Diastereoselective synthesis of Pro-Phe phosphinyl dipeptide isosteres

Article abstract of DOI:10.1016/j.tetasy.2012.10.019

The diastereoselective synthesis of Pro-Phe phosphinyl dipeptide isosteres in protected form was achieved by starting from optically active 1,1-diethoxyethyl(aminomethyl)phosphinate. Our methodology involves diastereoselective α-alkylation and β′-alkylation of phosphinate derivatives with an asymmetric center at the phosphorus atom.

Full text of DOI:10.1016/j.tetasy.2012.10.019

Tetrahedron: Asymmetry 23 (2012) 1633–1639
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Diastereoselective synthesis of Pro-Phe phosphinyl dipeptide isosteres
Takehiro Yamagishi a, , Atsushi Kinbara a, Noriko Okubo a, Shunpei Sato a, Haruhiko Fukaya b
⇑
a School of Pharmacy, Ohu University, 31-1 Tomita-machi, Misumidou, Kooriyama, Fukushima 963-8611, Japan
b 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:
Received 31 August 2012
Accepted 25 October 2012
The diastereoselective synthesis of Pro-Phe phosphinyl dipeptide isosteres in protected form was
achieved by starting from optically active 1,1-diethoxyethyl(aminomethyl)phosphinate. Our methodol-
ogy involves diastereoselective
asymmetric center at the phosphorus atom.
a
-alkylation and b0-alkylation of phosphinate derivatives with an
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
Therefore, isomers 1 and 10 needed to be prepared in order to
investigate protease inhibitors.
Several studies have demonstrated that the synthesis of
peptides with phosphinyl dipeptide isosteres (PDIs) 1 can be a very
effective approach for the development of highly potent and
selective inhibitors of aspartic proteases and Zn metalloproteases
(Fig. 1).1 PDIs contain the metabolically stable phosphinic moiety,
Proline amino acid mimetics (Pro-Xaa type PDIs) have shown
utility in medicinal chemistry. The Pro-Phe PDIs have been devel-
oped as potent and selective inhibitors of angiotensin-converting
enzyme 2 (ACE2),4 and as a useful scaffold for protease inhibitor
development because of their restricted conformation that mini-
mizes entropy upon enzyme binding, which can enhance activity.5
However, a lack of reliable synthetic methods6 and a review of the
literature revealed that Pro-Xaa type PDIs have not been prepared
in a stereocontrolled manner. Herein we focus on a concise, stere-
oselective synthesis of Pro-Phe PDI 2 and its diastereomer 20
(Fig. 2).
NH2XaaW[P(O)OHCH2]XaaOH, which mimics the tetrahedral
transition state of a scissile peptide bond during enzymatic hydro-
lysis. The stereochemistry of PDIs significantly affects their biolog-
ical activities and the peptide derivatives of 1, which possess
stereochemistry analogous to dipeptides composed of natural L-
amino acids and which show relatively good inhibitory activity
compared to those of other diastereomers.2 Recent studies of zinc
metalloprotease inhibitors by Dive et al. have reported that the ste-
reochemistry at the b0-position of PDIs influences the inhibitor’s
ability to discriminate between each protease enzyme. Thus, pep-
tides containing 1 caused the inhibition of angiotensin-converting
enzyme (ACE), endothelin-converting enzyme-1 (ECE-1), and
neprilysin (NEP), while peptides derived from diastereomer 10
were dual inhibitors of ACE and ECE-1, but did not inhibit NEP.3
O
O
N
H
P
OH
N
H
P
OH
O
OH
O
OH
Bn
Bn
2
2'
Figure 2. Structure of Pro-Phe PDIs 2 and 20.
