Asymmetric synthesis of optically active α-substituted α-amino-H-phosphinates through resolution of 1,1-diethoxyethyl(aminomethyl)phosphinates

Article abstract of DOI:10.1016/j.tetasy.2007.11.021

Both enantiomers of 1,1-diethoxyethyl(aminomethyl)phosphinates were prepared through chromatographic separation of a diastereomeric mixture derived from (S)-phenylethylamine and 1,1-diethoxyethyl-H-phosphinate. The individual enantiomer was transformed into α-substituted α-amino-H-phosphinate with high enantiomeric purity by a highly diastereoselective alkylation at the α-carbon on the basis of our previously developed method.

Full text of DOI:10.1016/j.tetasy.2007.11.021

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2886–2893
Asymmetric synthesis of optically active a-substituted
a-amino-H-phosphinates through resolution
of 1,1-diethoxyethyl(aminomethyl)phosphinates
Terumitsu Haruki, Takehiro Yamagishi and Tsutomu Yokomatsu*
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 3 October 2007; accepted 15 November 2007
Abstract—Both enantiomers of 1,1-diethoxyethyl(aminomethyl)phosphinates were prepared through chromatographic separation of a
diastereomeric mixture derived from (S)-phenylethylamine and 1,1-diethoxyethyl-H-phosphinate. The individual enantiomer was trans-
formed into a-substituted a-amino-H-phosphinate with high enantiomeric purity by a highly diastereoselective alkylation at the a-carbon
on the basis of our previously developed method.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
from the chirality of the phosphorus atom was utilized
without separation.
a-Aminophosphinic acid derivatives are of much interest
due to their usefulness both in the development of catalytic
antibodies1 and pharmacologically active substances.2
Some peptides incorporating these molecules have been
shown to be effective inhibitors against aspartic acid prote-
ases and Zn-metalloproteases.3 For the preparation of var-
ious a-aminophosphinic acid derivatives, a-substituted
a-amino-H-phosphinic acids have been utilized as versatile
synthetic intermediates.4 Inspection of the literature
revealed that the asymmetric synthesis of this class of com-
pounds has been attained relying upon resolution5 or
kinetic resolution with enzymes.6 An alternative synthesis
involves the alkylation at the a-carbon of imines derived
from optically active 2-hydroxypinan-3-one and amino-
methylphosphinate which has a diethoxymethyl function-
ality as a protecting group at the phosphorus atom.7
However, in this methodology, the diastereoselectivity for
the alkylation induced by the chiral auxiliary on the nitro-
gen was reported to be modest and the enantiomeric purity
of target a-substituted a-amino-H-phosphinic acids
resulted in low yields. The modest selectivity might be asso-
ciated with the diastereomeric purity of the substrate
imine; a 1:1 mixture of a diastereomeric isomer arising
We recently succeeded in the diastereoselective synthesis of
racemic a-substituted a-amino-H-phosphinates showing a
defined stereochemistry at both the phosphorus atom and
the a-carbon starting from ethyl 1,1-diethoxyethyl(amino-
methyl)phosphinate 1 (Scheme 1).8 In our methodology,
the alkylation of the phosphorus-stabilized carbanion is
controlled by the chirality of the phosphorus atom. The
protecting group on the phosphorus atom could be
removed under mild conditions without a loss of the phos-
phorus chirality.
O
P
Me
O
P
Me
Ph
Ph
H2N
OEt
OEt
N
OEt
OEt
OEt
OEt
1
O
Me
O
Me
Ph
Ph
H
N
P
OEt
OEt
Ts
N
P
OEt
OEt
OEt
OEt
R
R
O
H
Ts
N
P
H
OEt
R
*
Corresponding author. Tel./fax: +81 42 676 3239; e-mail: yokomatu@
ps.toyaku.ac.jp
Scheme 1.
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.11.021

T. Haruki et al. / Tetrahedron: Asymmetry 18 (2007) 2886–2893
2887
Based upon our methodology, the preparation of optically
active forms of a-substituted a-amino-H-phosphinates in
high optical purity would be feasible, if an optically active
form of ethyl 1,1-diethoxyethyl(aminomethyl)phosphinate
1 was used as a starting material. Herein, we report
the experimental results on the preparation of both the
enantiomer of ethyl 1,1-diethoxyethyl(aminomethyl)phos-
phinate through resolution and then conversion into
a-substituted a-amino-H-phosphinates.
2. Results and discussion
Figure 1. ORTEP drawing of the X-ray crystal structure of (R*,SPꢀ )-4.
2.1. Determination of stereochemistry of a-substituted
a-amino-H-phosphinates
As described in our previous paper,8 the deprotection step
of a 1,1-diethoxyethyl moiety for a-substituted N-Ts-a-
aminophosphinates into the corresponding a-amino-H-
phosphinates proceeded in a highly diastereoselective man-
ner (Scheme 1). The relative stereochemistry of the product
was estimated on the hypothesis that this deprotection step
proceeded with retention of the phosphorus chirality. To
confirm the stereochemistry of a-substituted N-Ts-a-ami-
no-H-phosphinates, we attempted to obtain a single crystal
suitable for X-ray crystallographic analysis. However, this
attempt failed. Therefore, in this study, we first surveyed
other derivatives suitable for X-ray crystallographic analy-
sis to verify the stereochemistry of a-substituted a-amino-
H-phosphinates. Via these efforts, racemic imine (R*,RPꢀ )-
2 was transformed into N-benzoyl derivative (R*,RPꢀ )-3
through sequential hydrogenolysis and benzoylation
(Scheme 2). Deprotection of a 1,1-diethoxyethyl moiety
in (R*,RꢀP)-3 was conducted with TMSCl and EtOH to fur-
nish a-substituted N-Bz-a-amino-H-phosphinate (R*,SPꢀ )-4
without detecting the (R*,RPꢀ )-isomer. The relative configu-
ration of (R*,SꢀP)-4 was determined unambiguously by X-
ray crystallographic analysis (Fig. 1). Thus, we confirmed
that the deprotection step proceeded in a retentive manner
of phosphorus chirality as predicted.
