A chemo-enzymatic synthesis of optically active 1,1- diethoxyethyl(aminomethyl)phosphinates: Useful chiral building blocks for phosphinyl dipeptide isosteres

Article abstract of DOI:10.1016/j.tetasy.2011.06.033

The kinetic resolution of 1,1-diethoxyethyl(hydroxymethyl)phosphinate possessing chirality at the phosphorus atom was achieved via a lipase-catalyzed acylation. The product was transformed into the corresponding imine, which in turn is a useful starting material for the preparation of phosphinyl dipeptide isosteres.

Full text of DOI:10.1016/j.tetasy.2011.06.033

Tetrahedron: Asymmetry 22 (2011) 1358–1363
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A chemo-enzymatic synthesis of optically active
1,1-diethoxyethyl(aminomethyl)phosphinates: useful chiral building blocks
for phosphinyl dipeptide isosteres
⇑
Takehiro Yamagishi , Jun-ichirou Mori, Terumitsu Haruki, Tsutomu Yokomatsu
School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The kinetic resolution of 1,1-diethoxyethyl(hydroxymethyl)phosphinate possessing chirality at the phos-
phorus atom was achieved via a lipase-catalyzed acylation. The product was transformed into the corre-
sponding imine, which in turn is a useful starting material for the preparation of phosphinyl dipeptide
isosteres.
Received 21 June 2010
Accepted 27 June 2011
Available online 22 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
stabilized carbanion generated from 1.4 The b0-substituent (R2)
was also stereoselectively incorporated via the alkylation of the
Several studies have demonstrated that the synthesis of
peptides with phosphinyl dipeptide isosteres can be a very effective
approach for the development of highly potent and selective
inhibitors of various aspartic proteases and Zn metalloproteases
(Fig. 1).1 Phosphinyl dipeptide isosteres contain the metabolically
lithium enolates generated from 4,5 which was prepared by the
stereospecific Michael reaction of stereodefined H-phosphinate 3,
readily available from 2, with an acrylate derivative (Scheme 1).
We have proven that two stereogenic centers at the
a- and
b0-positions are highly controlled under the influence of the phos-
phorus chirality.4,5 This means that the asymmetric synthesis of
phosphinyl dipeptide isosteres would be feasible through the
same sequence utilizing optically active 1,1-diethoxyethyl(amino-
methyl)phosphinate 1.
stable phosphinic moiety, NH2XaaW[P(O)OHCH2]XaaOH, which
mimics the transition state for the tetrahedral geometry of a scissile
peptide bond during enzymatic hydrolysis. Although the stereo-
chemistry of phosphinyl dipeptide isosteres affect their biological
activities,2 the number of methods for preparing phosphinyl
dipeptide isosteres in a highly stereocontrolled manner are rare.3
In our studies on the asymmetric synthesis of phosphinyl
dipeptide isosteres, we have previously elucidated that optically
active (RP)-1, leading to phosphinyl dipeptide isosteres possessing
a definite absolute configuration, could be prepared from (S)-phen-
ylethylamine (S)-6 as shown in Scheme 2.6 However, this method
requires the careful separation of diastereomeric intermediates
(S,RP)-7 and (S,SP)-7 by silica gel column chromatography and
was thus unsuitable for a larger scale synthesis of (RP)-1.
R1
O
H2N
P
OH
R2
OH
O
In order to develop a more facile method applicable to a larger
scale synthesis of optically active 1,1-diethoxyethyl(amino-
methyl)phosphinate 1, we examined a chemo-enzymatic route as
shown in Scheme 3, in which the lipase-catalyzed acyl transfer
reaction of hydroxymethylphosphinate derivative 8 was applied
as a key reaction and the resulting optically active alcohols were
chemically transformed into the target aminomethylphosphinates.