R1
O
R1
O
Racemic PDIs were successfully prepared in protected form 7 in
a highly stereocontrolled manner starting from ethyl 1,1-diethoxy-
ethyl(aminomethyl)phosphinate 37,8 (Scheme 1). In this method,
H2N
P
OH
H2N
P
OH
R2
R2
O
OH
O
OH
the a
-substituent (R1) of the PDI was introduced via stereoselective
alkylation of the phosphorus-stabilized carbanion generated from
3.7,9 The b0-substituent (R2) was also incorporated stereoselectively
via alkylation of the lithium enolates generated from 6, which was
prepared via conversion of 4 into the stereodefined H-phosphinate
5 and its stereospecific Michael reaction with tert-butyl acrylate.8
This method involved tight control of the two stereogenic centers
PDIs
1
1'
Figure 1. Structures of PDIs 1 and 10.
at the
chirality. The preparation of optically active 3 with an asymmetric
a
- and b0-positions under the influence of the phosphorus
⇑
Corresponding author. Tel./fax: +81 24 932 9212.
E-mail address: t-yamagishi@pha.ohu-u.ac.jp (T. Yamagishi).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.10.019

1634
T. Yamagishi et al. / Tetrahedron: Asymmetry 23 (2012) 1633–1639
R1
ever, the formation of the desired alkylation product did not occur,
LHMDS
R1X
O
Me
Ph
Ph
O
Me
Ph
Ph
and starting material (RP)-3 was recovered (entry 1). When the
reaction temperature was increased from ꢀ78 to ꢀ20 °C, (RP)-3
disappeared within 6 h, as verified by TLC, affording products
(RP)-14 and (RP)-140 in 66% yield in a ratio of 5.7:1 (entry 2). When
the reaction was conducted at 0 °C, the reaction time decreased
from 6 to 3 h, giving (RP)-14 and (RP)-140 in 66% yield with a ratio
of 6.0:1 (entry 3). Reaction at room temperature resulted in a de-
crease in the diastereomeric ratio (entry 4). In studies on alkylation
reactions of lithium enolates, LiCl has proven to be a useful addi-
tive for enhancing reactivity and influencing diastereoselectivity
N
P
OEt
N
P
OEt
OEt
OEt
OEt
OEt
3
4
dr: up to 10:1
R1
R1
O
O
O
P
PG
N
H
P
H
PG
N
H
O-t-Bu
OEt
OEt
6
5
PG=Ts, Trs
O
R1
LHMDS
R2X
O
P
by changing the aggregated states.13 When a similar
a-alkylation
PG
N
O-t-Bu
H
of (RP)-3 was attempted using LiCl as an additive at 0 °C, the selec-
tivity was slightly improved to 7.1:1, although the chemical yield
decreased to 46% (entry 5). Although the product (RP)-14 was ob-
tained as a mixture with the minor isomer (RP)-140, the corre-
sponding alcohol (RP)-15, prepared by desilylation with TBAF,
could be isolated by silica gel column chromatography. X-ray crys-
tallographic analysis of one of the diastereomers, racemic 15 was
performed (Fig. 3), which revealed the relative stereochemistry of
optically active (RP)-15.
OEt R2
PG=Ts; R1=R2=Bn; dr=4.0:1
PG=Trs; R1=R2=Bn; dr=21:1
7
Scheme 1. Stereocontrolled synthesis of racemic PDIs in protected form.
center at the phosphorus atom was accomplished using the
requisite chiral building block leading to PDIs with defined
absolute configuration, via resolution with (S)-phenylethylamine10
or the lipase-catalyzed acyl transfer reaction of 1,1-diethoxyeth-
yl(hydroxymethyl)phosphinate.11 In an effort to extend the scope
of this synthetic methodology to PDIs, optically active Pro-Phe PDIs
were synthesized in protected form. Herein we report the details of
our investigation.