both the enantiomer of 1,1-diethoxyethyl(aminomethyl)-
phosphinate 1, necessary for extending our methodology
to the enantio-divergent synthesis of a-substituted a-ami-
no-H-phosphinates. Racemic
1 has previously been
synthesized through the reductive debenzylation
of (benzylamino)methyl(1,1-diethoxyethyl)phosphinate 7,
prepared via the addition of 1,1-diethoxyethyl-H-phosphi-
nate 69 to 1,3,5-tribenzyl-1,3,5-triazinane 5 (Scheme 3). We
applied this method for the preparation of both enantio-
mers of 1. Thus, optically active triazinane 9 was prepared
from paraformaldehyde and (S)-phenylethylamine
8
according to a literature procedure (Scheme 4).10 Subse-
quently, 9 was treated with H-phosphinate 6 to give amino-
phosphinate 10 as a 1:1 mixture of diastereoisomers. The
separation of the individual diastereomer of 10 on column
chromatography under a variety of conditions failed due to
the high polarity of 10. Therefore, amine 10 was converted
into several secondary amine derivatives by introducing a
functionality, which was readily removed after separation.
For this purpose, a-picolineborane (a-pic-BH3)-mediated
reductive amination11 of several aromatic aldehydes
including benzaldehyde, 4-bromobenzaldehyde, 4-anisalde-
hyde, 1-naphthaldehyde, and 2-naphthaldehyde with
amine 10 was examined. We were pleased to find that
(S,RP)-11 and (S,SP)-11, derived from 2-naphthaldehyde,
proved to be optimum derivatives, which were provided
in relatively good yields (67%) and easily isolated by silica
gel column chromatography. Although the exact reason for
the facile separation of (S,RP)-11 and (S,SP)-11 is unclear,
it might be attributed to an increased hydrophobic prop-
erty. Hydrogenolysis of (S,RP)-11 over Pd(OH)2–C and
the subsequent transformation of the resulting amine to
imine furnished the desired optically active 1,1-diethoxy-
O
P
Me
O
P
Me
Ph
Ph
H
1) H2, Pd(OH)2-C
2) BzCl, Et3N
N
OEt
OEt
Bz
N
OEt
OEt
OEt
OEt
Bn
(R*,RP*)-2
Bn
(R*,RP*)-3 (54%, 2 steps)
O
TMSCl
EtOH
H
Bz
N
P
H
OEt
CH2Cl2
Bn
(R*,SP*)-4 (67%)
O
P
Me
H
OEt
OEt
Scheme 2.
Bn
N
OEt
O
P
Me
H
6
R
N
OEt
OEt
2.2. Preparation of optically active 1,1-diethoxyethyl-
(aminomethyl)phosphinate
toluene
reflux
N
N
OEt
Bn
Bn
7: R=Bn (85%)
1: R=H (83%)
5
Pd(OH)2-C
H2, MeOH
After the unambiguous establishment of the stereochemical
outcome in our synthesis of a-substituted a-amino-H-phos-
phinates, our attention next centered on the preparation of
Scheme 3.

2888
T. Haruki et al. / Tetrahedron: Asymmetry 18 (2007) 2886–2893
Me
Ph
N
O
P
Me
Ph
NH2
N
H
N
a
b
Ph
OEt
OEt
Me
Ph
N
Me
OEt
10
Me
Me
8
Me
Ph
9
R
R
O
Me
O
P
c
+
Ph
N
P
OEt
Ph
N
OEt
OEt
OEt
OEt
OEt
Me
Me
(S,RP)-11
(S,SP)-11
R=2-naphthyl
d,e
d,e
O
P
Me
O
P
Me
Ph
Ph
Ph
Ph
N
OEt
OEt
N
OEt
OEt
OEt
OEt
(RP)-12
(SP)-12
Scheme 4. Reagents and conditions: (a) (CH2O)n, TsOHꢂH2O, MeOH, reflux; (b) 6, toluene, reflux, 61% (2 steps); (c) a-pic-BH3, 2-naphthaldehyde,
MeOH/AcOH (10:1), rt, 67%; (d) H2, Pd(OH)2–C, MeOH; (e) benzophenone, toluene, reflux, (RP)-12: 51% (2 steps), (SP)-12: 45% (2 steps).
ethyl(aminomethyl)phosphinate (RP)-12. Enantiomer (SP)-
12 was also prepared from (S,SP)-11.
(RP)-12 through the same sequence (Scheme 6). The inter-
mediary free amine (R,RP)-18 was found to be almost
enantiomerically pure by 31P NMR analysis of the corre-
sponding (R)-MTPA and (S)-MTPA-amides, indicating
that no racemization occurred in this sequence.
2.3. Diastereoselective synthesis of optically active a-substi-
tuted a-amino-H-phosphinates
LHMDS
BnBr
O
P
Me
O
P
Me
With optically active 1,1-diethoxyethyl(aminomethyl)phos-
phinates in hand, we next directed our efforts toward their
conversion into a-amino-H-phosphinates (Scheme 5).