Although the lipase-catalyzed acyl transfer reaction has been uti-
lized as a concise and elegant method to prepare optically active
secondary and primary alcohol derivatives bearing an asymmetric
center at the carbon atom,7 this approach has rarely been applied
to obtain optically active hydroxymethylphosphinate deriva-
tives.8,9 However, a highly efficient resolution of 8 is feasible, since
several reports by Kielbasinski et al. have shown that some lipases
catalyze the acylation of a primary hydroxy group as discriminating
phosphinyl dipeptide isosteres
Figure 1.
Recent reports demonstrated that racemic phosphinyl dipeptide
isosteres could be efficiently prepared in a protected form and in a
highly diastereoselective manner starting from ethyl 1,1-diethoxy-
ethyl(aminomethyl)phosphinate 14,5 (Scheme 1). In our method,
the
a
-substituent (R1) of the phosphinyl dipeptide isosteres was
introduced via a stereoselective alkylation of the phosphorus-
⇑
Corresponding author. Tel./fax: +81 42 676 3239.
E-mail address: yokomatu@toyaku.ac.jp (T. Yokomatsu).
Present Address: School of Pharmacy, Ohu University, 31-1 Tomita-machi,
Misumidou, Kooriyama-city, Fukushima 963-8611, Japan.
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.06.033

T. Yamagishi et al. / Tetrahedron: Asymmetry 22 (2011) 1358–1363
1359
R1
LHMDS
R1X
O
Me
Ph
Ph
O
Me
Ph
Ph
N
P
OEt
OEt
N
P
OEt
OEt
OEt
OEt
1
2
de: up to 10:1
R1
R1
O
O
O
P
Trs NH
P
H
Trs NH
O-t-Bu
OEt
OEt
3
4
LHMDS
R2X
R1
O
O
Trs NH
P
O-t-Bu
OEt
R2
de: up to 29:1
5
Scheme 1. Stereocontrolled synthesis of phosphinyl dipeptide isosteres.
R
R
O
Me
O
Me
Ph
NH2
3 steps
Ph
N
P
OEt
OEt
Ph
N
P
OEt
OEt
+
Me
OEt
OEt
Me
Me
(S)-6
(S,RP)-7
Me
(S,SP)-7
R=2-naphthyl
''separation''
O
Ph
Ph
2 steps
N
P
OEt
OEt
OEt
(RP)-1
Scheme 2.
asymmetric environment of the remote phosphorus chirality.8
Herein, we fully describe the details of our results (Scheme 3).
hyde in the presence of Et3N according to the procedure in the
literature8b (Scheme 4).
O
Me
O
Me
R
(CH2O)n Et N
,
3
H
P
OEt
OEt
HO
P
OEt
OEt
O
P
Me
O
Me
toluene, reflux
68%
OAc
lipase
OEt
9
OEt
HO
OEt
OEt
AcO
HO
P
OEt
OEt
OEt
OEt
Scheme 4.
8
+
Acyl transfer reactions of 8 were examined under several condi-
tions and the results are shown in Table 1. First, 8 was acylated
with vinyl acetate as an acyl donor in the presence of lipase AK
(Pseudomonas fluorescens) and molecular sieves 3 Å (MS 3 Å) in
i-Pr2O (0.012 M solution of 8) at room temperature according to
the procedure of Shioji et al.9a We expected the reaction would
proceed efficiently by adding MS 3 Å because the water contents
in the reaction system were found to affect the activity of lipase.11
The reaction reached near to 50% conversion after 8 h as evidenced
by TLC monitoring, giving acetate (SP)-10 and alcohol (RP)-8 in 49%
and 31% yields, respectively (entry 1). These compounds could be
easily isolated by silica gel column chromatography. The acetyl
group of (SP)-10 was removed by treatment with Et3N in MeOH
to afford alcohol (SP)-8. While the enantiomeric purity of (SP)-8
was modest (70% ee), (RP)-8 showed excellent enantiomeric purity
(99% ee). From these data, the enantiomeric ratio (E)12 was
O
Me
O
Me
Ph
Ph
N
P
OEt
OEt
P
OEt
OEt
OEt
OEt
(RP)-1
Scheme 3. Chemo-enzymatic strategy for the synthesis of optically active 1,1-
diethoxyethyl(aminomethyl)phosphinate (Rp)-1.