Table 1
a-Alkylation of (RP)-3 with 13
LHMDS
I
OTBDPS
O
Me
Ph
Ph
13
2. Results and discussion
N
P
OEt
OEt
THF
OEt
The P-chiral (RP)-3 was readily prepared from racemic
1,1-diethoxyethyl(hydroxymethyl)phosphinate 8 according to a
previously reported procedure (Scheme 2).11 Treatment of 8 with
isopropenyl acetate in the presence of lipase AK (Pseudomonas
fluorescens) and molecular sieves 3 Å (MS 3 Å) in hexane at room
temperature afforded acetate (SP)-9 and alcohol (RP)-8 in 50% and
3
(RP)-
OR
Me
OR
Me
O
O
P
Ph
Ph
Ph
N
P
OEt
OEt
N
OEt
OEt
+
Ph
OEt
OEt
40% yields, respectively.
A good enantiomeric ratio (E) was
(RP)-14
(RP)-15
(RP)-14'
: R=TBDPS
: R=H
: R=TBDPS
: R=H
TBAF
(92%)
TBAF
observed (E = 82) with (SP)-9 obtained with 88% ee while (RP)-8
was obtained with excellent enantiomeric purity (99% ee). After
(RP)-8 was converted into tosylate (RP)-10, treatment with benzyl-
amine at 80 °C under solvent-free conditions afforded (RP)-11.
Hydrogenolytic removal of the benzyl group followed by formation
of the imine with benzophenone furnished (RP)-3.
(RP)-15'
Entry
Temp (°C)
Time (h)
Yielda (%)
Dr (14:140)b
1
2
3
ꢀ78
1
6
3
1
3
0
66
66
80
46
—
ꢀ78 to ꢀ20
ꢀ78 to 0
ꢀ78 to rt
ꢀ78 to 0
5.7:1
6.0:1
2.4:1
7.1:1
O
Me
O
Me
O
Me
4
a
HO
P
OEt
OEt
AcO
P
OEt
OEt
HO
P
OEt
OEt
+
5c
OEt
8
OEt
OEt
a
b
c
Combined yield of (RP)-14 and (RP)-140.
8
(RP)-
(SP)-9
Determined by 31P NMR (121 MHz, CDCl3) analysis of the crude products.
2 equiv of LiCl was used as an additive.
E=82
50% (88% ee)
40% (99% ee)
O
Me
O
Me
The stereoselectivity in the present
a-alkylation can be pro-
b
d
c
8
(RP)-
BnHN
P
OEt
OEt
duced through the anion intermediate A bearing a planar sp2 car-
banionic carbon,14 in which the lithium atom is coordinated with
a phosphinyl oxygen and a nitrogen atom (Fig. 4). The approach
of the electrophile from the side of the 1,1-diethoxyethyl group
was hindered by this bulky moiety, therefore, access to the electro-
phile occurred preferentially from the opposite side of the 1,1-
diethoxyethyl group to give (RP)-14 as the product, which is consis-
tent with a previously proposed model.7
TsO
H2N
P
OEt
OEt
OEt
OEt
11
(RP)-10
(RP)-
O
P
Me
O
P
Me
Ph
Ph
e
OEt
OEt
N
OEt
OEt
OEt
OEt
(RP)-3
(RP)-12
After establishing good conditions for the a-alkylation of (RP)-3
Scheme 2. Preparation of (RP)-3. Reagents and conditions: (a) isopropenyl acetate,
lipase AK, MS 3 Å, hexane, rt, 19 h; (b) TsCl, Et3N, CH2Cl2, rt, 90%; (c) BnNH2, 80 °C,
75%; (d) H2, Pd(OH)2-C, MeOH, rt, 97%; (e) Ph2CO, toluene, reflux, 77%.
