ4.6, 14.3 Hz), 1.28 )3H, t, Jˆ7.1 Hz); 31P NMR
)162 MHz, CD3OD) d 40.66; 13C NMR )100 MHz,
CD3OD) d 141.4, 140.8, 131.0, 130.0, 129.1, 127.9,
127.1, 68.6 )d, JPCˆ109.3 Hz), 64.5 )d, JPCˆ7.9 Hz), 60.3
)d, JPCˆ8.0 Hz), 55.3 )2 carbons), 34.4, 16.7 )d,
as a mixture of diastereomers in a ratio of 1:1. An oil; H
NMR )400 MHz, CD3OD) d 7.36±7.25 )10H, m), 7.13
)0.5H, d with small splits, Jˆ577.3 Hz), 7.02 )0.5H, d
with small splits, Jˆ569.9 Hz), 5.61±5.59 )1H, m), 4.23±
4.09 )2H, m), 3.87 )1H, d, Jˆ6.1 Hz), 3.83 )1H, d,
Jˆ6.1 Hz), 3.45±3.37 )3H, m), 2.20 )1.5H, s), 2.19 )1.5H,
s), 1.97±1.93 )2H, m), 1.35 )1.5H, t, Jˆ6.9 Hz), 1.32 )1.5H,
t, Jˆ7.0 Hz), 0.98 )1.5H, d, Jˆ6.6 Hz), 0.97 )1.5H, d,
Jˆ6.6 Hz), 0.57 )1.5H, d, Jˆ6.4Hz), 0.56 )1.5H, d,

2582
T. Yamagishi et al. / Tetrahedron 58 .2002) 2577±2583
Jˆ6.4Hz); 31P NMR )162 MHz, CD3OD) d 33.29, 32.58;
IR )neat) 1747, 1219 cm21; EIMS m/z 432 )MH1). High
resolution MS calcd for C24H35NO4P )MH1): 432.2303.
Found: 432.2299.
)7.5 mL, 57.6 mmol), pyridine )4.6 mL, 59.5 mmol) and
DMAP )234mg, 1.9 mmol) at 0 8C and the mixture was
stirred for 3 h at room temperature. The mixture was poured
into cold water and extracted with Et2O. The combined
extracts were washed with brine and dried over MgSO4.
Removal of the solvent gave a residue which was chroma-
tographed on silica gel )hexane/EtOAcˆ4:1 to 2:1) to give
1.4.3.
&1R,2S)-2-&Dibenzylamino)-1-&dimethoxyphos-
phoryl)-3-phenylpropyl acetate &6a). A solution of 5a
)564mg, 1.21 mmol), DMSO )0.1 mL, 1.45 mmol) and
iodine )30 mg, 0.12 mmol) in THF )4mL) was stirred for
5 h at 608C. The mixture was evaporated to give a residue.
To a stirred solution of the residue in CH2Cl2 )4mL) was
added TMSBr )0.4mL, 3.03 mmol) and stirred for 12 h at
room temperature. After the mixture was concentrated, the
residue was dissolved in MeOH )4mL) and stirred for 2 h at
room temperature. Evaporation of the mixture gave a
residue. To a stirred solution of the CH2N2 in Et2O
)25 mL), prepared from 70 % N-nitroso-N-methylurea
)713 mg, 4.84 mmol), was added a solution of the residue
in Et2O/MeOHˆ10:1 )6.6 mL) at 08C and the solution was
stirred for 30 min at the same temperature. After decompo-
sition of excess CH2N2 with AcOH )0.05 mL), the mixture
was diluted with H2O 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/EtOAcˆ2:1 to
26
8a )7.31 g, 75%). An oil; [a]D ˆ14.3 )c 0.61, CHCl3); 1H
NMR )400 MHz, CDCl3) d 7.25±6.99 )15H, m), 5.89 )1H, d
with small splits, Jˆ13.3 Hz), 4.14±4.06 )4H, m), 3.99±
3.93 )1H, m), 3.86 )2H, d, Jˆ13.9 Hz), 3.57±3.52 )1H,
m), 3.30 )2H, d, Jˆ13.9 Hz), 3.00 )1H, dd, Jˆ11.2,
14.7 Hz), 2.20 )3H, s), 1.30 )3H, t, Jˆ7.1 Hz), 1.22 )3H, t,
Jˆ7.1 Hz); 13C NMR )100 MHz, CDCl3) d 169.4, 139.8,
138.9, 129.6, 128.7, 128.0, 126.8, 125.9, 65.3 )d,
JPCˆ162.6 Hz), 62.7 )d, JPCˆ5.3 Hz, 2 carbons), 58.0 )d,
JPCˆ6.0 Hz), 53.1 )2 carbons), 33.5, 21.1, 16.4)d,
JPCˆ5.7 Hz), 16.3 )d, JPCˆ5.7 Hz), 15.2; 31P NMR
)162 MHz, CDCl3) d 21.13; IR )neat) 1749, 1222 cm21
;
EIMS m/z 510 )MH1). High resolution MS calcd for
C29H36NO5P )M1): 509.2331. Found: 509.2349.