According to our previous procedure, treatment of the
anion, generated from (SP)-12 and LHMDS, with benzyl
bromide at ꢁ78 °C gave (S,SP)-2 and (R,SP)-2 in a 10:1
ratio. The reaction with i-BuI proceeded at room tempera-
ture providing (S,SP)-13 and (R,SP)-13 in a ratio of
10:1. After sequential hydrogenolysis and tosylation of
(S,SP)-2, deprotection of the ketal moiety in tosylamide
(S,SP)-14 provided a-amino-H-phosphinate (S,RP)-16.
Moreover, (S,SP)-13 was converted into (S,RP)-17.
Ph
Ph
Ph
Ph
N
OEt
OEt
N
OEt
OEt
THF, -78 °C
OEt
OEt
Bn
(R,RP)-2 (73%, dr=10:1)
(RP)-12
H2
TsCl
Et3N
O
Me
O
P
Me
Pd(OH)2-C
H
H2N
P
OEt
OEt
Ts
N
OEt
OEt
MeOH
OEt
CH2Cl2
OEt
Bn
Bn
(R,RP)-18 (50%, >99% ee)
(R,RP)-14 (93%)
O
H
TMSCl
EtOH
Ts
N
P
H
LHMDS
O
P
Me
O
P
Me
Ph
Ph
Ph
Ph
BnBr or i-BuI
OEt
CH2Cl2
N
OEt
OEt
Bn
N
OEt
OEt
THF
-78 °C or rt
OEt
(R,SP)-16 (73%)
OEt
R
(SP)-12
(S,SP)-2: R=Bn (74%, dr=10:1)
(S,SP)-13: R=i-Bu (68%, dr=10:1)
Scheme 6.
The absolute configuration of (R,SP)-16 was determined
after conversion into the a-amino phosphonate (R)-19
through oxidation with DMSO and I2,12 followed by ester-
ification with diazoethane (Scheme 7). The negative sign of
1) H2
Pd(OH)2-C
O
O
P
Me
TMSCl
EtOH
H
H
Ts
N
P
H
Ts
N
OEt
OEt
2) TsCl, Et3N
OEt
OEt
CH2Cl2
R
R
(S,SP)-14: R=Bn (47%, 2 steps)
(S,SP)-15: R=i-Bu (58%, 2 steps)
(S,RP)-16: R=Bn (74%)
(S,RP)-17: R=i-Bu (93%)
O
O
H
H
1) DMSO, I2
2) CH3CHN2
Ts
N
P
H
Ts
N
P
OEt
Scheme 5.
OEt
OEt
Bn
(R,SP)-16
Bn
(R)-19
The optically active a-amino-H-phosphinates (R,SP)-16,
enantiomer of (S,RP)-16, was prepared starting from
Scheme 7.

T. Haruki et al. / Tetrahedron: Asymmetry 18 (2007) 2886–2893
2889
24
the optical rotation f½aꢃD ¼ ꢁ27:5 (c 0.2, CHCl3)} was
4.3 Hz), 57.7 (d, JCP = 7.7 Hz), 47.3 (d, JCP = 93.3 Hz),
35.1, 19.9 (d, JCP = 13.1 Hz), 16.5 (d, JCP = 4.9 Hz), 15.4,
opposite to that of known compound (S)-19 with 65% ee
20
f½aꢃD ¼ þ20:0 (c 0.1, CH2Cl2)}.13
14.9; 31P NMR (162 MHz, CDCl3)
d
42.44; IR
(KBr) 3296, 1649, 1159, 1034 cmꢁ1; MS m/z 434 (MH+);
HRMS: (MH+) calcd for C23H33NO5P, 434.2096; found,
434.2114.
3. Conclusion
4.2. (1R*,SꢀP)-Ethyl 1-benzoylamino-2-phenylethyl-
phosphinate (R*,SPꢀ )-4
In conclusion, we have developed a method for preparing
optically active aminomethylphosphinates via resolution
starting from (S)-phenylethylamine. These compounds
were converted into a-amino-H-phosphinates in a dia-
stereoselective manner via alkylation and deprotection of
the ketal moiety. Application of the synthesis of peptide
derivatives is currently ongoing.
To a solution of (R*,RPꢀ )-3 (380 mg, 0.88 mmol) in CH2Cl2
(18.3 mL) were added EtOH (103 lL), and TMSCl
(223 lL, 1.76 mmol) at room temperature. After stirring
for 2 h at the same temperature, the mixture was concen-
trated to give a residue, which was purified by column
chromatography (CHCl3) to give (R*,SPꢀ )-4 (188 mg,
67%). Colorless plates; mp 196–199 °C; 1H NMR
(400 MHz, CDCl3) d 7.66–7.21 (10H, m), 7.20 (1H, d,
J = 560.5 Hz), 4.80–4.74 (1H, m), 4.22–4.12 (2H, m),
3.33–3.20 (1H, m), 3.17–3.11 (1H, m), 1.37 (3H, t,
J = 7.1 Hz); 13C NMR (100 MHz, CDCl3) d 168.1,
136.7–127.4 (aromatic), 63.7, 50.0 (d, JCP = 107.6 Hz),
32.7, 16.6 (d, JCP = 5.7 Hz); 31P NMR (162 MHz, CDCl3)
d 32.82; IR (KBr) 3284, 2372, 1657, 1205, 1041 cmꢁ1; MS
m/z 318 (MH+); HRMS: (MH+) calcd for C17H21NO3P,
318.1259; found, 318.1257.