2. Results and discussion
2.1. Acyl transfer reaction of racemic substrate 8
The requisite starting material 8 was readily prepared by the
addition of 1,1-diethoxyethyl-H-phosphinate 910 to paraformalde-

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T. Yamagishi et al. / Tetrahedron: Asymmetry 22 (2011) 1358–1363
Table 1
Lipase-catalyzed acylation of 8a
R1
OAc
O
Me
O
Me
O
P
Me
lipase
HO
P
OEt
OEt
R2O
P
OEt
OEt
HO
OEt
OEt
+
solvent
MS 3Å, rt
OEt
8
OEt
OEt
(RP)-8
(SP)-10 R2=Ac
Et3N
MeOH
(SP)-8
R2=H
Entry
Solvent
Lipase
Time (h)
R1
Yield % (ee%)b of (SP)-15
Yield % (ee%)b of (RP)-8
E valuec
1
2
3
4
5
6
i-Pr2O
CPME
c-Hexane
Hexane
Hexane
Hexane
AK
AK
AK
AK
PS
8
9
6
7
9
H
H
H
H
H
Me
49 (70)
51 (77)
41 (89)
54 (77)
27 (47)
50 (88)
31 (99)
38 (74)
46 (87)
32 (99)
62 (76)
40 (99)
28
17
49
39
6
AK
19
82
a
b
c
All reactions were carried out in a 0.012 M solution of 8.
Determined by 1H NMR (300 MHz, CDCl3) analysis of the corresponding (R)- and (S)-MTPA esters.
Determined by Sih’s equation.12
determined to be 28. In an attempt to improve the E value, the sol-
vent effect on the enantioselectivity was examined. This survey
revealed that employing nonpolar solvents led to relatively good
results (entries 2–4). Although the E-value decreased in the case
of c-pentylmethylether (CPME),13 a replaceable solvent for THF,
employing c-hexane and hexane improved the selectivity up to E
= 49 and E = 39, respectively. Using lipase AK was crucial for high
enantioselectivity, as a reaction employing lipase PS (Pseudomonas
cepacia) resulted in low selectivity (entry 5). In some lipase-cata-
lyzed resolutions, the acetaldehyde generated from the vinyl ace-
tate is known to disturb reactions by forming Schiff bases14 with
the enzymes or forming hemiacetals with the substrate alcohols.15
In order to avoid these undesired reactions, isopropenyl acetate
was employed next in place of vinyl acetate as an acyl donor for
the lipase AK-catalyzed acylation (entry 6). We expected that rela-
tively unreactive acetone was formed and the undesired reaction
would be suppressed. While the reaction proceeded slowly, the de-
sired (SP)-10 and (RP)-8 were obtained in 50% and 40% yields,
respectively, after 19 h. The E value of this reaction was deter-
mined to be 82 and these conditions were found to yield the best
results.
desirable from an economic point of view and ease of reaction. We
found that the substrate concentration could be increased to a
0.05 M solution of 8 without a significant loss of enantiomeric pur-
ity of yield for (SP)-10 and (RP)-8 on a 10 g scale. When the reaction
was carried out at a substrate concentration of 0.1 M, the acylation
proceeded rapidly to give acetate (SP)-15 in 67% yield after 3 h. A
typical protocol is shown in Scheme 5. In this protocol, 10 g of 8
were acylated with isopropenyl acetate (33 mL) in hexane
(899 mL) in the presence of lipase AK (35.4 g) and MS 3 Å
(35.4 g) to give 4.1 g of (SP)-15 (35% yield, 95% ee) and 3.5 g of
(RP)-8 (35% yield, 92% ee), respectively. The enantiomeric purity
of (RP)-8 was increased to 99% ee by an enzymatic double resolu-
tion under the same conditions. Thus, using this protocol, we ob-
tained 2.9 g of (RP)-8 with high enantiomeric excess from
racemic 8 (10 g).