and verifying the product stereochemistry, the conversion of (RP)-
15 into the target molecule was attempted (Scheme 3). Hydrogen-
olysis of (RP)-15 with 10% Pd–C followed by tosylation of the
resulting amine in the presence of pyridine gave N-tosyl amide
(RP)-16. After transformation into mesylate (RP)-17, it was exposed
to K2CO3 in DMF at room temperature, causing cyclization that
proceeded to give pyrrolidine (RP)-18 in 92% yield. Removal of
With the requisite chiral building block (RP)-3 in hand, its
a-
alkylation with electrophile 13 was examined (Table 1). After
treatment of (RP)-3 with LHMDS in THF at ꢀ78 °C, the resulting
carbanion was treated with 1312 at the same temperature. How-

T. Yamagishi et al. / Tetrahedron: Asymmetry 23 (2012) 1633–1639
1635
adduct (SP)-20 in 95% yield. Upon treatment of (SP)-20 with LHMDS
(3 equiv) and then benzyl bromide (3 equiv) in THF at ꢀ78 °C, b0-
alkylation occurred to give (SP)-21 and (SP)-210 in 81% yield. The
diastereoselectivity ratio was determined to be 1:4.8 by 31P NMR
analysis of the crude products, while the inversed stereoselection
favoring the formation of (SP)-210 was observed as compared with
the b0-benzylation of NH-tosyl amide 6 (4.0:1 diastereoselectivity,
Scheme 1).8 When product (SP)-210 was treated with LHMDS and
then D2O at ꢀ78 °C, deuterium incorporation was not observed.
This result indicated that the b0-alkylation of (SP)-20 might not
be accompanied by the abstraction of an a-proton.
Stereochemical assignment of (SP)-210 based upon NMR spectra
and X-ray analysis, was attempted, but was unsuccessful. To con-
firm the relative configuration and find a possible selective synthe-
sis of the corresponding diastereomer, the preparation of one of the
diastereomers, racemic 21 was examined. As shown in Scheme 1,
the diastereoselective b0-alkylation of the lithium enolate gener-
ated from compound 6 bearing an acidic NH proton was already
established, giving product 7 whose stereochemistry had also been
established. Thus, b0-alkylation of the related compound, followed
by pyrrolidine construction, should lead to 21 with a defined
relative configuration. Transformation of the racemic alcohol 16
into TBDPS ether 22, which was subjected to deprotection of the
1,1-diethoxyethyl moiety with TMSCl and EtOH, gave H-phosphi-
nate 23 in 71% yield (Scheme 4). When 23 was treated with t-butyl
acrylate in the presence of t-BuOMgBr, the desired Michael
reaction proceeded sluggishly to afford adduct 24 in low yield
(33%) and the recovery of 23. A sluggish reaction was also observed
in the b0-alkylation of 24 with LHMDS and benzyl bromide, giving
25 in poor yield (20%) although producing relatively good diastere-
oselectivity (5.7:1). While the exact reason for the low yield in
these steps remains unclear, it might be due to the bulky TBDPS
group of the substrates hindering their reactivity. Removal of the
silyl group with TBAF furnished alcohol 26, which was converted
into pyrrolidine 21 through sequential mesylation and cyclization
with the N-tosyl amide moiety. The 1H and 31P NMR spectra of
21 were consistent with those of the minor isomer (SP)-21
prepared in Scheme 3, but not the major isomer (SP)-210. Thus,
the diastereoselection in the b0-alkylation of (SP)-20 was different
from those of substrates 6 and 24 bearing an acidic NH proton.
The reason for this inverse stereochemical outcome is currently
under investigation. Although the sequence shown in Scheme 4
Figure 3. ORTEP drawing of racemic 15.
Li
O
Ph
R
Ph
O
Me
Ph
N
H
N
P
OEt
OEt
Me
Ph
OEt
OEt
R-I
R-I
OEt
14
(RP)-
EtO
A
R=TBDPSO(CH2)3
Figure 4. Proposed model for diastereoselectivity in the alkylation of (RP)-3.