4. Experimental
All melting points were taken on a Yanagimoto micro-
melting point apparatus and are uncorrected. IR spectra
were recorded on a JASCO FTIR-620. Mass spectra were
measured on Micromass LCT and Micromass Autospec
by electrospray ionization. NMR spectra were obtained
on a Bruker DPX400 NMR spectrometer operated at
400 MHz for 1H, 100 MHz for 13C, and 162 MHz for
31P. The chemical shift data for each signal on 1H
NMR are given in units of d relative to CHCl3
(d = 7.26) for CDCl3 solution. For 13C NMR spectra,
the chemical shifts in CDCl3 are recorded relative to the
CDCl3 resonance (d = 77.0). The chemical shifts of 31P
are recorded relative to external 85% H3PO4 (d = 0) with
broad-band 1H decoupling. Flash column chromatogra-
phy was performed on 40–100 lm Silica Gel 60 (Kanto
Chemical Co., Inc.). Column chromatography was carried
out using 63–210 lm Silica Gel 60N (Kanto Chemical
Co., Inc.).
4.3. Crystal data for compound (R*,SPꢀ )-4
X-ray crystal data of (R*,SPꢀ )-4 were collected by a Mac-Sci-
ence DIP Image plate diffractometer. The structure was
solved by a direct method using SIR9714 and refined with
a full matrix least-squares method.15 Molecular for-
mula = C17H20NO3P, Mr = 317.31, monoclinic, space
˚
˚
group = P21/C,
a = 10.4630(18) A,
b = 9.5200(7) A,
3
˚
˚
c = 16.795(3) A, V = 1586.4(4) A , T = 100(2) K, Z = 4,
Dx = 1.329 mg mꢁ3
,
(Mo
Ka) = 0.71073 A,
l =
˚
0.185 mmꢁ1, R = 0.0933 over 3240 independent reflections.
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cam-
bridge Crystallographic Data Center as Supplementary
Publication Numbers CCDC 649212. Copies of the data
can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, UK [fax: +44(0)-
1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
4.1. (1R*,RꢀP)-1,1-diethoxyethyl(1-benzoylamino-2-phenyl-
ethyl)phosphinate (1R*,RPꢀ )-3
To a solution of (R*,RPꢀ )-2 (1.34 g, 2.72 mmol) in MeOH
(27.2 mL) was added 20% Pd(OH)2–C (163 mg) and stirred
for 23 h at room temperature under a hydrogen atmo-
sphere. The catalyst was removed by filtration through a
pad of Celite and the filtrate was concentrated to give a res-
idue. To a solution of the residue in CH2Cl2 (29.2 mL) were
added Et3N (0.76 mL, 5.5 mmol) and BzCl (0.32 mL,
3.8 mmol) and stirred for 30 min at room temperature.
After the mixture was concentrated, the residue was poured
into 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 purified by flash
column chromatography (CHCl3) to give (R*,RPꢀ )-3
(637 mg, 54%). Colorless plates; mp 152–154 °C; 1H
NMR (400 MHz, CDCl3) d 7.64–7.16 (10H, m), 5.14–
5.04 (1H, m), 4.30–4.17 (2H, m), 3.87–3.70 (4H, m),
3.39–3.29 (1H, m), 3.20–3.03 (1H, m), 1.58 (3H, d,
J = 12.1 Hz), 1.37 (3H, t, J = 7.0 Hz), 1.26 (3H, t, J =
7.1 Hz), 1.24 (3H, t, J = 7.0 Hz); 13C NMR (100 MHz,
CDCl 3) d 166.5, 137.5–126.6 (aromatic), 102.3 (d,
4.4. 1,3,5-Tris[(1S)-1-phenylethyl]-1,3,5-triazinane 9
To a solution of paraformaldehyde (6.0 g, 200 mmol) in
MeOH (200 mL) were added (S)-phenylethylamine 8
(25.6 mL, 200 mmol) and TsOHꢂH2O (7.6 g, 40 mmol)
and stirred for 20 h at 60 °C. After the mixture was concen-
trated, the residue was poured into satd NaHCO3 solution
and extracted with CHCl3. The combined extracts were
washed with brine and dried over MgSO4. Removal of
the solvent gave 9 (27.0 g). This compound was utilized
for the next reaction without further purification. Pale yel-
low oil; 1H NMR (400 MHz, CDCl3) d 7.45–7.15 (15H, m),
3.70 (3H, q, J = 6.6 Hz), 2.33 (3H, s), 1.41 (9H, d,
J = 6.6 Hz). The 13C NMR spectrum was identical to that
of a sample reported in the literature.10
JCP = 138.7 Hz), 62.3 (d, JCP = 7.5 Hz), 58.8 (d, JCP
=

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T. Haruki et al. / Tetrahedron: Asymmetry 18 (2007) 2886–2893
4.5. Ethyl 1,1-diethoxyethyl-({[(1S)-1-phenyl-
ethyl]amino}methyl)phosphinate 10
J = 9.2, 15.4 Hz), 1.45 (3H, d, J = 6.9 Hz), 1.42 (3H, d,
J = 10.8 Hz), 1.29 (3H, t, J = 7.1 Hz) 1.10 (3H, t, J =
7.0 Hz), 1.03 (3H, t, J = 7.1 Hz); 13C NMR (100 MHz,
A stirred solution of 6 (21.0 g, 100 mmol) and 9 (33.9 g,
100 mmol) in toluene (165 mL) was heated at reflux for
12 h followed by cooling to room temperature and concen-
tration under reduced pressure. The resulting residue was
purified by flash column chromatography (CHCl3/
MeOH = 1:0 to 20:1) to give 10 (20.8 g, 61%). This com-
pound was obtained as a mixture of diastereomers in a
CDCl3) d 142.9–125.8 (aromatic), 101.5 (d, JPC =
132.2 Hz), 62.0 (d, JPC = 7.3 Hz), 58.5 (d, JPC = 4.3 Hz),
58.3 (d, JPC = 6.9 Hz), 57.7 (d, JPC = 7.2 Hz), 56.3 (d,
JPC = 5.0 Hz), 45.2 (d, JPC = 98.7 Hz), 20.9 (d, JPC
=
11.4 Hz), 17.2 (d, JPC = 5.4 Hz) 15.8, 15.6, 14.5; 31P
NMR (162 MHz, CDCl3) d 46.04; IR (neat) 1155,
1038 cmꢁ1; MS m/z 484 (MH+); HRMS: (MH+) calcd
for C28H39NO4P, 484.2617; found, 484.2589.