2.3. Transformation of (RP)-8 to the target compound
To convert alcohol (RP)-8 into the required imine (RP)-1, tosylate
(RP)-11 was prepared under conventional conditions (Scheme 6).
When the nucleophilic substitution of (RP)-11 was performed with
NaN3 in DMF at 90 °C, the desired azide was obtained in poor yield
(25%). However, the treatment of (RP)-11 with benzylamine at
90 °C in solvent-free conditions gave (RP)-12 in 75% yield. Thus,
the preparation of (RP)-1 was accomplished from (RP)-12 by the
sequential removal of the benzyl group and the formation of an
imine with benzophenone. The absolute configuration of (RP)-1
was verified by comparison of the specific rotation with the
2.2. A larger scale synthesis of (Rp)-8
Having established good conditions for the lipase AK-catalyzed
acylation of 8 and the substrate specificity on a small scale, we next
focused our attention onto the resolution of 8 on a larger scale. For
these studies, reducing the volume of the solvent used was highly
Conditions of 1 st enzymatic resolution
(SP)-10 (4.1 g)
(RP)-8 (3.5 g)
substrate 8
hexane
10 g (41.6 mmol)
832 mL
35% (95% ee)
35% (92% ee)
lipase AK
isopropenyl acetate
MS 3Å
35.4 g
2nd enzymatic
resolution
33 mL (299.5 mmol)
35.4 g
(RP)-8 (2.9 g)
(99% ee)
time
3 h
Scheme 5.

T. Yamagishi et al. / Tetrahedron: Asymmetry 22 (2011) 1358–1363
1361
O
Me
O
Me
BnNH2
RO
P
OEt
OEt
BnHN
P
OEt
OEt
80 ºC
75%
OEt
OEt
(RP)-8
(RP)-12
: R=H
TsCl, Et3N
90%
(RP)-11
: R=Ts
H2
O
P
Me
O
P
Me
Ph
Ph
Ph2CO
Pd(OH)2-C
H2N
OEt
OEt
N
OEt
OEt
toluene
reflux
77%
MeOH
97%
OEt
(RP)-13
OEt
(RP)-1
Scheme 6.
reported value.6 At this stage, based on these results, the absolute
configuration of alcohol (RP)-8 was deduced. This sequence was
also applied to the synthesis of (SP)-1 from (SP)-8 (see Section 4).
1151, 1037 cmꢀ1; MS m/z 263 (MNa+); HRMS Calcd for C9H21O5P-
Na: 263.1024 (MNa+). Found: 263.1013.
4.2. (SP)-Ethyl acetoxymethyl(1,1-diethoxyethyl)phosphinate
(SP)-10 and (RP)-ethyl hydroxymethyl(1,1-diethoxyethyl)-
phosphinate (RP)-8
3. Conclusion
In conclusion, we have developed a new and practical method
to prepare optically active aminomethylphosphinate (RP)-1, a use-
ful chiral building block for phosphinyl dipeptide isosteres, via the
lipase AK-catalyzed kinetic resolution of hydroxymethylphosphi-
nate 8 bearing P-chirality. This method was applicable on a 10 g
scale resolution, resolving the issues of our previous methodology.
The practical preparation of optically active phosphinyl dipeptide
isostere derivatives is ongoing.
To a suspension of MS 3 Å (850 mg) in hexane (85 mL) were
added 8 (240 mg, 1 mmol), lipase AK (850 mg), and vinyl acetate
(0.72 mL, 7.2 mmol) and stirred for 7 h at room temperature. The
mixture was filtered through a pad of Celite and the filtrate was
concentrated to give a residue, which was purified by column chro-
matography (hexane/AcOEt = 1:1 to AcOEt) to give (SP)-10
(155.5 mg, 54%, 77% ee) and (RP)-8 (79.4 mg, 32%, 99% ee).
