Diastereoselective alkylation of iminomethylenephosphinates possessing an asymmetric center at the phosphorus atom

Article abstract of DOI:10.1016/j.tet.2006.07.029

Diastereoselective synthesis of α-aminophosphinates was achieved by alkylation of imines with a 1,1-diethoxyethylphosphinyl group. These products were readily converted into α-amino-H-phosphinates.

Full text of DOI:10.1016/j.tet.2006.07.029

Tetrahedron 62 (2006) 9210–9217
Diastereoselective alkylation of iminomethylenephosphinates
possessing an asymmetric center at the phosphorus atom
*
Takehiro Yamagishi, Terumitsu Haruki and Tsutomu Yokomatsu
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 1 June 2006; revised 3 July 2006; accepted 11 July 2006
Available online 31 July 2006
Abstract—Diastereoselective synthesis of a-aminophosphinates was achieved by alkylation of imines with a 1,1-diethoxyethylphosphinyl
group. These products were readily converted into a-amino-H-phosphinates.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
the carbanions and could work as a good directing group for
the diastereoselective alkylation of the carbanions.
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 were shown
to be effective inhibitors against aspartic acid proteases
and Zn metalloproteases.3 For the preparation of various
a-aminophosphinic acid derivatives, a-amino-H-phosphi-
nates have been utilized as versatile synthetic intermedi-
ates.4 This class of compounds has previously been
prepared through the addition of phosphinic acid5 or silyl
phosphonite6 to imines. An alternative synthesis of a-amino-
H-phosphinates involves the alkylation of iminomethyl-
enephosphinates having a diethoxymethyl group at the
phosphorus atom, followed by conversion of the diethoxy-
methylphosphinyl moiety to P–H group with 6 M HCl at
reflux.7 In this methodology, the alkylated products were
given as a mixture of diastereomers arising from the chirality
of the phosphorus atom, and the relative configuration of
the major isomer as well as its stereoselectivity remained
unclear. The methodology was limited by the harsh condi-
tions necessary for the deprotection of the acetal group.8
In this paper, we wish to describe our experimental results
on the alkylation of racemic iminomethylenephosphinates
possessing a 1,1-diethoxyethyl group at the phosphorus
atom. As expected, these reactions proceeded in a highly
diastereoselective manner to give a-substituted a-amino-
phosphinates, which were readily converted to a-substituted
a-amino-H-phosphinates under mild conditions (Scheme 1).
O Me
O Me
P
OEt
Ph
Ph
Ph
Ph
base, RX
N
P
OEt
OEt
N
OEt
OEt
OEt
R
O
P H
H
N
Ts
OEt
R
Scheme 1.
2. Results and discussion
The requisite starting materials 4 and 5 were prepared as
shown in Scheme 2. The addition of H-phosphinate 18 to
1,3,5-hexahydrotriazine provided benzylamine 2, which
was subjected to hydrogenolytic removal of the benzyl
group giving amine 3. Treatment of 3 with benzophenone
in toluene at reflux afforded imine 4. Following Hoppe’s
procedure,9 3 was converted to imine 5.
During our studies on the stereoselctive synthesis of a-amino-
H-phosphinic acid derivatives, we envisioned iminomethyl-
enephosphinates bearing a 1,1-diethoxyethyl group instead
of a diethoxymethyl group, which could be successfully
employed as a substrate for the stereoselective alkylation
of phosphorus-stabilized carbanions. The 1,1-diethoxyethyl
group may give rise to a pronounced steric hindrance around
First, alkylation of 4 with benzyl bromide (2 equiv) was
examined in THF at ꢀ78 ꢁC by using representative strong
bases (Scheme 3). When BuLi was used as a basic reagent,
the reaction was completed within 1.5 h to give a diastereo-
meric mixture of (R*,RP*)-6 and (S*,RP*)-6 in a 51% yield.
Keywords: a-Amino-H-phosphinates; Phosphorus; Alkylations; Diastereo-
selectivity.
* Corresponding author. Tel./fax: +81 426 76 3239; e-mail: yokomatu@
ps.toyaku.ac.jp
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.029

T. Yamagishi et al. / Tetrahedron 62 (2006) 9210–9217
9211
O Me
P
OEt
1
O Me
P
OEt
O Me
P
OEt
5
S
LHMDS, BnBr
H
N
a
H
OEt
X
OEt
N
OEt
THF, -78 °C,
S
OEt
OEt
OEt
1.5 h
2: X=Bn
b
3: X=H
O Me
O Me
P OEt
S
S
N
P
OEt
OEt
OEt
N
+
c
S
S
OEt
d
OEt
Bn
Bn
(R*,RP*)-7
(S*,RP*)-7
O Me
P
O Me
P OEt
OEt
OEt
S
Ph
Ph
81% yield, (R*,RP*):(S*,RP*)=5:1
N
OEt
OEt
N
S
OEt
4
5
Scheme 4.
Scheme 2. Reagents and conditions: (a) 1,3,5-tribenzylhexahydrotriazine,
toluene, reflux, 85%; (b) H2, Pd(OH)2–C, MeOH, 83%; (c) benzophenone,
toluene, reflux, 87%; (d) CS2, 1,2-dibromoethane, NEt3, K2CO3, CHCl3,
reflux, 32%.
crystallographic analysis (Fig. 1). The relative configuration
of (R*,RP*)-7 was ascertained by comparison with an authen-
tic sample prepared from (R*,RP*)-6 through exchanging the
protecting group at the nitrogen atom.
The ratio was determined to be 2.2:1 preferring (R*,RP*)-6
on the basis of 31P (121 MHz) NMR analysis. Upon using
LDA, the yield was significantly increased to 70% albeit
the diastereoselectivity was similar to that for BuLi. While
utilizing lithium 2,2,6,6-tetramethylpiperidide (LTMP)
took longer reaction time (20 h) compared to the cases
of BuLi and LDA (1.5 h), the diastereoselectivity was
improved up to 6.9:1. KHMDS was found to be a good
base for inducing a high diastereoselectivity with a modest
yield. The best result was observed when the reaction was
carried out with LHMDS; (R*,RP*)-6 and (S*,RP*)-6 were
obtained in a 78% yield with a ratio of 10.1:1 and the indi-
vidual diastereomers were isolated in a pure state by flash
column chromatography on silica gel. Although the exact
reason why LHMDS was the most effective among exam-
ined basic reagents remained unclear, it seems likely to be
associated with steric bulk of the basic reagents.
O Me
P
O Me
P OEt
Ph
Ph
H
N
1) H2, Pd(OH)2-C
2) TsCl, Et3N
N
OEt
Ts
OEt
OEt
OEt
OEt
Bn
Bn
(R*,RP*)-6
(73%, two steps)
8
Scheme 5.
O Me
Ph
Ph
base, BnBr
N
P
OEt
OEt
THF, -78 °C,
OEt
4
O Me
O Me
P OEt
Ph
Ph
Ph
Ph
Figure 1. ORTEP drawing of the X-ray crystal structure of 8.
N
P
OEt
OEt
OEt
N
+
OEt
OEt
Bn
Bn
The diastereoselective alkylation of 4 with several electro-
philes was further examined. The results are summarized
in Table 1.
(R*,RP*)-6
(S*,RP*)-6
base
BuLi
time (h)
1.5
yield (%)
(R*,RP*):(S*,RP*)
2.2:1
51
70
58
52
78
LDA
1.5
3.0:1
Reactions with allyl bromide derivatives and iodomethane
proceeded smoothly at ꢀ78 ꢁC and were completed within
1.5 h providing (R*,RP*)-9–11 and (S*,RP*)-9–11 in good
yields (entries 1–3). On the other hand, when the same
conditions were applied to the less reactive alkyl halides
(n-BuBr, i-PrI, i-BuBr), reactions were quite sluggish. How-
ever, the alkylation products ((R*,RP*)-12–14 and (S*,RP*)-
12–14) were obtained in 47–71% yields, upon warming the
reaction mixture from ꢀ78 to 0 ꢁC or at room temperature
(entries 4–6). In view of diastereoselectivity, the reaction
of allyl bromide gave (R*,RP*)-9 predominantly in a ratio
of 7.7:1 (entry 1). The reactions of methallyl bromide and
i-BuBr also showed good selectivity (entries 2 and 6). Unfor-
tunately, reactions with other electrophiles (MeI, n-BuBr,
i-PrI) resulted in decrease of diastereoselectivity (entries
3–5). The relative configuration of (R*,RP*)-9–14 was esti-
mated analogously to (R*,RP*)-6, whose stereochemistry
was previously determined. Although a similar reaction of
LTMP
20
6.9:1
KHMDS
LHMDS
1.5
10.1:1
1.5
10.1:1
Scheme 3.