1.4.6. &1R,2S)-2-&Dibenzylamino)-1-&diethoxyphosphoryl)-
4-methylpentyl acetate &8b). The compound 8b was
prepared from 7b )1.23 g, 2.8 mmol) in an analogous
manner to that for preparation of 8a. Puri®cation of the
residue by column chromatography )hexane/EtOAcˆ3:1
25
EtOAc) to give 6a )63 mg, 11%). An oil; [a]D ˆ17.0 )c
1
0.49, CHCl3); H NMR )400 MHz, CDCl3) d 7.25±7.01
26
)15H, m), 5.88 )1H, d with small splits, Jˆ13.2 Hz), 3.84
)2H, d, Jˆ13.8 Hz), 3.75 )3H, d, Jˆ10.8 Hz), 3.65 )3H, d,
Jˆ10.6 Hz), 3.56±3.50 )1H, m), 3.31 )2H, d, Jˆ13.8 Hz),
3.22 )1H, dd, Jˆ3.4, 14.7 Hz), 3.01 )1H, dd, Jˆ10.9,
14.7 Hz), 2.18 )3H, s); 13C NMR )100 MHz, CDCl3) d
169.4 , 139.7, 138.7, 129.5, 128.7, 128.0, 126.8, 125.9,
65.5 )d, JPCˆ162.2 Hz), 60.3, 58.0 )d, JPCˆ5.7 Hz), 53.2
)d, JPCˆ10.2 Hz), 53.1 )d, JPCˆ10.7 Hz), 33.4, 21.0, 14.2;
to 1:1) gave 8b )929 mg, 70%). An oil; [a]D ˆ237.7 )c
1
0.62, CHCl3); H NMR )400 MHz, CDCl3) d 7.33±7.20
)10H, m), 5.85 )1H, d, Jˆ13.6 Hz), 4.15±4.06 )4H, m),
4.02±3.94 )1H, m), 3.82 )2H, d, Jˆ13.4Hz), 3.24)2H, d,
Jˆ13.4Hz), 2.15 )3H, s), 1.99±1.89 )1H, m), 1.81±1.74
)1H, m), 1.51±1.44 )1H, m), 1.30 )3H, t, Jˆ7.1 Hz), 1.24
)3H, t, Jˆ7.1 Hz), 0.93 )3H, d, Jˆ6.8 Hz), 0.42 )3H, d,
Jˆ6.5 Hz); 13C NMR )100 MHz, CDCl3) d 169.5, 139.6,
129.4, 129.2, 128.1, 127.0, 65.8 )d, JPCˆ162.3 Hz), 62.6
)2 carbons, d, JPCˆ6.9 Hz), 54.1 )d, JPCˆ5.7 Hz), 53.2,
36.3, 24.2, 24.0, 21.0, 20.8, 20.6, 16.5 )d, JPCˆ5.8 Hz),
16.4)d, JPCˆ6.0 Hz); 31P NMR )162 MHz, CDCl3) d
21.51; IR )neat) 1749, 1224 cm21; EIMS m/z 476 )MH1).
High resolution MS calcd for C26H38NO5P )M1): 475.2487.
Found: 475.2473.
31P NMR )162 MHz, CDCl3)
d
23.56; IR )neat)
1748, 1222 cm21; EIMS m/z 482 )MH1). High resolution
MS calcd for C27H31NO5P )M12H): 480.1939. Found:
480.1944.
1.4.4.