1
ratio of 1:1. Pale yellow oil; H NMR (400 MHz, CDCl3)
d 7.34–7.21 (5H, m), 4.27–4.11 (2H, m), 3.81 (0.5H, q,
J = 6.6 Hz), 3.80 (0.5H, q, J = 6.9 Hz), 3.73–3.57 (4H,
m), 2.94–2.87 (1H, m), 2.83–2.74 (1H, m), 1.53 (1.5H, t,
J = 9.6 Hz), 1.51 (1.5H, t, J = 9.6 Hz), 1.35 (1.5H, t, J =
6.6 Hz), 1.35 (1.5H, t, J = 6.6 Hz), 1.33 (1.5H, t,
J = 7.1 Hz), 1.31 (1.5H, t, J = 7.1 Hz), 1.19 (1.5H, t, J =
7.0 Hz), 1.17 (1.5H, t, J = 7.1 Hz), 1.16 (1.5H, t, J =
7.1 Hz), 1.15 (1.5H, t, J = 7.1 Hz); 31P NMR (162 MHz,
4.7. (RP)-Ethyl 1,1-diethoxyethyl{[(diphenylmethylene)-
amino]methyl}phosphinate (RP)-12
To a solution of (S,RP)-11 (1.7 g, 3.5 mmol) in MeOH
(35 mL) was added 20% Pd(OH)2–C (700 mg) and stirred
for 5 h at room temperature under a hydrogen atmosphere.
The catalyst was removed by filtration through a pad of
Celite and the filtrate was concentrated to give a residue.
To a solution of the residue in CH2Cl2 (40 mL) was added
Et3N (0.49 mL, 3.5 mmol) and the mixture was stirred for
30 min at room temperature. To the mixture was added
Et2O (10 mL) and the resulting crystal was removed by fil-
tration. The filtrate was concentrated to give a residue. A
suspension of the residue and benzophenone (700 mg,
3.9 mmol) in toluene (10 mL) was heated at reflux for
12 h with azeotropic removal of water in a Dean-Stark
trap. The mixture was cooled to room temperature and
concentrated to give a residue, which was purified by flash
column chromatography (hexane/EtOAc = 5:1 to 1:1) to
CDCl3) d 44.98, 44.64; IR (neat) 3452, 1155, 1038 cmꢁ1
;
MS m/z 344 (MH+); HRMS: (MH+) calcd for
C17H31NO4P, 344.1991; found, 344.2004.
4.6. Ethyl 1,1-diethoxyethyl-{(2-naphthylmethyl) [(1S)-1-
phenylethyl]amino}methylphosphinates (S,RP)-11 and
(S,SP)-11
To a stirred solution of 10 (343 mg, 1.0 mmol) and 2-naph-
thaldehyde (172 mg, 1.1 mmol) in MeOH/AcOH (10:1,
3.3 mL) were added a-pic-BH3 (160 mg, 1.5 mmol) and
stirred for 20 h at room temperature. The mixture was
added with 1 M HCl and stirred for 15 min. The mixture
was poured into satd Na2CO3 solution and extracted with
AcOEt. The combined extracts were washed with brine and
dried over K2CO3. Removal of the solvent gave a residue,
which was purified by column chromatography (hexane/
EtOAc = 5:1 to 2:1) to give a mixture of (S,RP)-11 and
(S,SP)-11 (323 mg, 67%). Each isomer was isolated upon
re-purification by flash column chromatography (hexane/
EtOAc = 5:1 to 2:1).
give (RP)-12 (720 mg, 51%). Colorless plates; mp 47–
24
48 °C; ½aꢃD ¼ ꢁ17:8 (c 0.4, CHCl3). The 1H and 31P
NMR spectra were identical to those of a racemic sample
reported in the literature.8
4.8. (SP)-Ethyl 1,1-diethoxyethyl{[(diphenylmethylene)-
amino]methyl}phosphinate (SP)-12
This compound was prepared from (S,SP)-11 (285 mg,
1.2 mmol) in an analogous manner to that for (RP)-12.
Purification of the residue by flash column chromato-
25
1
(S,RP)-11: Colorless oil; ½aꢃD ¼ ꢁ54:6 (c 1.9, CHCl3); H
NMR (400 MHz, CDCl3) d 7.82–7.23 (12H, m), 4.35–
4.16 (3H, m), 4.00 (1H, d, J = 13.6 Hz), 3.88 (1H, d,
J = 13.8 Hz), 3.64–3.46 (4H, m), 3.01 (1H, dd, J = 8.3,
15.4 Hz), 2.91 (1H, dd, J = 3.0, 15.4 Hz), 1.45 (3H, d,
J = 6.9 Hz), 1.35 (3H, d, J = 10.8 Hz), 1.33 (3H, t, J =
7.0 Hz) 1.07 (3H, t, J = 7.0 Hz), 1.02 (3H, t, J = 7.1 Hz);
13C NMR (100 MHz, CDCl3) d 141.8–125.4 (aromatic),
101.1 (d, JPC = 132.6 Hz), 61.5 (d, JPC = 7.2 Hz), 58.3,
graphy (hexane/EtOAc = 5:1 to 1:1) gave (SP)-12
24
(218 mg, 45%). Colorless oil; ½aꢃD ¼ þ16:6 (c 0.6, CHCl3).