The benzylation of 5 under optimized conditions provided
(R*,RP*)-7 and (S*,RP*)-7 in a 81% yield, however,
(R*,RP*)-selectivity (5:1) was eroded in comparison to the
case of 4 (Scheme 4). This result indicated N-diphenyl-
methyleneamine derivative 4 was a relatively good substrate.
The relative stereochemistry of (R*,RP*)-6 was verified after
conversion to the corresponding tosylamide 8 (Scheme 5).
Hydrogenolysis of (R*,RP*)-6 in the presence of Pd(OH)2–C,
followed by tosylation of the resulting amine afforded 8.
The stereochemistry of 8 was confirmed by X-ray

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T. Yamagishi et al. / Tetrahedron 62 (2006) 9210–9217
Table 1. Diastereoselective alkylation of 4 with several electrophiles
of the lithium atom to the nitrogen atom of the substrates is
likely to be a significant factor for the occurrence of good
(R*,RP*)-selectivity.
O Me
Ph
Ph
LHMDS, RX
THF
N
P
OEt
OEt
OEt
4
On the basis of the above-mentioned results, the stereoselec-
tivity in the alkylation of 4 is possibly accounted for by
invoking the anion intermediate 17 bearing a planar sp2
carbanionic carbon, wherein the lithium atom is coordinated
by phosphinyl oxygen and a nitrogen atom (Fig. 2). An
approach of electrophiles from the side of the 1,1-diethoxy-
ethyl group was hindered by this bulky moiety, therefore,
the access of the electrophiles occurred preferentially from
the opposite side of a 1,1-diethoxyethyl group leading to
(R*,RP*)-products. Similar working models were proposed
by Denmark and Hannesian for the asymmetric alkylation
of anions derived from phosphonamidates10 and phosphon-
amide,11 respectively.
O Me
O Me
P OEt
Ph
Ph
Ph
Ph
N
P
OEt
OEt
N
+
OEt
OEt
OEt
R
R
(R*,RP*)-9-14
(S*,RP*)-9-14
Entry RXa
Temp
(ꢁC)
Time Product Yield (R*,RP*):
(h)
(%)b (S*,RP*)c
1
2
Allyl bromide ꢀ78
1.5
1
9
10
90
98
7.7:1
7.8:1
Methallyl
bromide
MeI
ꢀ78
ꢀ78
3
4
5
6
1.5
11
12
13
14
77
50
47
71
4.5:1
4.8:1
6.8:1
n-BuBr
i-PrI
ꢀ78 to 0 24
ꢀ78 to 0 24
ꢀ78 to rt 20
i-BuId
10.0:1
a
b
c
d
Li
Electrophiles (2 equiv) were utilized unless stated otherwise.
Combined yield of (R*,RP*)- and (S*,RP*)-products.
Ph
O Me
Ph
Ph
Ph
Me
OEt
OEt
Determined by 31P NMR (121 MHz, CDCl3) analysis of crude products.
i-BuI (5 equiv) was utilized.
N
H
N
P
OEt
OEt
OEt
O
R
RX
RX
(R*,RP*)
EtO
4 with p-nitrobromobenzene was examined, formation of
any SNAr products was not detected. Thus, suitable electro-
philes in this methodology were confirmed to be alkyl halide
derivatives.
17
Figure 2.
Finally, the 1,1-diethoxyethyl moiety of 8 was readily
removed by treatment with TMSCl and ethanol at room tem-
perature furnishing a-amino-H-phosphinate 18 (Scheme 8).
It is worthy to note that this deprotection step proceeded in
a highly diastereoselective manner (20:1) to give 18 in
good yield, while the deprotection step may be prone to epi-
merization at the phosphorus atom. Compound 18 was iso-
lated in pure form by column chromatography on silica gel.
To probe the origin of the diastereocontrol, we performed the
following experiments. The LHMDS-mediated benzylation
of phosphinate 15 without a nitrogen atom, prepared from
1 and 3,3-diphenylpropyl bromide, proceeded in a nonstereo-
selective manner ((R*,RP*)-16/(S*,RP*)-16¼1:1) in contrast
to the reaction of 4 (Scheme 6). When the LHMDS-mediated
benzylation of 4 was carried out in the presence of additive
HMPA (3 equiv), the diastereoselectivity was lowered
((R*,RP*)-6/(S*,RP*)-6¼2:1) compared to that without
HMPA (Scheme 7). These results represent that the chelation
O Me
P
O
P
H
N
H
N
TMSCl, EtOH
Ts
OEt
Ts
H
CH2Cl2, rt, 24 h
OEt
OEt
OEt
Bn
Bn
O Me
(83%)
8
18
LHMDS, BnBr
Ph
P
OEt
OEt
OEt
THF, 1.5 h
-78 °C to rt
Scheme 8.
Ph
15
O Me
O Me
P OEt
3. Conclusion
Ph
P
OEt
OEt
Ph
+
OEt
OEt
OEt
Ph Bn
Ph Bn
In conclusion, we have developed a method for preparing
a-aminophosphinatesthroughalkylationofiminomethylene-
phosphinates with 1,1-diethoxyethyl moiety. The feature of
this method is a high diastereoselectivity controlled by the
asymmetric center at the phosphorus atom. The protective
group of the alkylated product was removed under mild con-
ditions giving a-amino-H-phosphinate. Application to chiral
variants is ongoing.
(R*,RP*)-16
(S*,RP*)-16
45% yield, (R*,RP*):(S*,RP*)=1:1
Scheme 6.
LHMDS, BnBr
O Me
P
OEt
Ph
HMPA (3 equiv)
N
OEt
THF, 1.5 h
Ph
OEt
-78 °C
4
O Me
O Me
P OEt
Ph
Ph
Ph
Ph
4. Experimental
4.1. General
N
P
OEt
OEt
N
+
OEt
OEt
OEt
Bn
Bn
(R*,RP*)-6
(S*,RP*)-6
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
65% yield, (R*,RP*):(S*,RP*)=2:1
Scheme 7.

T. Yamagishi et al. / Tetrahedron 62 (2006) 9210–9217
9213
measured on a Finnigan TSQ-700 by electrospray ioniza-
tion. Elemental analysis were recorded on an Elemental
Vavio EL. NMR spectra were obtained on Bruker DPX400
NMR spectrometer operating at 400 MHz for 1H, 100 MHz
for 13C, and 162 MHz for 31P. 31P NMR spectra were also
obtained on Varian Mercury-300BB instrument operating
at 121 MHz. The chemical shift data for each signal on
1H 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 recorded relative to the CDCl3 resonance
(d¼77.0). The chemical shifts of 31P are recorded relative
JCP¼85.4 Hz), 19.7 (d, JCP¼11.6 Hz), 16.4 (d, JCP¼4.9 Hz),
15.1, 15.0; 31P NMR (162 MHz, CDCl3) d 44.29; IR (neat)
3012, 1160, 1036 cmꢀ1; MS m/z 240 (MH+). HRMS calcd
for C9H23NO4P: 240.1365 (MH+). Found: 240.1360.