(SP)-10: A colorless oil; ½a D20
¼ þ6:1 (c 1.2, CHCl3) for a sample of
ꢁ
77% ee; 1H NMR (400 MHz, CDCl3) d: 4.47 (1H, dd, J = 7.2, 14.3 Hz),
4.36 (1H, d, J = 7.2, 14.3 Hz), 4.21 (2H, dq, J = 7.1, 7.1 Hz), 3.74–3.60
(4H, m), 2.09 (3H, s), 1.51 (3H, d, J = 11.5 Hz), 1.31 (3H, t, J = 7.1 Hz),
1.17 (3H, t, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) d: 170.1(d,
JCP = 7.0 Hz), 101.1 (d, JCP = 145.4 Hz), 62.3 (d, JCP = 7.2 Hz), 58.4
(d, JCP = 5.4 Hz), 58.0 (d, JCP = 7.3 Hz), 57.9 (d, JCP = 100.1 Hz), 20.7,
20.4 (d, JCP = 12.1 Hz), 16.7 (d, JCP = 5.0 Hz), 15.5, 15.3; 31P NMR
(122 MHz, CDCl3) d: 38.35; IR (neat) 1753, 1158, 1038 cmꢀ1; MS
m/z 305 (MNa+); HRMS Calcd for C11H23O6PNa: 305.1130 (MNa+).
Found: 305.1132.
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 Bruker DPX400 NMR spectrometer oper-
ating at 400 MHz for 1H, 100 MHz for 13C. 31P NMR spectra were
obtained on Varian Mercury-300BB instrument operating at
122 MHz. The chemical shift data for each signal on 1H NMR
(400 MHz) are expressed as relative ppm from CHCl3 (d 7.26) or
CH3OH (d 3.30). The chemical shifts of 13C are reported relative
to CDCl3 (d 77.0) or CD3OD (d 49.0). The chemical shifts of 31P
are recorded relative to external 85% H3PO4 (d = 0) with broad-
band 1H decoupling. Optical rotations were measured with a JASCO
P1030 digital polarimeter. Column chromatography was carried
(RP)-8: A colorless oil; ½a D20
¼ ꢀ11:8 (c 0.4, CHCl3) for a sample
ꢁ
of 99% ee; the 1H NMR spectrum of was identical to that of 9.
4.3. (SP)-Ethyl hydroxymethyl(1,1-diethoxyethyl)phosphinate
(SP)-8
To a solution of (SP)-10 (61.5 mg, 0.22 mmol) in MeOH (5.4 mL)
was added Et3N (1.1 mL, 7.85 mL) and stirred for 12 h at room tem-
perature. The mixture was concentrated to give a residue, which
was purified by column chromatography (hexane/AcOEt = 3:1 to
AcOEt) to give (SP)-8 (48.3 mg, 92%). The 1H NMR spectrum was
identical to that of 8.
out using 63–210 lm Silica Gel 60N (Kanto Chemical Co., Inc.).
4.1. Ethyl 1,1-diethoxyethyl(hydroxymethyl)phosphinate 8
A solution of 9 (7.04 g, 33.5 mmol), Et3N (2.33 mL, 167.6 mmol)
and paraformaldehyde (5.03 g, 167.6 mmol) in toluene (67.0 mL)
was stirred for 8 h at 100 °C. The mixture was cooled to room tem-
perature and concentrated under reduced pressure. The resulting
residue was purified by column chromatography (hexane/
AcOEt = 1:1 to AcOEt) to give 8 (5.47 g, 68%) as a colorless oil; 1H
NMR (400 MHz, CDCl3) d: 4.22 (2H, dq, J = 7.1, 7.1 Hz), 4.02 (2H,
d, J = 14.7 Hz), 3.91 (2H, dd, J = 3.4, 14.7 Hz), 3.74–3.59 (4H, m),
1.53 (3H, d, J = 11.0 Hz), 1.32 (3H, t, J = 7.1 Hz), 1.18 (3H, t,
J = 7.0 Hz); 13C NMR (100 MHz, CDCl3) d: 101.7 (d, JCP = 136.0 Hz),
62.3 (d, JCP = 7.5 Hz), 58.5 (d, JCP = 4.8 Hz), 58.1 (d, JCP = 93.1 Hz),