1
The H and 31P NMR spectra were identical to those of a
racemic sample reported in the literature.8
4.9. (1S,SP)-Ethyl-1,1-diethoxyethyl{1-[(diphenylmethyl-
ene)amino]-2-phenylethyl}phosphinate (S,SP)-2
(d, JPC = 6.8 Hz), 58.0 (d, JPC = 4.4 Hz), 57.3 (d, JPC
=
To a solution of (SP)-12 (200 mg, 0.5 mmol) in THF
(2.4 mL) was added 1.0 M THF solution of LHMDS
(0.75 mL, 0.75 mmol) at ꢁ78 °C and stirred for 30 min at
the same temperature. To the mixture was added BnBr
(0.12 mL, 1.0 mmol) and stirred for 1.5 h at the same tem-
perature. The mixture was diluted with satd NH4Cl solu-
tion and extracted with Et2O. The combined extracts
7.1 Hz), 55.6 (d, JPC = 5.5 Hz), 45.1 (d, JPC = 98.6 Hz),
20.3 (d, JPC = 11.6 Hz), 16.7 (d, JPC = 5.1 Hz), 15.6, 15.3,
15.1; 31P NMR (162 MHz, CDCl3) d 45.35; IR (neat)
1155, 1038 cmꢁ1; MS m/z 484 (MH+); HRMS: (MH+)
calcd for C28H39NO4P, 484.2617; found, 484.2593.
25
1
(S,SP)-11: Colorless oil; ½aꢃ ¼ ꢁ39:5 (c 2.2, CHCl3); H
NMR (400 MHz, CDCl3)Dd 7.82–7.24 (12H, m), 4.31
(1H, q, J = 6.8 Hz), 4.13–3.98 (2H, m), 3.98 (1H, d,
J = 13.5 Hz), 3.93 (1H, d, J = 13.7 Hz), 3.64–3.44 (4H,
m), 3.16 (1H, dd, J = 15.3, 15.3 Hz), 2.80 (1H, dd,
were washed with brine and dried over MgSO4. Removal
of the solvent gave a residue, which was purified by flash
column chromatography (CHCl3) to give a mixture of
(S,SP)-2 and (R,SP)-2 (183 mg, 74%). (S,SP)-2 was isolated
upon re-purification by flash column chromatography

T. Haruki et al. / Tetrahedron: Asymmetry 18 (2007) 2886–2893
2891
24
(hexane/EtOAc = 5:1 to 1:1). Pale yellow oil; ½aꢃD ¼ þ83:5
JPC = 7.5 Hz), 22.7, 21.7, 21.4, 19.6 (d, JPC = 11.9 Hz),
16.4 (d, JPC = 5.1 Hz), 15.3, 15.1; 31P NMR (162 MHz,
(c 0.1, CHCl3). The H and 31P NMR spectra were identi-
1
cal to those of a racemic sample reported in the literature.8
CDCl3) d 41.96; IR (neat) 3125, 1336, 1162, 1038 cmꢁ1
;
MS m/z 450 (MH+); HRMS: (MH+) calcd for
4.10. (1S,SP)-Ethyl 1,1-diethoxyethyl{1-[(diphenylmethyl-
ene)amino]-3-methylbutyl}phosphinate (S,SP)-13
C20H36NO6PS, 450.2079; found, 450.2074.
4.13. (1S,RP)-Ethyl 1-{[(4-methylphenyl)sulfonyl]amino}-2-
phenylethylphosphinate (S,RP)-16
To a solution of (SP)-12 (146 mg, 0.36 mmol) in THF
(1.8 mL) was added 1.0 M THF solution of LHMDS
(0.54 mL, 0.54 mmol) at ꢁ78 °C and stirred for 30 min at
the same temperature. To the mixture was added i-BuI
(0.21 mL, 1.8 mmol) and stirred for 1.5 h at room temper-
ature. The mixture was diluted with satd NH4Cl 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 purified by flash col-
umn chromatography (CHCl3) to give a mixture of (S,SP)-
13 and (R,SP)-13 (112 mg, 68%). (S,SP)-13 was isolated
To a solution of (S,SP)-14 (42 mg, 0.08 mmol) in CH2Cl2
(0.3 mL) was added EtOH (34 lL) and TMSCl (20 lL,
0.16 mmol) at room temperature. After stirring for 2.5 h
at the same temperature, the mixture was concentrated to
give a residue, which was purified by flash column chroma-
tography (CHCl3/MeOH = 40:1 to 20:1) to give (S,RP)-16
24
(22 mg, 74%). A colorless oil; ½aꢃD ¼ þ69:2 (c 0.08,
1
CHCl3). The H and 31P NMR spectra were identical to
those of a racemic sample reported in the literature.8
upon re-purification by flash column chromatography
24
(hexane/EtOAc = 5:1 to 1:1). Pale yellow oil; ½aꢃD
¼
4.14. (1S,RP)-Ethyl 1-{[(4-methylphenyl)sulfonyl]amino}-3-
methylbutylphosphinate (S,RP)-17
ꢁ13:8 (c 0.2, CHCl3). The H and 31P NMR spectra were
identical to those of a racemic sample reported in the
literature.8
1
This compound was prepared from (S,SP)-15 (46 mg,
0.1 mmol), EtOH (40 lL), and TMSCl (22 lL, 0.2 mmol)
in an analogous manner to that for (S,RP)-16. Purification
of the residue by flash column chromatography (hexane/
4.11. (1S,SP)-1,1-Diethoxyethyl(1-{[(4-methylphenyl)sulfon-
yl]amino}-2-phenylethyl)phosphinate (S,SP)-14
EtOAc = 3:1 to 1:1) gave (S,RP)-17 (31 mg, 93%). Color-
24
To a solution of (S,SP)-2 (146 mg, 0.3 mmol) in MeOH
(3 mL) was added 20% Pd(OH)2–C (18 mg) and stirred
for 40 h at room temperature under a hydrogen atmo-
sphere. The catalyst was removed by filtration through a