OH
OH
Me
O
P
Me
O
P
Ph
Ph
a,b
N
OEt
OEt
Ts
N
H
OEt
OEt
OEt
OEt
(RP)-15
(RP)-16
OMs
OEt
O
Me
O
Me
c
d
N
P
OEt
Ts
N
P
H
OEt
Ts
OEt
OR
Me
OTBDPS
OEt
OEt
(RP)-
O
P
O
b
17
18
(RP)-
Ts
a
N
H
OEt
OEt
Ts
N
H
P
H
O
OEt
OEt
O
O
e
g
f
23
16 : R=H
N
P
H
N
P
O-t-Bu
22
: R=TBDPS
Ts
OEt
Ts
OEt
(SP)-19
(SP)-20
OTBDPS
O
OTBDPS
O
c
d
O
O
O
O
O
O
P
Ts
Ts
N
H
P
O-t-Bu
Ts
N
P
O-t-Bu
H
+
N
P
O-t-Bu
N
O-t-Bu
OEt
OEt
Bn
Ts
OEt
Bn
Ts
OEt Bn
25
24
dr=5.7:1
(SP)-21
(SP)-21'
OH
O
(SP)-21:(SP)-21'=1:4.8
O
O
P
O
f,g
e
Scheme 3. Preparation of (SP)-210 from (RP)-15. Reagents and conditions: (a) H2,
Pd–C, MeOH, rt; (b) TsCl, pyridine, CH2Cl2, rt, 62% for two steps; (c) MsCl, Et3N,
CH2Cl2, rt, 86%; (d) K2CO3, DMF, rt, 92%; (e) TMSCl, EtOH, CH2Cl2, rt, 84%; (f) t-
BuOMgBr, t-butyl acrylate, THF, 0 °C, 95%; (g) LHMDS, BnBr, THF, ꢀ78 °C, 81%.
N
O-t-Bu
N
H
P
O-t-Bu
Ts
OEt
Bn
OEt
Bn
21
26
Scheme 4. Preparation of racemic 21 from 16. Reagents and conditions: (a)
TBDPSCl, imidazole, DMF, rt, 98%; (b) TMSCl, EtOH, CH2Cl2, rt, 71%; (c) t-BuOMgBr,
t-butyl acrylate, THF, 0 °C, 33%; (d) LHMDS, BnBr, THF, ꢀ78 °C, 20%; (e) TBAF, THF,
rt, 84%; (f) MsCl, Et3N, CH2Cl2, rt; (g) K2CO3, DMF, rt, 46% for two steps.
the 1,1-diethoxyethyl moiety by TMSCl and EtOH15 gave H-phos-
phinate (SP)-19, which underwent Michael addition to t-butyl acry-
late in the presence of t-BuOMgBr as a basic reagent,16 affording

1636
T. Yamagishi et al. / Tetrahedron: Asymmetry 23 (2012) 1633–1639
needs further optimization, it might be useful for the diastereose-
lective synthesis of optically active (SP)-21.
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 CHCl3/AcOEt = 1:5) to give (RP)-15 (3.06 g, 79%)
and (RP)-150 (494 mg, 13%). (RP)-15: White crystals; mp 87–
3. Conclusions
90 °C; ½a 2D7
ꢁ
¼ þ29:25 (c 0.18, CHCl3); 1H NMR (300 MHz, CDCl3)
In conclusion, a new method for the preparation of optically ac-
tive Pro-Phe PDIs in a protected form has been developed; optically
active Pro-Phe PDIs have not been prepared in a diastereoselective
d: 7.64–7.27 (10H, m), 4.31–4.16 (2H, m), 3.97 (1H, dt, J = 3.8,
9.5 Hz), 3.76–3.53 (6H, m), 2.20–2.12 (2H, m), 1.78–1.64 (1H, m),
1.59 (3H, d, J = 11.2 Hz), 1.52–1.37 (1H, m), 1.33 (3H, t, J =
7.0 Hz), 1.17 (3H, t, J = 7.0 Hz), 1.15 (3H, t, J = 7.0 Hz); 13C NMR
manner. Our method relied upon the diastereoselective
a-alkyl-
ation of optically active 1,1-diethoxyethyl(aminomethyl)phosphi-
nate to construct a pyrrolidine moiety, and b0-alkylation utilizing
an asymmetric center at the phosphorus atom. The other diaste-
reomer of the Pro-Phe PDIs derivative could be selectively pre-
pared as a racemate through a procedure involving b0-alkylation
and subsequent pyrrolidine formation. The synthesis of their
peptide derivatives and their evaluation as protease inhibitors
are under investigation.