&1R,2S)-2-&Dibenzylamino)-1-&dimethoxyphos-
phoryl)-4-methylpentyl acetate &6b). The compound 6b
was prepared from 5b )1.70 g, 4.0 mmol) in an analogous
manner to that for preparation of 6a. Puri®cation of the
residue by column chromatography )hexane:EtOAcˆ3:1
1.4.7.
&1R,2S)-2-&Dibenzylamino)-1-&dimethoxyphos-
phoryl)-3-phenylpropyl acetate &6a). To a stirred solution
of 8a )1.22 g, 2.4mmol) in CH 2Cl2 )8 mL) was added
TMSBr )1.7 mL, 9.6 mmol) and stirred for 12 h at room
temperature. After the mixture was concentrated, the resi-
due was dissolved in MeOH )11 mL) and stirred for 2 h at
room temperature. Evaporation of the mixture gave a resi-
due. To a stirred solution of the CH2N2 in Et2O )54mL),
prepared from 70% N-nitroso-N-methylurea )1.40 g,
9.6 mmol), was added a solution of the residue in Et2O/
MeOHˆ10:1 )14.9 mL) at 08C and the solution was stirred
for 30 min at the same temperature. After decomposition of
excess CH2N2 with AcOH )0.1 mL), the mixture was diluted
with H2O 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/EtOAcˆ2:1 to EtOAc) to give 6a
25
to 1:1) gave 6b )126 mg, 7%). An oil; [a]D ˆ235.0 )c
1
0.85, CHCl3); H NMR )400 MHz, CDCl3) d 7.33±7.21
)10H, m), 5.86 )1H, d, Jˆ13.8 Hz), 3.82 )2H, d,
Jˆ13.4Hz), 3.74 )3H, d, Jˆ10.7 Hz), 3.67 )3H, d,
Jˆ10.6 Hz), 3.24)2H, d, Jˆ13.4Hz), 3.21±3.18 )1H, m),
2.15 )3H, s), 1.99±1.88 )1H, m), 1.81±1.74)1H, m), 1.45±
1.38 )1H, m), 0.93 )3H, d, Jˆ6.8 Hz), 0.43 )3H, d,
Jˆ6.5 Hz); 13C NMR )100 MHz, CDCl3) d 169.4, 139.4,
129.2, 128.1, 127.0, 126.8, 65.5 )d, JPCˆ161.5 Hz), 54.0
)d, JPCˆ 5.9 Hz), 53.3, 53.0 )d, JPCˆ6.5 Hz), 52.9 )d,
JPCˆ7.2 Hz), 36.3, 24.0, 20.9, 20.6; 31P NMR )162 MHz,
CDCl3) d 23.94; IR )neat) 1748, 1223 cm21; EIMS m/z 448
)MH1). High resolution MS calcd for C24H35NO5P )MH1):
448.2252. Found: 448.2208.
25
1.4.5. &1R,2S)-2-&Dibenzylamino)-1-&diethoxyphosphoryl)-
3-phenylpropyl acetate &8a). To a stirred solution of 7a
)7.81 g, 19.2 mmol) in CH2Cl2 )58 mL) was added Ac2O
)702 mg, 61%). [a]D ˆ17.9 )c 0.96, CHCl3). The 1H
NMR spectrum was identical with that of the authentic
sample prepared from anti-4a.

T. Yamagishi et al. / Tetrahedron 58 .2002) 2577±2583
2583
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 and references
cited therein.
1.4.8.
&1R,2S)-2-&Dibenzylamino)-1-&dimethoxyphos-
phoryl)-4-methylpentyl acetate &6b). The compound 6b
was prepared from 8b )784mg, 1.7 mmol) in an analogous
manner to that for preparation of 6a. Puri®cation of the
residue by column chromatography )hexane/EtOAcˆ3:1±
4. Yamagishi, T.; Yokomatsu, T.; Suemune, K.; Shibuya, S.
Tetrahedron 1999, 55, 12125.
25
1:1) gave 6b )406 mg, 55%). [a]D ˆ236.9 )c 0.70,
1
5. Froestl, W.; Mickel, S. J.; Sprecher, G.; Diel, P. J.; Hall, R. G.;
Maier, L.; Strub, D.; Melillo, V.; Baumann, P. A.; Bernasconi,
R.; Gentsch, C.; Hauser, K.; Jaekel, J.; Karlsson, G.; Klebs, K.;
CHCl3). The H NMR spectrum was identical with that of
the authentic sample prepared from anti-4b.