4.1.3. Ethyl 1,1-diethoxyethyl{[(diphenylmethylene)ami-
no]methyl}phosphinate (4). A suspension of 3 (970 mg,
4.0 mmol) and benzophenone (810 mg, 4.0 mmol) in toluene
(11 mL) was heated to 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 resi-
due, which was purified by flash column chromatography
(CHCl3) to give 4 (1.42 g, 87%). A colorless oil; TLC
Rf¼0.26 (hexane/EtOAc¼1:1); 1H NMR (400 MHz,
CDCl3) d 7.65–7.24 (10H, m), 4.27–4.23 (2H, m), 4.05
(1H, dd, J¼14.0, 26.9 Hz), 3.98 (1H, dd, J¼14.0, 26.9 Hz),
3.73–3.61 (4H, m), 1.57 (3H, d, J¼11.2 Hz), 1.34 (3H, t,
J¼7.1 Hz), 1.14 (6H, t, J¼7.1 Hz); 13C NMR (100 MHz,
CDCl3) d 139.2, 135.5, 130.2, 128.5–127.9 (aromatic),
101.2 (d, JPC¼140.4 Hz), 62.0 (d, JPC¼7.3 Hz), 57.9 (d,
JPC¼5.1 Hz), 57.7 (d, JPC¼6.9 Hz), 51.8 (d, JPC¼96.6 Hz),
20.5 (d, JPC¼11.8 Hz), 16.6 (d, JPC¼5.1 Hz), 15.3, 15.1;
31P NMR (162 MHz, CDCl3) d 42.44; IR (neat) 1620,
1158, 1036 cmꢀ1; MS m/z 404 (MH+). HRMS calcd for
C22H31NO4P (MH+): 404.1991. Found: 404.1994.
1
to external 85% H3PO4 (d¼0) with broadband H decou-
pling. Flash column chromatography was performed on
40–100 mm silica gel 60 (Kanto Chemical Co., Inc.). Column
chromatography was carried out using 63–210 mm silica gel
60N (Kanto Chemical Co., Inc.). 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; flow
rate, 15.0 mL minꢀ1. Analytical TLC was carried out with
precoated silica gel 60 F254 plates (Merck).
4.1.1. Ethyl (benzylamino)methyl(1,1-diethoxyethyl)-
phosphinate (2).
A stirred solution of 1 (22.4 g,
100 mmol) and 1,3,5-tribenzylhexahydro-1,3,5-triazine
(11.79 g, 33 mmol) in toluene (165 mL) was heated to reflux
for 12 h followed by cooling to room temperature and
concentration under reduced pressure. The resulting residue
was purified by flash column chromatography (CHCl3/
MeOH¼1:0 to 20:1) to give 2 (27.9 g, 85%). A pale yellow
oil; TLC Rf¼0.36 (CHCl3/MeOH¼20:1); 1H NMR
(400 MHz, CDCl3) d 7.32–7.22 (5H, m), 4.30–4.19 (2H,
m), 3.90 (1H, d, J¼13.4 Hz), 3.86 (1H, d, J¼13.4 Hz),
3.76–3.67 (4H, m), 3.08 (1H, dd, J¼6.4, 14.6 Hz), 2.95
(1H, dd, J¼9.8, 14.6 Hz), 1.54 (3H, d, J¼11.0 Hz), 1.34
(3H, t, J¼7.1 Hz), 1.19 (3H, t, J¼7.1 Hz), 1.18 (3H, t,
J¼7.1 Hz); 13C NMR (100 MHz, CDCl3) d 139.2, 128.1,
4.1.4. Ethyl 1,1-diethoxyethyl[(1,3-dithiolan-2-ylidene-
amino)methyl]phosphinate (5). To a solution of 3 (5.00 g,
20.9 mmol) in CHCl3 (42 mL) was added CS2 (3.1 mL,
52.0 mmol) and Et3N (11.7 mL, 83.6 mmol) and stirred for
30 min at room temperature. To the mixture was added
1,2-dibromoethane (4.5 mL, 52 mmol) and heated to reflux
for 1 h. Concentration of the mixture gave a residue, which
was dissolved in EtOH (25 mL). To this solution was added
K2CO3 (2.89 g, 20.9 mmol) and heated to reflux for 4 h. The
mixture 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
5 (2.30 g, 32%). A pale yellow oil; TLC Rf¼0.37 (CHCl3/
127.9, 126.1, 101.1 (d, JCP¼137.2 Hz), 61.6 (d, JCP
¼
7.2 Hz), 58.0 (d, JCP¼4.9 Hz), 57.4 (d, JCP¼7.0 Hz), 54.8
(d, JCP¼13.1 Hz), 44.5 (d, JCP¼92.5 Hz), 20.3 (d, JCP
¼
11.7 Hz), 16.5 (d, JCP¼5.1 Hz), 15.2, 15.0; 31P NMR
(162 MHz, CDCl3) d 43.63; IR (neat) 3321, 1155,
1036 cmꢀ1; MS m/z 330 (MH+). HRMS calcd for
C16H29NO4P: 330.1834 (MH+). Found: 330.1831.
MeOH¼20:1); H NMR (400 MHz, CDCl3) d 4.27 (1H,
1
dd, J¼7.1, 14.3 Hz), 4.25 (1H, dd, J¼7.1, 14.3 Hz), 3.95
(1H, dd, J¼10.5, 14.5 Hz), 3.91 (1H, dd, J¼12.0, 14.5 Hz),
3.83–3.63 (4H, m), 3.59 (2H, t, J¼6.1 Hz), 3.43 (2H, t,
J¼6.5 Hz), 1.57 (3H, t, J¼11.2 Hz), 1.34 (3H, t,
J¼7.1 Hz), 1.21 (3H, t, J¼7.0 Hz), 1.20 (3H, t, J¼7.0 Hz);
13C NMR (100 MHz, CDCl3) d 172.4 (d, JPC¼16.5 Hz),
100.9 (d, JPC¼141.2 Hz), 61.8 (d, JPC¼7.2 Hz), 57.8 (d,
JPC¼5.1 Hz), 57.4 (d, JPC¼7.1 Hz), 56.5 (d, JPC¼97.2 Hz),
37.5, 34.6, 20.3 (d, JPC¼11.8 Hz), 16.3 (d, JPC¼5.0 Hz),
15.2, 15.0; 31P NMR (162 MHz, CDCl3) d 40.22; IR (neat)
1595, 1157, 1037 cmꢀ1; MS m/z 342 (MH+). HRMS calcd
for C12H25NO4PS2 (MH+): 342.0963. Found: 342.0948.
4.1.2. Ethyl aminomethyl(1,1-diethoxyethyl)phosphinate
(3). To a solution of 2 (10.01 g, 30.4 mmol) in MeOH
(304 mL) was added Pd(OH)2–C (1.83 g) 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 (334 mL) was added
Et3N (6.9 mL, 6.7 mmol) and the mixture was stirred for
30 min at room temperature. To the mixture was added
Et2O (100 mL) and resulting crystal was removed by filtra-
tion. The filtrate was concentrated to give 3 (6.03 g, 83%).
A pale yellow oil; TLC Rf¼0.30 (CHCl3/MeOH¼20:1);
1H NMR (400 MHz, CDCl3) d 4.28–4.19 (2H, m), 3.79–
3.62 (4H, m), 3.11 (1H, dd, J¼2.1, 15.7 Hz), 2.98 (1H, dd,
J¼7.3, 15.7 Hz), 1.53 (3H, d, J¼10.9 Hz), 1.34 (3H, t,
J¼7.0 Hz), 1.21 (6H, t, J¼7.0 Hz); 13C NMR (100 MHz,
CDCl3) d 101.3 (d, JCP¼29.0 Hz), 61.6 (d, JCP¼7.3 Hz),
58.0 (d, JCP¼4.9 Hz), 57.4 (d, JCP¼6.6 Hz), 38.2 (d,
4.1.5. (1R*,RP*)- and (1S*,RP*)-Ethyl 1,1-diethoxy-
ethyl{1-[(diphenylmethylene)amino]-2-phenylethyl}-
phosphinate ((R*,RP*)-6 and (S*,RP*)-6). To a solution of
4 (400 mg, 1.0 mmol) in THF (4.7 mL) was added 1.0 M
THF solution of LHMDS (1.5 mL, 1.5 mmol) and stirred for
30 min at the same temperature. To the mixture was added
benzyl bromide (0.24 mL, 2.0 mmol) and stirred for 1.5 h
at the same temperature. The mixture was diluted with
satd NH4Cl solution and extracted with Et2O. The combined

9214
T. Yamagishi et al. / Tetrahedron 62 (2006) 9210–9217
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 a mixture
of (R*,RP*)-6 and (S*,RP*)-6 (358 mg, 78%). Analytical
samples of individual isomers were obtained upon re-purifi-
cation by flash column chromatography (hexane/EtOAc¼
5:1 to 1:1).