57.8 (d, JCP = 6.9 Hz), 20.3 (d, JCP = 11.1 Hz), 16.7 (d, JCP = 5.2 Hz),
15.5, 15.3; 31P NMR (122 MHz, CDCl3) d: 42.87; IR (neat) 3156,
4.4. The (R)-MTPA ester of (RP)-8
To a stirred suspension of (R)-MTPA (26.8 mg, 0.125 mmol),
DCC (25.8 mg, 0.125 mmol), and DMAP (1.5 mg, 0.012 mmol) in
CH2Cl2 (0.35 mL) was added
a solution of (RP)-8 (15 mg,
0.062 mmol) in CH2Cl2 (0.7 mL) and stirred at room temperature
until the starting material disappeared by TLC monitoring. 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 filtered through

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T. Yamagishi et al. / Tetrahedron: Asymmetry 22 (2011) 1358–1363
a pad of silica gel (AcOEt) and the filtrate was concentrated to give
(R)-MTPA ester of (RP)-8 as a white oil; 1H NMR (300 MHz, CDCl3)
d: 7.55–7.38 (5H, m), 4.74 (1H, dd, J = 5.7, 14.2 Hz), 4.64 (1H, dd,
J = 4.5,14.2 Hz), 4.22–4.15 (2H, m), 3.74–3.57 (7H, m), 1.43 (3H,
d, J = 11.8 Hz), 1.28 (3H, t, J = 7.1 Hz), 1.16 (6H, t, J = 7.0 Hz); 31P
NMR (122 MHz, CDCl3) d: 37.66.
4.9. (RP)-Ethyl (benzylamino)methyl(1,1-diethoxyethyl)-
phosphinate (RP)-12
A solution of (RP)-11 (154.4 mg, 0.39 mmol) in benzylamine
(0.39 mL, 3.57 mmol) was stirred for 4 h at 80 °C, followed by cool-
ing to room temperature. The mixture was poured into 2 M NaOH
and extracted with AcOEt. The combined extracts were washed
with brine and dried over MgSO4. Removal of the solvent gave a
residue, which was purified by column chromatography (hexane/
AcOEt = 1:1 to AcOEt) to give (RP)-12 (96.8 mg, 75%).
4.5. The (S)-MTPA ester of (RP)-8
This compound was prepared from (S)-MTPA (26.8 mg,
0.125 mmol) in an analogous manner to that for the (R)-MTPA es-
ter of (RP)-8 and was obtained as a white oil; 1H NMR (300 MHz,
CDCl3) d: 7.55–7.39 (5H, m), 4.83 (1H, dd, J = 6.9, 14.1 Hz), 4.52
(1H, dd, J = 3.8,14.1 Hz), 4.23–4.11 (2H, m), 3.78–3.16 (7H, m),
1.46 (3H, d, J = 11.7 Hz), 1.28 (3H, t, J = 7.1 Hz), 1.17 (6H, t,
J = 7.0 Hz); 31P NMR (122 MHz, CDCl3) d: 36.83.
½
a 2D0
ꢁ
¼ ꢀ20:8 (c 0.7, CHCl3); the 1H and 31P NMR spectra were iden-
tical to those of a racemic sample reported in the literature.6
4.10. (SP)-Ethyl (benzylamino)methyl(1,1-diethoxyethyl)-
phosphinate (SP)-12
This compound was prepared from (SP)-11 (8.44 g, 21.4 mmol)
in an analogous manner to that for (RP)-12. Purification of the res-
idue by column chromatography (hexane/AcOEt = 1:1 to AcOEt)
4.6. A larger scale synthesis of (RP)-8
gave (SP)-12 (5.47 g, 78%), ½a D20
ꢁ
¼ þ20:0 (c 0.2, CHCl3); the 1H and
To a suspension of MS 3 Å (35.4 g) in hexane (832 mL) were
added 8 (10 g, 41.6 mmol), lipase AK (35.4 g), and isopropenyl ace-
tate (33 mL, 299.5 mmol) and stirred for 3 h at room temperature.