(75 MHz, CDCl3) d: 139.4–128.0 (aromatic), 102.2 (d, JCP
=
134.2 Hz), 63.1 (d, JCP = 96.3 Hz), 62.3, 62.1 (d, JCP = 7.4 Hz), 57.8
(2 carbons), 30.1 (d, JCP = 11.8 Hz), 26.9, 20.8 (d, JCP = 11.8 Hz),
16.7 (d, JCP = 5.0 Hz), 15.5, 15.2; 31P NMR (122 MHz, CDCl3) d:
42.16; IR (neat) 3386, 1158, 1024 cmꢀ1; MS m/z 462 (MH+); HRMS
calcd for C25H37NO5P: 462.2409 (MH+). Found: 462.2407. (RP)-150:
Pale yellow oil; ½a D27
ꢁ
¼ ꢀ16:4 (c 0.21, CHCl3); 1H NMR (300 MHz,
CDCl3) d: 7.67–7.23 (10H, m), 4.27–4.18 (2H, m), 4.02 (1H, dt,
J = 2.2, 6.3 Hz), 3.77–3.50 (6H, m), 2.20–2.10 (2H, m), 1.68–1.56
(1H, m), 1.42–1.32 (1H, m), 1.36 (3H, d, J = 11.0 Hz), 1.27 (3H, t,
J = 7.0 Hz), 1.11 (3H, t, J = 7.1 Hz), 1.06 (3H, t, J = 7.1 Hz); 13C NMR
(75 MHz, CDCl3) d: 139.2–127.9 (aromatic), 101.7 (d,
JCP = 136.7 Hz), 62.2 (d, JCP = 7.4 Hz), 62.1, 61.0 (d, JCP = 94.4 Hz),
58.3 (d, JCP = 4.3 Hz), 57.4 (d, JCP = 6.8 Hz), 29.9 (d, JCP = 12.4 Hz),
27.0, 20.4 (d, JCP = 11.8 Hz), 16.8 (d, JCP = 5.0 Hz), 15.3, 15.1; 31P
NMR (122 MHz, CDCl3) d: 42.61; IR (neat) 3381, 1151,
1027 cmꢀ1; MS m/z 462 (MH+); HRMS calcd for C25H37NO5P:
462.2409 (MH+). Found: 462.2407.
4. Experimental
All melting points were obtained on a Yanagimoto micro-melt-
ing point apparatus and are uncorrected. IR spectra were recorded
on
a JASCO FTIR-4100 instrument. Optical rotations were
measured with a JASCO P-1020 polarimeter. Mass spectra were
measured on a JEOL JMS-MS700 V instrument by FAB+. X-ray
crystal data were collected by a Mac-Science DIP Image plate dif-
fractometer. NMR spectra were obtained on a JEOL JNM-AL300
instrument. The chemical shift data for each signal on 1H NMR
are given in units of d relative to CHCl3 (d = 7.26) for CDCl3 solu-
tion. 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.
4.3. (1R⁄,RP )-Ethyl 1,1-diethoxyethyl{1-[(diphenylmethylene)amino]-
⁄
4-hydroxybutyl}phosphinate 15
Colorless plates; mp 90–91 °C. The 1H NMR spectrum was iden-
tical to that of (RP)-15. Crystallographic data (excluding structure
factors) for the structures herein have been deposited with
Cambridge Crystallographic Data Center as supplementary
publication numbers CCDC 882508. 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,RP)-Ethyl 1,1-diethoxyethyl{1-[(diphenylmethylene)amino]-
4-tert-butyl(diphenyl)silyloxybutyl}phosphinate (RP)-14 and (1S,RP)-
isomer (RP)-140
To a stirred solution of (RP)-3 (201 mg, 0.50 mmol), prepared
according to our previously reported method,11 in THF (1.5 mL)
was added a 1.0 M THF solution of LHMDS (0.75 mL, 0.75 mmol)
at ꢀ78 °C. After stirring for 30 min at the same temperature, a solu-
tion of 13 (318 mg, 0.75 mmol) in THF (1 mL) was added to the
mixture and stirred for 3 h at 0 °C. The mixture was diluted with
aqueous saturated 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 chromatography (Hexane/AcOEt = 5:1 to 1:1) to give a
mixture of (RP)-14 and (RP)-140 (231 mg, 66%) in a ratio of 6.0:1.