(5H, m), 4.35–4.26 (2H, m), 3.98–3.90 (1H, m), 3.76–3.60
(4H, m), 3.49 (1H, ddd, J¼5.4, 11.1, 13.4 Hz), 3.34–3.15
(4H, m), 3.04 (1H, ddd, J¼2.1, 5.4, 13.4 Hz), 1.56 (3H, d,
J¼10.9 Hz), 1.38 (3H, t, J¼7.1 Hz), 1.22 (6H, t,
J¼7.1 Hz); 13C NMR (100 MHz, CDCl3) d 172.3 (d,
JPC¼16.0 Hz), 138.5 (d, JPC¼14.1 Hz), 129.9, 128.0,
126.2, 101.6 (d, JPC¼138.5 Hz), 70.7 (d, JPC¼95.7 Hz),
62.3 (d, JPC¼7.5 Hz), 58.5 (d, JPC¼4.3 Hz), 57.7 (d,
JPC¼8.0 Hz), 37.4, 35.9, 34.4, 20.9 (d, JPC¼11.4 Hz), 16.8
(d, JPC¼4.2 Hz), 15.7, 15.3; 31P NMR (162 MHz, CDCl3)
d 41.08; IR (neat) 1591, 1151, 1034 cmꢀ1; MS m/z 432
(MH+). HRMS calcd for C19H31NO4PS2 (MH+): 432.1432.
Found: 432.1409.
(R*,RP*)-6: A pale yellow oil; TLC Rf¼0.61 (hexane/
EtOAc¼1:2); 1H NMR (400 MHz, CDCl3) d 7.57–6.96
(15H, m), 4.32–4.18 (2H, m), 4.04–4.00 (1H, m), 3.83–
3.64 (4H, m), 3.46 (1H, ddd, J¼1.9, 6.2, 13.3 Hz), 3.36–
3.31 (1H, m), 1.66 (3H, d, J¼11.1 Hz), 1.34 (3H, t,
J¼7.1 Hz), 1.21 (3H, t, J¼7.0 Hz), 1.18 (3H, t, J¼7.0 Hz);
13C NMR (100 MHz, CDCl3) d 139.3, 135.4–126.1 (aro-
matic), 102.2 (d, JPC¼134.7 Hz), 65.8 (d, JPC¼95.3 Hz),
4.1.7. (1R*,RP*)-Ethyl 1,1-diethoxyethyl(1-{[(4-methyl-
phenyl)sulfonyl]amino}-2-phenylethyl)phosphinate (8).
To a solution of (R*,R*P)-6 (360 mg, 0.72 mmol) in MeOH
(7.2 mL) was added Pd(OH)2–C (43.2 mg) and stirred for
40 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 (3.2 mL) was added Et3N
(0.21 mL, 1.51 mmol) and TsCl (288 mg, 1.51 mmol) and
the mixture was stirred for 2 h at room temperature. The
mixture 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 8 (306 mg, 88%). Colorless plates; mp 126–132 ꢁC;
62.0 (d, JPC¼7.1 Hz), 58.0 (d, JPC¼6.5 Hz), 57.8 (d, JPC
¼
4.8 Hz), 36.8, 21.0 (d, JPC¼12.1 Hz), 16.7 (d, JPC¼4.9 Hz),
15.5, 15.3; 31P NMR (162 MHz, CDCl3) d 42.44; IR (neat)
1620, 1155, 1034 cmꢀ1; MS m/z 494 (MH+). HRMS calcd
for C29H37NO4P (MH+): 494.2460. Found: 494.2451.
(S*,RP*)-6: A pale yellow oil; TLC Rf¼0.53 (hexane/
EtOAc¼1:2); 1H NMR (400 MHz, CDCl3) d 7.61–6.98
(15H, m), 4.30–4.17 (2H, m), 4.08–4.06 (1H, m), 3.86–
3.65 (4H, m), 3.51–3.46 (1H, m), 3.38–3.31 (1H, m), 1.43
(3H, d, J¼10.9 Hz), 1.27 (3H, t, J¼7.1 Hz), 1.15 (3H, t,
J¼7.0 Hz), 1.11 (3H, t, J¼7.1 Hz); 13C NMR (100 MHz,
CDCl3) d 139.2, 135.7–126.1 (aromatic), 102.1 (d, JPC
¼
1
136.7 Hz), 64.1 (d, JPC¼92.7 Hz), 62.1 (d, JPC¼7.5 Hz),
58.4 (d, JPC¼4.7 Hz), 57.5 (d, JPC¼7.2 Hz), 36.9, 20.6
(d, JPC¼11.8 Hz), 16.9 (d, JPC¼4.8 Hz), 15.4, 15.3;
31P NMR (162 MHz, CDCl3) d 42.59; IR (neat) 1618,
1153, 1034 cmꢀ1; MS m/z 494 (MH+). HRMS calcd for
C29H37NO4P (MH+): 494.2460. Found: 494.2442.
TLC Rf¼0.38 (CHCl3/MeOH¼20:1); H NMR (400 MHz,
CDCl3) d 7.47–7.09 (5H, m), 5.59 (1H, dd, J¼7.5,
7.7 Hz), 4.24–4.12 (2H, m), 4.10–4.00 (1H, m), 3.79–3.63
(4H, m), 3.22 (1H, ddd, J¼6.3, 9.8, 14.5 Hz), 2.89 (1H,
ddd, J¼7.7, 12.0, 14.3 Hz), 2.37 (3H, s), 1.53 (3H, d,
J¼11.6 Hz), 1.25 (3H, t, J¼7.0 Hz), 1.20 (6H, t,
J¼7.0 Hz); 13C NMR (100 MHz, CDCl3) d 142.8, 138.8,
137.5, 129.5–126.4 (aromatic), 102.9 (d, JPC¼141.2 Hz),
62.3 (d, JPC¼7.5 Hz), 58.9 (d, JPC¼4.5 Hz), 58.2 (d,
JPC¼7.4 Hz), 53.1 (d, JPC¼87.1 Hz), 36.9, 21.4, 19.5
(d, JPC¼12.1 Hz), 16.3 (d, JPC¼5.8 Hz), 15.4, 15.2;
31P NMR (162 MHz, CDCl3) d 41.19; IR (KBr) 3117,
1332, 1156, 1034 cmꢀ1; MS m/z 484 (MH+). Anal. Calcd
for C23H34NO6PS: C, 57.13; H, 7.09. Found: C, 57.12;
H, 7.01.
4.1.6. (1R*,RP*)- and (1S*,RP*)-Ethyl 1,1-diethoxy-
ethyl[1-(1,3-dithiolan-2-ylideneamino)-2-phenylethyl]-
phosphinate ((R*,RP*)-7 and(S*,RP*)-7). These compounds
were prepared from 5 (341 mg, 1.0 mmol) in an analogous
manner to that for (R*,RP*)-6. Purification of the residue
by flash column chromatography (CHCl3) gave a mixture of
(R*,RP*)-7 and (S*,RP*)-7 (350 mg, 81%). Analytical sam-
ples of individual isomers were obtained upon re-purification
by flash column chromatography (hexane/EtOAc¼5:1 to 1:1).
4.2. Crystal data for compound 8
(R*,RP*)-7: A pale yellow oil; TLC Rf¼0.38 (hexane/
EtOAc¼1:3); 1H NMR (400 MHz, CDCl3) d 7.26–7.15
(5H, m), 4.32–4.25 (2H, m), 3.80–3.66 (5H, m), 3.34–3.28
(3H, m), 3.21–3.16 (3H, m), 1.60 (3H, d, J¼11.1 Hz), 1.35
(3H, t, J¼7.1 Hz), 1.23 (3H, t, J¼6.9 Hz), 1.21 (3H, t,
J¼7.0 Hz); 13C NMR (100 MHz, CDCl3) d 171.7 (d,
JPC¼17.5 Hz), 138.5 (d, JPC¼13.6 Hz), 129.9, 127.9,
126.2, 102.1 (d, JPC¼135.7 Hz), 71.4 (d, JPC¼100.6 Hz),
62.1 (d, JPC¼7.4 Hz), 58.2 (d, JPC¼4.2 Hz), 57.6 (d,
JPC¼7.4 Hz), 37.4, 35.8, 34.3, 20.9 (d, JPC¼12.0 Hz), 16.7
(d, JPC¼4.9 Hz), 15.6, 15.2; 31P NMR (162 MHz, CDCl3)
d 40.97; IR (neat) 1591, 1153, 1039 cmꢀ1; MS m/z 432
(MH+). HRMS calcd for C19H31NO4PS2 (MH+): 432.1432.