The mixture was filtered through a pad of Celite and the filtrate
was concentrated to give a residue, which was purified by column
chromatography (hexane/AcOEt = 1:1 to AcOEt) to give (SP)-10
(4.1 g, 35%, 95% ee) and (RP)-8 (3.5 g, 35%, 92% ee). To a suspension
of the obtained (RP)-8 (3.5 g, 14.6 mmol) and MS 3 Å (12.4 g) in
hexane (292 mL) was added lipase AK (12.4 g), isopropenyl acetate
(11.4 mL, 105.1 mmol) and then stirred for 2 h at room tempera-
ture as a 2nd enzymatic resolution. Purification in an analogous
manner to that of the aforementioned 1st enzymatic resolution
gave (RP)-8 (2.9 g, 99% ee).
31P NMR spectra were identical to those of a racemic sample re-
ported in the literature.6
4.11. (RP)-Ethyl aminomethyl(1,1-diethoxyethyl)phosphinate
(RP)-13
To a solution of (RP)-12 (19.5 g, 59.1 mmol) in MeOH (592 mL)
was added 20% Pd(OH)2–C (1.83 g) and stirred for 6 h at room tem-
perature under a hydrogen atmosphere. The catalyst was removed
by filtration through a pad of Celite and the filtrate was concen-
trated to give a residue. To a solution of the residue in CH2Cl2
(648 mL) was added Et3N (13.4 mL, 13 mmol) and the mixture
was stirred for 30 min at room temperature. To the mixture was
added Et2O (194 mL) and the resulting crystal was removed by fil-
tration. The filtrate was concentrated to give (RP)-13 (13.7 g, 97%).
4.7. (RP)-[(1,1-Diethoxyethyl)(ethoxy)phosphoryl]methyl 4-
methylbenzenesulfonate (RP)-11
½
a 2D0
ꢁ
¼ ꢀ21:8 (c 0.7, CHCl3); the 1H and 31P NMR spectra were iden-
tical to those of a racemic sample reported in the literature.6
To a solution of (RP)-8 (480 mg, 2 mmol) in CH2Cl2 (9.6 mL)
were added Et3N (0.42 mL, 2.4 mmol), DMAP (24.4 mg, 0.2 mmol)
and TsCl (475.6 mg, 2.4 mmol) and the mixture was stirred for
3.5 h at room temperature. The mixture was then 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 column chromatography (hexane/
AcOEt = 10:1 to hexane/AcOEt = 1:1) to give (RP)-11 (710.3 mg,
4.12. (SP)-Ethyl aminomethyl (1,1-diethoxyethyl)phosphinate
(SP)-13
This compound was prepared from (SP)-12 (5.47 g, 16.6 mmol)
in an analogous manner to that for (RP)-13. Purification of the res-
idue gave (SP)-13 (3.8 g, 96%); ½a D20
ꢁ
¼ þ20:8 (c 0.2, CHCl3); the 1H
and 31P NMR spectra were identical to those of a racemic sample
reported in the literature.6
90%) as a colorless oil; ½a D20
ꢁ
¼ ꢀ17:7 (c 0.6, CHCl3) 1H NMR
(400 MHz, CDCl3) d: 7.78 (2H, d, J = 8.4 Hz), 7.34 (2H, d,
J = 8.4 Hz), 4.30 (2H, dd, J = 4.5, 13.0 Hz), 4.21–4.14 (2H, m), 3.73–
3.54 (4H, m), 2.43 (3H, s), 1.49 (3H, d, J = 11.7 Hz), 1.30 (3H, t,
J = 7.0 Hz), 1.15 (3H, t, J = 6.6 Hz), 1.13 (3H, t, J = 6.6 Hz); 13C NMR
4.13. (RP)-Ethyl 1,1-diethoxyethyl{[(diphenylmethylene)-
amino]methyl}phosphinate (RP)-1
(100 MHz, CDCl3) d: 145.5–128.4 (aromatic), 101.0 (d, JCP
=
A suspension of (RP)-13 (4 g, 8.4 mmol) and benzophenone
(3.36 g, 18.4 mmol) in toluene (43 mL) was heated at reflux for
12 h with the 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 chromatog-
149.9 Hz), 62.7 (d, JCP = 7.5 Hz), 61.9 (d, JCP = 95.3 Hz), 58.6 (d,
JCP = 5.6 Hz), 58.1 (d, JCP = 7.7 Hz), 21.8, 20.5 (d, JCP = 11.9 Hz),
16.6 (d, JCP = 4.8 Hz), 15.4, 15.3; 31P NMR (122 MHz, CDCl3) d:
35.89; IR (neat) 1370, 1180, 1034 cmꢀ1; MS m/z 417 (MNa+); HRMS
Calcd for C16H27O7PSNa: 417.1113 (MNa+). Found: 417.1112.