Pale yellow oil; 1H NMR (300 MHz, CDCl3) d: 7.64–7.25 (20H, m),
4.31–4.16 (2H, m), 3.96–3.85 (1H, m), 3.75–3.55 (6H, m),
2.22–2.12 (2H, m), 1.76–1.66 (1H, m), 1.58 (3H, d, J = 11.0 Hz),
1.41–1.30 (1H, m), 1.26 (3H, t, J = 7.1 Hz), 1.14 (3H, t, J = 7.0 Hz),
1.13 (3H, t, J = 7.0 Hz), 1.02 (9H, s); 31P NMR (122 MHz, CDCl3) d:
41.76 (major isomer), 42.34 (minor isomer); IR (neat) 1109,
1028 cmꢀ1; MS m/z 700 (MH+); HRMS calcd for C41H55NO5PSi:
700.3587 (MH+). Found: 700.3569.
4.4. (1R,RP)-Ethyl 1,1-diethoxyethyl(1-{[(4-methylphenyl)sulfonyl]
amino}-4-hydroxybutyl)phosphinate (RP)-16
To a solution of (RP)-15 (797 mg, 1.72 mmol) in MeOH (30 mL)
was added 10% Pd–C (103 mg) and stirred for 12 h at room temper-
ature 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 this residue in CH2Cl2 (2.4 mL)
were added pyridine (0.14 mL, 1.72 mmol) and a solution of TsCl
(295 mg, 1.55 mmol) in CH2Cl2 (2.4 mL) at 0 °C and the mixture
was stirred for 12 h at room temperature. The mixture was poured
into H2O and extracted with CHCl3. The combined extracts were
washed with brine and dried over MgSO4. Removal of the solvent
gave a residue, which was purified by column chromatography
(Hexane/AcOEt = 1:1 to CHCl3/MeOH = 40:1) to give (RP)-16
(481 mg, 62%). Colorless oil; ½a D27
ꢁ
¼ ꢀ18:2 (c 0.08, CHCl3); 1H
NMR (300 MHz, CDCl3) d: 7.77 (2H, d, J = 8.1 Hz), 7.29 (2H, d,
J = 8.1 Hz), 6.10 (1H, dd, J = 4.4, 8.8 Hz), 4.22–4.09 (2H, m),
4.00–3.89 (1H, m), 3.75–3.43 (6H, m), 2.42 (3H, s), 1.89–1.59
(4H, m), 1.51 (3H, d, J = 11.7 Hz), 1.27 (3H, t, J = 7.2 Hz), 1.222
(3H, t, J = 7.1 Hz), 1.218 (3H, t, J = 7.1 Hz); 13C NMR (75 MHz, CDCl3)
d: 143.2–127.0 (aromatic), 102.4 (d, JCP = 140.4 Hz), 62.5 (d,
JCP = 7.4 Hz), 62.1, 58.6 (d, JCP = 5.0 Hz), 58.0 (d, JCP = 7.4 Hz), 49.8
(d, JCP = 91.9 Hz), 28.7 (d, JCP = 5.6 Hz), 27.3, 21.5, 19.8 (d,
JCP = 12.4 Hz), 16.5 (d, JCP = 5.6 Hz), 15.4, 15.1; 31P NMR
4.2. (1R,RP)-Ethyl 1,1-diethoxyethyl{1-[(diphenylmethylene)amino]-
4-hydroxybutyl}phosphinate (RP)-15 and (1S,RP)-isomer (RP)-150
To a solution of the mixture of (RP)-14 and (RP)-140 (5.90 g,
8.40 mmol) in THF (25 mL) was added a 1.0 M THF solution of TBAF
(16.8 mL, 16.8 mmol) at 0 °C and the mixture was stirred for 3 h at
room temperature. The mixture was poured into H2O and