Found: 432.1408.
X-ray crystal data of 8 were collected by Mac-Science DIP
Image plate diffractometer. The structure was solved by a
direct method using SIR9712 and refined with a full matrix
least-squares method.13 Molecular formula¼C23H34NO6PS,
Mr¼483.55, monoclinic, space group¼P21/C, a¼13.0570
˚
˚
˚
(3) A, b¼15.2600 (3) A, c¼16.0060 (3) A, V¼2547.50
3
(10) A , T¼100 (2) K, Z¼4, Dx¼1.261 mg mꢀ3, (Mo
˚
Ka)¼0.71073 A, m¼0.226 mmꢀ1, R¼0.0538 over 5574
˚
independent reflections. Crystallographic data (excluding
structure factors) for the structures in this paper have
been deposited with the Cambridge Crystallographic Data
Center as supplementary publication numbers CCDC
600772. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [fax: +44 1223 336033 or e-mail: deposit@ccdc.
cam.ac.uk].
(S*,RP*)-7: A pale yellow oil; TLC Rf¼0.25 (hexane/
EtOAc¼1:3); 1H NMR (400 MHz, CDCl3) d 7.24–7.17

T. Yamagishi et al. / Tetrahedron 62 (2006) 9210–9217
9215
4.3. Preparation of various a-aminophosphinates
J¼7.1 Hz); 13C NMR (100 MHz, CDCl3) d 139.6 (d,
JPC¼2.4 Hz), 135.6, 132.3–127.8 (aromatic), 114.0, 102.1
(d, JPC¼134.8 Hz), 61.9 (d, JPC¼96.2 Hz), 61.9 (d,
JPC¼7.3 Hz), 57.8 (d, JPC¼6.2 Hz), 57.7 (d, JPC¼4.2 Hz),
38.9, 22.3, 20.9 (d, JPC¼12.0 Hz), 16.6 (d, JPC¼5.1 Hz),
15.5, 15.2; 31P NMR (162 MHz, CDCl3) d 42.75; IR (neat)
1649, 1620, 1155, 1034 cmꢀ1; MS m/z 458 (MH+). HRMS
calcd for C26H37NO4P (MH+): 458.2460. Found: 458.2485.
4.3.1. (1R*,RP*)- and (1S*,RP*)-Ethyl 1,1-diethoxy-
ethyl{1-[(diphenylmethylene)amino]but-3-enyl}phosphi-
nate ((R*,RP*)-9 and (S*,RP*)-9). This compound was
prepared from 4 (200 mg, 0.5 mmol), 1.0 M THF solution
of LHMDS (0.75 mL, 0.75 mmol) and allyl bromide
(85 mL, 1.0 mmol) in an analogous manner to that for
(R*,RP*)-6. Purification of the residue by flash column chro-
matography (CHCl3) gave a mixture of (R*,RP*)-9 and
(S*,RP*)-9 (200 mg, 90%). Analytical samples of individual
isomers were obtained upon re-purification by flash column
chromatography (hexane/EtOAc¼5:1 to 2:1).
(S*,RP*)-10: A colorless oil; TLC Rf¼0.30 (hexane/
EtOAc¼1:1); 1H NMR (400 MHz, CDCl3) d 7.67–7.21
(10H, m), 4.71 (1H, s), 4.65 (1H, s), 4.24–4.18 (2H, m),
4.12–4.08 (1H, m), 3.82–3.64 (4H, m), 2.78 (2H, t,
J¼4.0 Hz), 1.44 (3H, d, J¼10.9 Hz), 1.37 (3H, s), 1.25
(3H, t, J¼7.1 Hz), 1.13 (3H, t, J¼7.1 Hz), 1.10 (3H, t,
J¼7.1 Hz); 13C NMR (100 MHz, CDCl3) d 139.6, 135.9,
130.0–127.9 (aromatic), 114.2, 102.1 (d, JPC¼136.8 Hz),
62.0 (d, JPC¼7.3 Hz), 60.4 (d, JPC¼94.6 Hz), 58.4 (d,
JPC¼4.6 Hz), 57.5 (d, JPC¼7.2 Hz), 38.9, 22.5, 20.6 (d,
JPC¼11.7 Hz), 16.8 (d, JPC¼4.8 Hz), 15.4, 15.3; 31P NMR
(162 MHz, CDCl3) d 43.03; IR (neat) 1653, 1618, 1153,
1036 cmꢀ1; MS m/z 458 (MH+). HRMS calcd for
C26H37NO4P (MH+): 458.2460. Found: 458.2443.
(R*,RP*)-9: A pale yellow oil; TLC Rf¼0.34 (hexane/
EtOAc¼1:1); 1H NMR (400 MHz, CDCl3) d 7.63–7.23
(10H, m), 5.61–5.50 (1H, m), 5.04–4.96 (2H, m), 4.31–
4.17 (2H, m), 3.99 (1H, ddd, J¼3.3, 9.7, 9.7 Hz), 3.76–
3.66 (4H, m), 2.90–2.79 (2H, m), 1.59 (3H, d, J¼11.0 Hz),
1.33 (3H, t, J¼7.1 Hz), 1.18 (3H, t, J¼7.1 Hz), 1.15 (3H,
t, J¼7.1 Hz); 13C NMR (100 MHz, CDCl3) d 139.5, 135.9,
135.6–127.9 (aromatic), 117.2, 102.0 (d, JPC¼134.6 Hz),
63.3 (d, JPC¼96.2 Hz), 61.9 (d, JPC¼7.3 Hz), 57.8 (d, JPC
¼
6.6 Hz), 57.7 (d, JPC¼4.9 Hz), 35.1, 21.0 (d, JPC¼12.2 Hz),
16.7 (d, JPC¼4.9 Hz), 15.5, 15.2; 31P NMR (162 MHz,
4.3.3. (1R*,RP*)- and (1S*,RP*)-Ethyl 1,1-diethoxy-
ethyl{1-[(diphenylmethylene)amino]ethyl}phosphinate
((R*,RP*)-11 and (S*,RP*)-11). These compounds were
prepared from 4 (200 mg, 0.5 mmol), 1.0 M THF solution of
LHMDS (0.75 mL, 0.75 mmol), and methyl iodide (62 mL,
1.0 mmol) in an analogous manner to that for (R*,RP*)-6.
Purification of the residue by flash column chromatography
(CHCl3) gave a mixture of (R*,RP*)-11 and (S*,RP*)-11
(161 mg, 77%). Analytical samples of individual isomers
were obtained upon re-purification by preparative HPLC
(EtOAc/MeOH¼50:1).
CDCl3) d 42.27; IR (neat) 1639, 1618, 1155, 1032 cmꢀ1
;
MS m/z 444 (MH+). HRMS calcd for C25H35NO4P (MH+):