raphy (CHCl3) to give (RP)-1 (5.2 g, 77%); ½a D20
¼ ꢀ17:2 (c 0.8,
ꢁ
CHCl3); the 1H and 31P NMR spectra were identical to those of a
racemic sample reported in the literature.6
4.8. (SP)-[(1,1-Diethoxyethyl)(ethoxy)phosphoryl]methyl
4-methyl benzenesulfonate (SP)-11
This compound was prepared from (SP)-8 with 95% ee (5.30 g,
22.1 mmol) in an analogous manner to that for (RP)-11. Purification
of the residue by column chromatography (hexane/AcOEt = 10:1 to
hexane/AcOEt = 1:1) gave (SP)-11 (8.44 g, 97%) as a colorless oil;
4.14. (SP)-Ethyl 1,1-diethoxyethyl{[(diphenylmethylene)-
amino]methyl}phosphinate (SP)-1
This compound was prepared from (SP)-13 (3.8 g, 15.9 mmol) in
an analogous manner to that for (RP)-1. Purification of the residue
by column chromatography (CHCl3) gave (SP)-1 (4.6 g, 72%);
½
a 2D0
ꢁ
¼ þ16:9 (c 0.2, CHCl3); The 1H NMR spectrum was identical
to that of (RP)-11.

T. Yamagishi et al. / Tetrahedron: Asymmetry 22 (2011) 1358–1363
1363
a 2D0
ꢁ
¼ þ17:4 (c 0.2, CHCl3); the 1H and 31P NMR spectra were iden-
individual phosphinic dipeptide stereoisomers using HPLC has already been
reported, see: (f) Mucha, A.; Lammerhofer, M.; Lindner, W.; Pawelczak, M.;
Kafarski, P. Bioorg. Med. Chem. Lett. 2008, 18, 1550.
½
tical to those of a racemic sample reported in the literature.6
4. Yamagishi, T.; Haruki, T.; Yokomatsu, T. Tetrahedron 2006, 62, 9210.
5. Yamagishi, T.; Ichikawa, H.; Haruki, T.; Yokomatsu, T. Org. Lett. 2008, 10, 4347.
6. Haruki, T.; Yamagishi, T.; Yokomatsu, T. Tetrahedron: Asymmetry 2007, 18,
2886.
7. For a recent review, see: Ghanem, A. Tetrahedron 2007, 63, 1721.
8. (a) Kielbasinski, P.; Omelanczuk, J.; Mikolajczyk, M. Tetrahedron: Asymmetry
1998, 9, 3283; (b) Kielbasinski, P.; Albrycht, A.; Luczak, J.; Mikolajczyk, M.
Tetrahedron: Asymmetry 2002, 13, 735; (c) Albrycht, A.; Kielbasinski, P.;
Drabowicz, J.; Mikolajczyk, M.; Matsuda, T.; Harada, T.; Nakamura, N.
Tetrahedron: Asymmetry 2005, 16, 2015.
Acknowledgments
This work was partially supported by a grant for private univer-
sities from The Promotion and Mutual Aid Corporation for Private
Schools of Japan and the Ministry of Education, Culture, Sports,
Science, and Technology.
9. For reports on the enzymatic resolution of
a-hydroxyphosphinates with two
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