pad of Celite and the filtrate was concentrated to give a res-
idue. To a solution of this residue in CH2Cl2 (3.3 mL) were
added Et3N (89 lL, 0.64 mmol) and TsCl (121 mg,
0.64 mmol) and stirred for 2 h at room temperature. After
the mixture was concentrated, the residue was poured into
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 purified by flash column
less oil; ½aꢃD ¼ þ50:5 (c 0.16, CHCl3); 1H NMR
(400 MHz, CDCl3) d 7.79–7.30 (4H, m), 6.87 (1H, d,
J = 559.7 Hz), 5.16 (1H, br s), 4.16–4.04 (2H, m), 3.56–
3.53 (1H, m), 2.43 (3H, s), 1.61–1.46 (2H, m), 1.33 (3H,
t, J = 7.1 Hz), 0.84 (3H, d, J = 6.6 Hz), 0.69 (3H, d,
J = 6.4 Hz); 13C NMR (100 MHz, CDCl3) d 143.6–127.1
(aromatic), 63.2 (d, JPC = 7.5 Hz), 50.3 (d, JPC
=
109.9 Hz), 35.9, 23.8 (d, JPC = 9.6 Hz), 22.9, 21.5, 21.0,
16.2 (d, JPC = 5.5 Hz); 31P NMR (162 MHz, CDCl3) d
34.37; IR (neat) 3082, 1330, 1165, 1050 cmꢁ1; MS m/z
368 (MH+); HRMS: (MH+) calcd for C14H25NO4PS,
334.1242; found, 334.1237.
chromatography (CHCl3) to give (S,SP)-14 (68 mg, 47%).
24
A colorless oil; ½aꢃD ¼ þ80:0 (c 0.07, CHCl3). The 1H
4.15. (1R,RP)-Ethyl-1,1-diethoxyethyl{1-[(diphenylmethyl-
ene)amino]-2-phenylethyl}phosphinate (R,RP)-2
and 31P NMR spectra were identical to those of a racemic
sample reported in the literature.8
This compound was prepared from (RP)-12 (200 mg,
0.5 mmol), 1.0 M THF solution of LHMDS (0.75 mL,
0.75 mmol), and BnBr (0.12 mL, 1.0 mmol) in an analo-
gous manner to that for (S,SP)-2. Purification of the resi-
due by flash column chromatography (CHCl3) gave a
mixture of (R,RP)-2 and (S,RP)-2 (181 mg, 73%). (R,RP)-2
was isolated upon re-purification by flash column chroma-
4.12. (1S,SP)-1,1-Diethoxyethyl(1-{[(4-methylphenyl)sulfon-
yl]amino}-3-methylbutyl)phosphinate (S,SP)-15
This compound was prepared from (S,SP)-13 (90 mg,
0.2 mmol), 20% Pd(OH)2–C (12 mg), Et3N (60 lL,
0.43 mmol), and TsCl (82 mg, 0.43 mmol) in an analogous
manner to that for (S,SP)-14. Purification of the residue by
tography (hexane/EtOAc = 5:1 to 1:1). A pale yellow oil;
24
flash column chromatography (hexane/EtOAc = 3:1 to
½aꢃD ¼ ꢁ84:0 (c 0.1, CHCl3). The 1H and 31P NMR spectra
24
1:1) gave (S,SP)-15 (52 mg, 58%). Colorless oil; ½aꢃD
¼
were identical to those of a racemic sample reported in the
literature.8
þ16:5 (c 0.2, CHCl3); 1H NMR (400 MHz, CDCl3) d
7.76–7.28 (4H, m), 5.39 (1H, dd, J = 6.2, 8.7 Hz), 4.17–
4.08 (2H, m), 3.87–3.81 (1H, m), 3.79–3.60 (4H, m), 2.42
(3H, s), 1.75–1.41 (2H, m), 1.51 (3H, d, J = 11.4 Hz),
1.26 (3H, t, J = 7.0 Hz), 1.23 (6H, t, J = 7.1 Hz), 0.82
(3H, d, J = 6.5 Hz), 0.80 (3H, d, J = 6.4 Hz); 13C NMR
(100 MHz, CDCl3) d 142.9–127.0 (aromatic), 102.7 (d,
JPC = 139.9 Hz), 62.1 (d, JPC = 7.2 Hz), 58.7, 57.9 (d,
JPC = 7.0 Hz), 49.5 (d, JPC = 90.2 Hz), 40.0, 24.5 (d,
4.16. (1R,RP)-Ethyl 1-amino-2-phenylethyl(1,1-diethoxy-
ethyl)phosphinate (R,RP)-18
To a solution of (R,RP)-2 (327 mg, 0.66 mmol) in MeOH
(6.6 mL) was added 20% Pd(OH)2–C (60 mg) and stirred
for 40 h at room temperature under a hydrogen atmo-
sphere. The catalyst was removed by filtration through a

2892
T. Haruki et al. / Tetrahedron: Asymmetry 18 (2007) 2886–2893
1
pad of Celite and the filtrate was concentrated to give a res-
idue, which was purified by flash column chromatography
0.2, CHCl3). The H and 31P NMR spectra were identical
to those of a racemic sample reported in the literature.8
(CHCl3/MeOH = 1:0 to 20:1) to give (R,RP)-18 (108 mg,
24
50%). Pale yellow oil; ½aꢃD ¼ ꢁ22:6 (c 0.3, CHCl3); 1H
4.20. (1R)-Diethyl 1-{[(4-methylphenyl)sulfonyl]amino}-2-
phenylethylphosphonate (R)-19
NMR (400 MHz, CDCl3) d 7.34–7.21 (5H, m), 4.30–4.23
(2H, m), 3.84–3.68 (4H, m), 3.35 (1H, ddd, J = 3.2, 3.2,
11.3 Hz), 3.21 (1H, ddd, J = 3.2, 5.2, 13.8 Hz), 2.74 (1H,
ddd, J = 7.4, 11.3, 13.8 Hz), 1.63 (3H, d, J = 10.7 Hz),
1.35 (3H, t, J = 7.1 Hz), 1.22 (6H, t, J = 7.1 Hz); 13C
NMR (100 MHz, CDCl3) d 138.1 (d, JCP = 12.9 Hz),
129.1, 128.3, 126.4, 101.3 (d, JCP = 131.6 Hz), 62.0 (d,
A solution of (R,SP)-16 (19 mg, 0.05 mmol), DMSO
(3.6 lL, 0.05 mmol), and iodine (0.2 mg, 0.01 mmol) in
THF (3.5 mL) was stirred for 1 h at room temperature.