Ã
Maõtre, L.; Marescaux, C.; Pozza, M. F.; Schmutz, M.;
1.4.9. &1R,2S)-2-&Dibenzylamino)-1-hydroxy-3-phenyl-
propyl&ethyl)phosphinic acid &9). To a stirred solution of
anti-3 )187 mg, 0.41 mmol) in CH2Cl2 )2 mL) was added
TMSBr )0.11 mL, 0.82 mmol) at 08C and the mixture was
stirred for 12 h at room temperature. After the mixture was
concentrated, the residue was dissolved in MeOH )1 mL)
and stirred for 1 h at room temperature. Evaporation of the
Steinmann, M. W.; Riezen, H.; Vassout, A.; Mondadori, C.;
Olpe, H.-R.; Waldmeier, P. C.; Bittiger, H. J. Med. Chem.
1995, 38, 3313.
6. Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1991, 30, 1531.
7. Fitch, S. J. J. Am. Chem. Soc. 1964, 86, 61.
8. Preliminary communication of this work: Yamagishi, T.;
Suemune, K.; Yokomatsu, T.; Shibuya, S. Tetrahedron Lett.
2001, 42, 5033.
25
solvent gave 9 )161 mg, 93%). Amorphous; [a]D ˆ123.2
)c 0.69, MeOH); 1H NMR )400 MHz, CD3OD) d 7.61±6.89
)15H, m), 4.97±4.88 )1H, m), 4.56±4.46 )1H, m), 4.42 )1H,
dd, Jˆ5.3, 9.4 Hz), 4.32±4.21 )1H, m), 4.15±4.06 )1H, m),
4.05±3.97 )1H, m), 3.58 )1H, dd, Jˆ4.5, 15.8 Hz), 3.51 )1H,
dd, Jˆ7.2, 15.8 Hz), 1.83±1.70 )1H, m), 1.50±1.37 )1H, m),
1.01 )3H, td, Jˆ7.7, 18.2 Hz); 31P NMR )162 MHz,
CD3OD) d 56.02; 13C NMR )100 MHz, CD3OD) d 138.7,
132.2, 131.7, 131.2, 131.1, 130.6, 130.3, 130.2, 128.6, 65.4
)d, JPCˆ108.3 Hz), 65.2 )d, JPCˆ5.5 Hz), 56.8, 55.8, 31.8 )d,
JPCˆ7.5 Hz), 19.3 )d, JPCˆ90.9 Hz), 5.1 )d, JPCˆ5.8 Hz);
IR )KBr) 3208, 1149 cm21. FABMS m/z 424 )MH1). High
resolution MS calcd for C25H31NO3P )MH1): 424.2041.
Found: 424.2035.
9. 31P NMR spectroscopic analysis has been successfully
applied to determine the diastereomeric excess of chiral
phosphonate derivatives. See: )a) Yokomatsu, T.; Yamagishi,
T.; Shibuya, S. J. Chem. Soc., Perkin Trans. 1 1997, 1527.
)b) Hammerschmidt, F.; Li, Y.-F. Tetrahedron 1994, 50,
10253. )c) Kozlowski, J. K.; Rath, N. P.; Spilling, C. D.
Tetrahedron 1995, 51, 6385.
10. In our earlier study, the reaction of 2a with diethyl t-butyl-
dimethylsilylphosphite
gave
anti-b-amino-a-hydroxy-
phosphonate with modest selectivity )syn/antiˆ1:2.8). See:
Yokomatsu, T.; Yamagishi, T.; Shibuya, S. Tetrahedron:
Asymmetry 1993, 4, 1401.
11. The moderate yield of products might be due to partial
hydrolysis of the ethyl phosphinate functionality during the
work up.
Acknowledgements
12. We con®rmed that the ratio of anti-4a-B to anti-4a-A was not
changed after re¯uxing a solution of anti-4a in ethyl acetate
for 4h. Thus, there was no possibility of epimerization from
anti-4a-B to anti-4a-A in the recrystallization.
13. Albouy, D.; Brun, A.; Munoz, A.; Etemad-Moghadam, G.
J. Org. Chem. 1995, 60, 6656.
The authors wish to thank Mr Haruhiko Fukaya )the
analytical center of this university) for the X-ray crystal-
lographic analysis.
References
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16. Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G.;
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