444.2304. Found: 444.2281.
(S*,RP*)-9: A pale yellow oil; TLC Rf¼0.28 (hexane/
EtOAc¼1:1); 1H NMR (400 MHz, CDCl3) d 7.80–7.24
(10H, m), 5.63–5.51 (1H, m), 5.04–4.96 (2H, m), 4.32–
4.18 (2H, m), 4.04–4.02 (1H, m), 3.75–3.61 (4H, m),
2.89–2.70 (2H, m), 1.38 (3H, d, J¼11.1 Hz), 1.27 (3H, t,
J¼7.1 Hz), 1.18 (3H, t, J¼7.0 Hz), 1.15 (3H, t, J¼7.1 Hz);
13C NMR (100 MHz, CDCl3) d 139.4 (d, JPC¼2.5 Hz),
136.0, 117.2, 101.8 (d, JPC¼136.6 Hz), 62.0 (d, JPC
¼
(R*,RP*)-11: A colorless oil; TLC Rf¼0.18 (hexane/
EtOAc¼1:1); 1H NMR (400 MHz, CDCl3) d 7.65–7.21
(10H, m), 4.09–4.03 (2H, m), 3.95 (1H, ddd, J¼6.8, 6.8,
13.1 Hz), 3.75–3.56 (4H, m), 1.59 (3H, d, J¼11.0 Hz),
1.47 (3H, dd, J¼7.0, 15.5 Hz), 1.29 (3H, t, J¼7.0 Hz),
1.16 (3H, t, J¼7.1 Hz), 1.14 (3H, t, J¼7.1 Hz); 13C NMR
(100 MHz, CDCl3) d 139.2 (d, JPC¼2.0 Hz), 135.7–127.7
(aromatic), 101.8 (d, JPC¼133.4 Hz), 61.7 (d, JPC¼7.2 Hz),
58.1 (d, JPC¼97.0 Hz), 57.5 (d, JPC¼4.7 Hz), 57.4 (d,
JPC¼6.9 Hz), 20.9 (d, JPC¼12.0 Hz), 16.6 (d, JPC¼5.0 Hz),
16.1 (d, JPC¼4.1 Hz), 15.5, 15.1; 31P NMR (162 MHz,
CDCl3) d 43.62; IR (neat) 1618, 1155, 1039 cmꢀ1; MS m/z
418 (MH+). HRMS calcd for C23H33NO4P (MH+):
418.2147. Found: 418.2150.
6.8 Hz), 61.6 (d, JPC¼95.2 Hz), 58.2 (d, JPC¼4.5 Hz), 57.3
(d, JPC¼7.1 Hz), 35.2 (d, JPC¼1.9 Hz), 20.6 (d, JPC
¼
12.0 Hz), 16.8 (d, JPC¼4.8 Hz), 15.4, 15.2; 31P NMR
(162 MHz, CDCl3) d 42.72; IR (neat) 1635, 1618, 1155,
1032 cmꢀ1; MS m/z 444 (MH+). HRMS calcd for
C25H35NO4P (MH+): 444.2304. Found: 444.2299.
4.3.2. (1R*,RP*)- and (1S*,RP*)-Ethyl 1,1-diethoxy-
ethyl{1-[(diphenylmethylene)amino]-3-methylbut-3-
enyl}phosphinate ((R*,RP*)-10 and (S*,RP*)-10). These
compounds were prepared from 4 (200 mg, 0.5 mmol),
1.0 M THF solution of LHMDS (0.75 mL, 0.75 mmol),
and methallyl bromide (0.1 mL, 1.0 mmol) in an analogous
manner to that for (R*,RP*)-6. Purification of the residue by
flash column chromatography (CHCl3) gave a mixture of
(R*,RP*)-10 and (S*,RP*)-10 (224 mg, 98%). Analytical
samples of individual isomers were obtained upon re-purifi-
cation by flash column chromatography (hexane/EtOAc¼
10:1 to 2:1).
(S*,RP*)-11: A colorless oil; TLC Rf¼0.18 (hexane/
EtOAc¼1:1); 1H NMR (400 MHz, CDCl3) d 7.80–7.19
(10H, m), 4.31–4.24 (2H, m), 4.04 (1H, ddd, J¼6.9, 6.9,
13.8 Hz), 3.79–3.49 (4H, m), 1.48 (3H, dd, J¼6.9,
15.5 Hz), 1.41 (3H, d, J¼10.8 Hz), 1.33 (3H, t, J¼7.1 Hz),
1.12 (3H, t, J¼7.1 Hz), 1.07 (3H, t, J¼7.1 Hz); 13C NMR
(100 MHz, CDCl3) d 139.2 (d, JPC¼2.1 Hz), 136.0–127.7
(aromatic), 101.6 (d, JPC¼135.7 Hz), 62.0 (d, JPC¼7.5 Hz),
(R*,RP*)-10: A colorless oil; TLC Rf¼0.38 (hexane/
EtOAc¼1:1); 1H NMR (400 MHz, CDCl3) d 7.63–7.26
(10H, m), 4.68 (1H, s), 4.66 (1H, s), 4.32–4.19 (2H, m),
4.09–4.02 (1H, m), 3.75–3.62 (4H, m), 2.78 (2H, t,
J¼6.9 Hz), 1.60 (3H, d, J¼11.1 Hz), 1.39 (3H, s), 1.35
(3H, t, J¼7.1 Hz), 1.19 (3H, t, J¼7.1 Hz), 1.16 (3H, t,
58.1 (d, JPC¼4.5 Hz), 57.4 (d, JPC¼6.9 Hz), 56.8 (d, JPC
¼
100.0 Hz), 20.8 (d, JPC¼11.7 Hz), 16.8 (d, JPC¼4.8 Hz),
16.3 (d, JPC¼4.7 Hz), 15.4, 15.1; 31P NMR (162 MHz,
CDCl3) d 44.09; IR (neat) 1616, 1153, 1034 cmꢀ1; MS

9216
T. Yamagishi et al. / Tetrahedron 62 (2006) 9210–9217
m/z 418 (MH+). HRMS calcd for C23H33NO4P (MH+):
418.2147. Found: 418.2136.
(R*,RP*)-13: A colorless oil; TLC Rf¼0.37 (hexane/EtOAc¼
1
1:1); H NMR (400 MHz, CDCl3) d 7.64–7.26 (10H, m),
4.29–4.13 (2H, m), 3.82–3.60 (4H, m), 3.70 (1H, dd,
J¼3.5, 3.5 Hz), 2.64–2.54 (1H, m), 1.52 (3H, d, J¼
11.0 Hz), 1.31 (3H, t, J¼7.1 Hz), 1.16 (3H, t, J¼6.9 Hz),
1.14 (3H, t, J¼7.0 Hz), 1.04 (3H, d, J¼6.7 Hz), 0.92 (3H,
d, J¼6.8 Hz); 13C NMR (100 MHz, CDCl3) d 139.9
4.3.4. (1R*,RP*)- and (1S*,RP*)-Ethyl 1,1-diethoxy-
ethyl{1-[(diphenylmethylene)amino]pentyl}phosphinate
((R*,RP*)-12 and (S*,RP*)-12). To a solution of 4 (200 mg,
0.5 mmol) in THF (2.5 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
n-butyl bromide (107 mL, 1.0 mmol) and stirred for 24 h at
0 ꢁC. 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 column chro-
matography (hexane/EtOAc¼10:1 to 2:1) to give a mixture
of (R*,RP*)-12 and (S*,RP*)-12 (115 mg, 50%). Analytical
samples of individual isomers were obtained upon re-purifi-
cation by preparative HPLC (CHCl3/MeOH¼50:1).
(d, JPC¼2.9 Hz), 135.8–127.9 (aromatic), 102.0 (d, JPC
¼
134.0 Hz), 68.9 (d, JPC¼94.4 Hz), 61.6 (d, JPC¼7.4 Hz),
57.8 (d, JPC¼4.6 Hz), 57.7 (d, JPC¼6.9 Hz), 30.2, 21.7 (d,
JPC¼8.9 Hz), 20.8 (d, JPC¼12.3 Hz), 19.4 (d, JPC¼6.4 Hz),
16.7 (d, JPC¼5.1 Hz), 15.5, 15.2; 31P NMR (162 MHz,
CDCl3) d 42.63; IR (neat) 1616, 1155, 1034 cmꢀ1; MS
m/z 446 (MH+). HRMS calcd for C25H37NO4P (MH+):