The mixture was evaporated to give a residue. To a stirred
solution of CH3CHN2, prepared from 58% N-nitroso-N-
ethylurea (23 mg, 0.2 mmol), was added a solution of the
residue in Et2O/EtOH = 10:1 (1.1 mL) at 0 °C and the
solution was stirred for 30 min at the same temperature.
After decomposition of excess CH3CHN2 with AcOH,
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 purified by preparative TLC (hexane/
JCP = 7.6 Hz), 58.3 (d, JCP = 4.4 Hz), 57.5 (d, JCP
6.8 Hz), 50.5 (d, JCP = 90.7 Hz), 36.1, 20.6 (d, JCP
=
=
11.5 Hz), 16.5 (d, JCP = 4.9 Hz), 15.3, 15.1; 31P NMR
(162 MHz, CDCl3) d 45.32; IR (neat) 3100, 1155,
1034 cmꢁ1; MS m/z 330 (MH+); HRMS: (MH+) calcd
for C16H28NO4P, 330.1834; found, 330.1821.
4.17. The procedure for the preparation of the (R)-MTPA
and (S)-MTPA-amides of (R,RP)-18
EtOAc = 2:1) to give (R)-19 (7.6 mg, 37%). Pale yellow
24
oil; ½aꢃD ¼ ꢁ27:5 (c 0.2, CHCl3); 1H NMR (400 MHz,
To a stirred suspension of (R)-MTPA (20 mg, 0.06 mmol),
DCC (31 mg, 0.12 mmol), and DMAP (1.5 mg, 0.012
mmol) in CH2Cl2 (0.5 mL) was added a solution of
(R,RP)-18 (20 mg, 0.06 mmol) in CH2Cl2 (1 mL) at 0 °C.
After stirring at room temperature until the starting mate-
rial disappeared, as evidenced by TLC, the mixture was
diluted with H2O and extracted with CHCl3. The combined
extracts were washed with brine and dried over MgSO4.
Removal of solvent gave a residue which was diluted with
Et2O and passed through silica gel. The filtrate was evapo-
rated to leave (R)-MTPA-amide of (R,RP)-18. (S)-MTPA-
amide of (R,Rp)-18 was also prepared from (S)-MTPA by
the same procedure. In the 31P NMR spectra of both
amides, signals due to the corresponding diastereoisomer
were not detected.
CDCl3) d 7.54–7.06 (9H, m), 5.37 (1H, dd, J = 3.5,
9.5 Hz), 4.14–4.06 (5H, m), 3.08 (1H, ddd, J = 5.9, 14.3,
14.3 Hz), 2.86 (1H, ddd, J = 7.5, 12.5, 14.3 Hz), 2.38 (3H,
s), 1.21 (3H, t, J = 7.1 Hz), 1.20 (3H, t, J = 7.1 Hz). The
13C and 31P NMR spectra were identical to those of a sam-
ple reported in the literature.13
Acknowledgments
This work was partially supported by a grant for private
universities from The Promotion and Mutual Aid Corpo-
ration for Private Schools of Japan and the Ministry of
Education, Culture, Sports, Science, and Technology.
The authors wish to thank Mr. Haruhiko Fukaya (the ana-
lytical center of this university) for the X-ray crystallo-
graphic analysis.
4.18. (1R,RP)-Ethyl 1,1-diethoxyethyl(1-{[(4-methyl-
phenyl)sulfonyl]amino}-2-phenylethyl)phosphinate (R,RP)-14
References
To a solution of (R,RP)-18 (46 mg, 0.14 mmol) in CH2Cl2
(1.0 mL) were added Et3N (21 lL, 0.29 mmol) and TsCl
(57 mg, 0.29 mmol) and stirred for 2 h at room tempera-
ture. After the mixture was concentrated, the residue was
poured into 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 purified
by flash column chromatography (CHCl3) to give (R,RP)-
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24
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73%). Colorless plates; mp 112–114 °C; ½aꢃD ¼ ꢁ70:1 (c

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