446.2460. Found: 446.2479.
(S*,RP*)-13: A colorless oil; TLC Rf¼0.37 (hexane/
EtOAc¼1:1); 1H NMR (400 MHz, CDCl3) d 7.68–7.26
(10H, m), 4.25–4.16 (2H, m), 3.87 (1H, dd, J¼3.1,
3.1 Hz), 3.78–3.50 (4H, m), 2.64–2.54 (1H, m), 1.36 (3H,
d, J¼12.8 Hz), 1.25 (3H, t, J¼6.9 Hz), 1.24 (3H, d,
J¼6.1 Hz), 1.12 (3H, t, J¼7.0 Hz), 1.04 (3H, t, J¼7.1 Hz),
0.82 (3H, d, J¼6.8 Hz); 13C NMR (100 MHz, CDCl3)
d 139.8 (d, JPC¼2.8 Hz), 136.0–127.9 (aromatic), 101.9
(R*,RP*)-12: A colorless oil; TLC Rf¼0.38 (hexane/
EtOAc¼1:1); 1H NMR (400 MHz, CDCl3) d 7.68–7.24
(10H, m), 4.27–4.16 (2H, m), 3.95 (1H, ddd, J¼2.7, 2.7,
10.2 Hz), 3.79–3.49 (4H, m), 2.17–2.03 (2H, m), 1.37 (3H,
d, J¼10.9 Hz), 1.25 (3H, t, J¼7.1 Hz), 1.22–1.17 (2H, m),
1.14 (3H, t, J¼7.1 Hz), 1.12 (3H, t, J¼7.1 Hz), 1.03–0.95
(2H, m), 0.83 (3H, t, J¼7.3 Hz); 13C NMR (100 MHz,
CDCl3) d 139.9 (d, JPC¼2.8 Hz), 136.7–128.4 (aromatic),
102.3 (d, JPC¼135.4 Hz), 62.3 (d, JPC¼94.4 Hz), 62.3 (d,
JPC¼7.4 Hz), 58.7 (d, JPC¼4.4 Hz), 57.8 (d, JPC¼7.1 Hz),
30.6 (d, JPC¼2.4 Hz), 29.6 (d, JPC¼13.1 Hz), 22.9, 21.0
(d, JPC¼12.0 Hz), 17.3 (d, JPC¼4.8 Hz), 15.8, 15.6, 14.3;
31P NMR (162 MHz, CDCl3) d 42.77; IR (neat) 1616,
1153, 1034 cmꢀ1; MS m/z 460 (MH+). HRMS calcd for
C26H38NO4P (MH+): 460.2617. Found: 460.2627.
(d, JPC¼134.9 Hz), 66.2 (d, JPC¼93.8 Hz), 61.7 (d, JPC
¼
7.3 Hz), 58.4 (d, JPC¼3.9 Hz), 57.2 (d, JPC¼7.6 Hz), 30.3,
22.2 (d, JPC¼12.8 Hz), 20.6 (d, JPC¼12.1 Hz), 18.5 (d,
JPC¼3.1 Hz), 16.8 (d, JPC¼4.9 Hz), 15.4, 15.2; 31P NMR
(162 MHz, CDCl3) d 43.14; IR (neat) 1616, 1153,
1034 cmꢀ1; MS m/z 446 (MH+). HRMS calcd for
C25H37NO4P (MH+): 446.2460. Found: 446.2457.
4.3.6. (1R*,RP*)- and (1S*,RP*)-Ethyl 1,1-diethoxy-
ethyl{1-[(diphenylmethylene)amino]-3-methylbutyl}-
phosphinate ((R*,RP*)-14 and (S*,RP*)-14). These
compounds were prepared from 4 (200 mg, 0.5 mmol),
1.0 M THF solution of LHMDS (0.75 mL, 0.75 mmol),
and iso-butyl iodide (0.29 mL, 2.5 mmol) in an analogous
manner to that for (R*,RP*)-12. Purification of the residue
by flash column chromatography (CHCl3) gave a mixture
of (R*,RP*)-14 and (S*,RP*)-14 (162 mg, 71%). Analyti-
cal samples of individual isomers were obtained upon
re-purification by flash column chromatography (hexane/
EtOAc¼5:1 to 2:1).
(S*,RP*)-12: A colorless oil; TLC Rf¼0.32 (hexane/
EtOAc¼1:1); 1H NMR (400 MHz, CDCl3) d 7.68–7.24
(10H, m), 4.25–4.16 (2H, m), 3.95 (1H, ddd, J¼2.6, 2.6,
10.2 Hz), 3.78–3.49 (4H, m), 2.17–2.00 (2H, m), 1.37 (3H,
d, J¼10.9 Hz), 1.25 (3H, t, J¼7.1 Hz), 1.23–1.16 (2H, m),
1.14 (3H, t, J¼7.1 Hz), 1.08 (3H, t, J¼7.1 Hz), 1.01–0.95
(2H, m), 0.83 (3H, t, J¼7.3 Hz); 13C NMR (100 MHz,
CDCl3) d 139.6 (d, JPC¼2.8 Hz), 136.1–127.9 (aromatic),
102.1 (d, JPC¼133.5 Hz), 63.8 (d, JPC¼95.8 Hz), 61.9 (d,
JPC¼7.3 Hz), 57.8 (d, JPC¼6.4 Hz), 57.7 (d, JPC¼4.8 Hz),
30.2, 29.4 (d, JPC¼12.9 Hz), 22.5, 21.0 (d, JPC¼12.1 Hz),
16.7 (d, JPC¼4.9 Hz), 15.5, 15.2, 13.9; 31P NMR
(162 MHz, CDCl3) d 43.16; IR (neat) 1618, 1155,
1034 cmꢀ1; MS m/z 460 (MH+). HRMS calcd for
C26H38NO4P (MH+): 460.2617. Found: 460.2620.
(R*,RP*)-14: A pale yellow oil; TLC Rf¼0.33 (hexane/
EtOAc¼1:1); 1H NMR (400 MHz, CDCl3) d 8.01–7.12
(10H, m), 4.18–4.02 (2H, m), 3.90 (1H, ddd, J¼2.5, 9.8,
9.8 Hz), 3.60–3.44 (4H, m), 1.92–1.85 (2H, m), 1.80–1.71
(1H, m), 1.44 (3H, d, J¼11.0 Hz), 1.20 (3H, t, J¼7.1 Hz),
1.04 (3H, t, J¼7.0 Hz), 0.99 (3H, t, J¼7.1 Hz), 0.71 (3H,
d, J¼6.6 Hz), 0.38 (3H, d, J¼6.5 Hz); 13C NMR
(100 MHz, CDCl3) d 139.7, 130.0–127.9 (aromatic), 102.2
(d, JPC¼134.2 Hz), 62.2 (d, JPC¼94.9 Hz), 62.0 (d,
JPC¼7.3 Hz), 57.8 (d, JPC¼6.4 Hz), 57.7 (d, JPC¼4.8 Hz),
39.8, 24.8 (d, JPC¼12.6 Hz), 23.7, 21.3, 20.6 (d,
JPC¼12.1 Hz), 16.7 (d, JPC¼5.0 Hz), 15.5, 15.2; 31P NMR
(162 MHz, CDCl3) d 43.15; IR (neat) 1618, 1155,
1034 cmꢀ1; MS m/z 460 (MH+). HRMS calcd for
C26H39NO4P (MH+): 460.2617. Found: 460.2641.
4.3.5. (1R*,RP*)- and (1S*,RP*)-Ethyl 1,1-diethoxy-
ethyl{1-[(diphenylmethylene)amino]-2-methylpropyl}-
phosphinate ((R*,RP*)-13 and (S*,RP*)-13). These
compounds were prepared from 4 (200 mg, 0.5 mmol),
1.0 M THF solution of LHMDS (0.75 mL, 0.75 mmol),
and iso-propyl iodide (100 mL, 1.0 mmol) in an analogous
manner to that for (R*,RP*)-12. Purification of the residue
by column chromatography (hexane/EtOAc¼5:1 to 1:1)
gave a mixture of (R*,RP*)-13 and (S*,RP*)-13 (104 mg,
47%). Analytical samples of individual isomers were ob-
tained upon re-purification by preparative HPLC (CHCl3/
MeOH¼50:1).
4.3.7. Ethyl 3,3-diphenylpropyl(1,1-diethoxyethyl)phos-
phinate (15). To a stirred suspension of 60% NaH (420 mg,

T. Yamagishi et al. / Tetrahedron 62 (2006) 9210–9217
9217
10.5 mmol) in DMF (25 mL) was added a solution of 1
(2.19 g, 10.0 mmol) in THF (10 mL). After stirring for 1 h
at 0 ꢁC, stirring was continued for 3 h at room temperature.
To the mixture was added a solution of 3,3-diphenylpropyl
bromide (4.19 g, 15 mmol) in THF (15 mL) at 0 ꢁC and
stirred for 12 h at room temperature. The mixture 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 col-
umn chromatography (CHCl3) to give 15 (2.32 g, 57%). A
colorless oil; TLC Rf¼0.33 (hexane/EtOAc¼1:1); 1H NMR
(400 MHz, CDCl3) d 7.30–7.16 (10H, m), 4.29–4.10 (2H,
m), 3.93 (1H, t, J¼7.9 Hz), 3.80–3.56 (4H, m), 2.52–2.34
(2H, m), 1.80–1.55 (2H, m), 1.42 (3H, d, J¼11.1 Hz), 1.30
(3H, t, J¼7.1 Hz), 1.17 (3H, t, J¼6.8 Hz), 1.15 (3H, t,
63.3 (d, JPC¼7.4 Hz), 53.5 (d, JPC¼109.3 Hz), 33.1, 21.5,
16.1 (d, JPC¼5.7 Hz); 31P NMR (162 MHz, CDCl3)
d 34.83; IR (KBr) 3087, 1331, 1161, 1043 cmꢀ1; MS m/z
368 (MH+). HRMS calcd for C17H23NO4PS (MH+):
368.1085. Found: 368.1080.
Acknowledgements
This work was partially supported by a grant for private
universities from The Promotion and Mutual Aid Corpora-
tion for Private Schools of Japan and the Ministry of Educa-
tion, Culture, Sports, Science, and Technology. The authors
wish to thank Mr. Haruhiko Fukaya (the analytical center of
this university) for the X-ray crystallographic analysis.
J¼6.8 Hz); 13C NMR (100 MHz, CDCl3) d 143.9 (d, JPC
¼
References and notes
17.3 Hz), 128.4–126.2 (aromatic), 101.1 (d, JPC¼138.1 Hz),
61.3 (d, JPC¼6.7 Hz), 57.9 (d, JPC¼4.7 Hz), 57.4 (d,
JPC¼7.0 Hz), 52.0 (d, JPC¼14.4 Hz), 26.9 (d, JPC¼3.9 Hz),
24.2 (d, JPC¼86.3 Hz), 20.4 (d, JPC¼12.4 Hz), 16.6 (d,
JPC¼5.3 Hz), 15.4, 15.1; 31P NMR (162 MHz, CDCl3)
d 50.09; IR (neat) 1158, 1038 cmꢀ1; MS m/z 405 (MH+).
HRMS calcd for C23H34O4P (MH+): 405.2195. Found:
405.2181.
1. (a) Martin, M. T.; Angeles, T. S.; Sugasawara, R.; Aman, N. I.;
Napper, A. D.; Darsley, M. J.; Sanchez, R. I.; Booth, P.; Titmas,
R. C. J. Am. Chem. Soc. 1994, 116, 6508; (b) Li, T.; Janda, K. D.
Bioorg. Med. Chem. Lett. 1995, 5, 2001.
2. Aminophosphonic and Aminophosphinic Acids: Chemistry and
Biological Activity; Kukhar, V. P., Hudson, H. R., Eds.; Wiley:
Chichester, UK, 2000.
ꢀ
3. For a review, see: Collinsova, M.; Jiracek, J. Curr. Med. Chem.
ꢀ
4.3.8. (1R*,RP*)- and (1S*,RP*)-Ethyl 1-benzyl-3,3-di-
phenylpropyl(1,1-diethoxyethyl)phosphinate ((R*,RP*)-
16 and (S*,RP*)-16). These compounds were prepared from
15 (210 mg, 0.49 mmol), 1.0 M THF solution of LHMDS
(0.74 mL, 0.74 mmol), and benzyl bromide (0.12 mL,
0.98 mmol) in an analogous manner to that for (R*,RP*)-
12. Purification of the residue by flash column chromato-
graphy (hexane/EtOAc¼4:1 to 1:1) gave a mixture of
(R*,RP*)-16 and (S*,RP*)-16 (108 mg, 45%) in a ratio of
1:1. A colorless oil; TLC Rf¼0.30 (hexane/EtOAc¼1:1);
1H NMR (400 MHz, CDCl3) d 7.27–6.77 (15H, m), 4.36–
4.06 (2H, m), 4.03–3.95 (0.5H, m), 3.92–3.88 (0.5H, m),
3.79–3.57 (4H, m), 3.49–3.43 (0.5H, m), 3.40–3.34 (0.5H,
m), 2.83–2.57 (2H, m), 2.18–2.03 (2H, m), 1.45 (1.5H, d,
J¼10.9 Hz), 1.38 (1.5H, t, J¼7.1 Hz), 1.37 (3H, d,
J¼11.3 Hz), 1.28–1.13 (7.5H, m); 31P NMR (162 MHz,
CDCl3) d 49.89, 48.88; IR (neat) 1153, 1035 cmꢀ1; MS
m/z 495 (MH+). HRMS calcd for C30H40O4P (MH+):
495.2640. Found: 495.2645.
2000, 7, 629.
4. For selected examples: (a) Matziari, M.; Georgiadis, D.; Dive,
V.; Yiotakis, A. Org. Lett. 2001, 3, 659; (b) Cristau, H.-J.;
Coulombeeau, A.; Genevois-Borella, A.; Sanchez, F.; Pirat,
J.-L. J. Organomet. Chem. 2002, 643–644, 381; (c) Liu, X.;
Hu, X. E.; Tian, X.; Mazur, A.; Ebetino, F. H. J. Organomet.
Chem. 2002, 646, 212.
5. Baylis, E. K.; Campbell, C. D.; Dingwall, J. G. J. Chem. Soc.,
Perkin Trans. 1 1984, 2845.
6. (a) Jiao, X.-Y.; Verbruggen, C.; Borloo, M.; Bollaert, W.;
Groot, A. D.; Dommisse, R.; Haemers, A. Synthesis 1994,
23; (b) Boyd, E. A.; Chan, W. C.; Loh, V. M., Jr. Tetrahedron
Lett. 1996, 37, 1647.
7. McCleery, P. P.; Tuck, B. J. Chem. Soc., Perkin Trans. 1 1989,
1319.
8. (a) Baylis, E. K. Tetrahedron Lett. 1995, 36, 9385; (b) Froestl,
W.; Mickel, S. J.; Hall, R. G.; Sprecher, G.; Strub, D.;
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H.-R.; Rihs, G.; Vassout, A.; Waldmeier, P. C.; Bittiger, H.
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(b) Denmark, S. E.; Chen, C.-T. J. Am. Chem. Soc. 1995, 117,
11879.
4.3.9. (1R*,RP*)-Ethyl 1-{[(4-methylphenyl)sulfonyl]-
amino}-2-phenylethylphosphinate (18). To a solution of
(R*,RP*)-8 (60 mg, 0.12 mmol) in CH2Cl2 (0.4 mL) was
added EtOH (50 mL) and TMSCl (32 mL, 0.24 mmol) at
room temperature. After stirring for 2.5 h at the same tem-
perature, the mixture was concentrated to give a residue,
which was purified by flash column chromatography
(CHCl3/MeOH¼40:1 to 20:1) to give 18 (37 mg, 83%). Col-
orless crystals; mp 121–124 ꢁC; TLC Rf¼0.28 (CHCl3/
11. (a) Hanessian, S.; Bennani, Y. L.; Delome, D. Tetrahedron Lett.
1990, 31, 6461; (b) Hanessian, S.; Bennani, Y. L. Tetrahedron
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Lett. 1990, 31, 6465; (c) Hanessian, S.; Bennani, Y. L.; Herve,
Y. Synlett 1993, 35.
1
MeOH¼20:1); H NMR (400 MHz, CDCl3) d 7.49–7.02
12. Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.;
Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Spagna,
R. J. Appl. Crystallogr. 1999, 32, 115.
(9H, m), 7.12 (1H, d, J¼570.7 Hz), 4.12–4.06 (2H, m),
3.74 (1H, ddd, J¼5.7, 9.0, 16.5 Hz), 3.04 (1H, ddd, J¼5.6,
9.5, 14.6 Hz), 2.89 (1H, ddd, J¼9.3, 12.0, 14.1 Hz), 2.37
(3H, s), 1.30 (3H, t, J¼7.1 Hz); 13C NMR (100 MHz,
CDCl3) d 143.2, 137.2, 135.5, 129.6–126.4 (aromatic),
13. Sheldrick, G. M. SHELXL97, Program for the Refinement of
€
Crystal Structures; University of Gottingen: Gottingen,
€
Germany, 1997.