T. Yamagishi et al. / Tetrahedron: Asymmetry 23 (2012) 1633–1639
1637
(122 MHz, CDCl3) d: 42.07; IR (neat) 3103, 1332, 1156, 1028 cmꢀ1
;
(1H, m), 1.59–1.52 (1H, m), 1.38 (3H, t, J = 7.1 Hz); 13C NMR
(75 MHz, CDCl3) d: 144.2–127.7 (aromatic), 63.0 (d, JCP = 7.5 Hz),
57.0 (d, JCP = 119.9 Hz), 49.4 (d, JCP = 2.5 Hz), 25.3 (d, JCP = 1.9 Hz),
25.0 (d, JCP = 1.2 Hz), 21.5, 16.3 (d, JCP = 5.6 Hz); 31P NMR
(122 MHz, CDCl3) d: 35.77; IR (neat) 1345, 1157, 1030 cmꢀ1; MS
m/z 318 (MH+); HRMS calcd for C13H21NO4PS: 318.0929 (MH+).
Found: 318.0913.
MS m/z 452 (MH+); HRMS calcd for C19H35NO7PS: 452.1872 (MH+).
Found: 452.1884.
4.5. (1R,RP)-Ethyl 1,1-diethoxyethyl(1-{[(4-methylphenyl)sulfonyl]amino}-
4-methanesulfonyloxybutyl)phosphinate (RP)-17
To
a solution of (RP)-16 (713 mg, 1.58 mmol) in CH2Cl2
(3.2 mL) were added Et3N (0.31 mL, 2.24 mmol) and a solution
of MsCl (0.15 mL, 1.92 mmol) in CH2Cl2 (3.2 mL) at 0 °C and
the mixture was stirred for 1 h at room temperature. The mix-
ture was poured into H2O and extracted with AcOEt. After the
combined extracts were washed with brine and dried over
MgSO4, removal of the solvent gave a residue, which was puri-
fied by column chromatography (Hexane/AcOEt = 1:1 to AcOEt)
to give (RP)-17 (728 mg, 86%). White crystals; mp 99–101 °C;
4.8. (1R,SP)-tert-Butyl 3-[ethoxy(1-{[(4-methylphenyl)sulfonyl]-
2-pyrrolidinyl})phosphoryl]propanoate (SP)-20
To a stirred solution of (SP)-19 (244 mg, 0.77 mmol) and tert-bu-
tyl acrylate (138 mg, 1.08 mmol) in THF (3.2 mL) was added a solu-
tion of t-BuOMgBr in THF (1.2 mL) at 0 °C, prepared from t-BuOH
(57 mg, 0.77 mmol) and
a 1.10 M THF solution of MeMgBr
(0.70 mL, 0.77 mmol) in situ. After stirring for 4 h at the same tem-
perature, to the mixture was slowly added H2O 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
½
a 2D7
ꢁ
¼ þ6:4 (c 0.10, CHCl3); 1H NMR (300 MHz, CDCl3) d: 7.77
(2H, d, J = 8.1 Hz), 7.32 (2H, d, J = 8.1 Hz), 5.62 (1H, dd, J = 7.4,
7.4 Hz), 4.19–4.01 (4H, m), 3.82–3.57 (5H, m), 2.98 (3H, s),
2.43 (3H, s), 2.05–1.75 (4H, m), 1.45 (3H, d, J = 11.7 Hz), 1.25
(3H, t, J = 7.0 Hz), 1.22 (3H, t, J = 7.0 Hz), 1.20 (3H, t, J = 7.0 Hz);
13C NMR (75 MHz, CDCl3) d: 143.5–127.0 (aromatic), 102.7 (d,
JCP = 142.9 Hz), 69.5, 62.5 (d, JCP = 7.5 Hz), 58.9 (d, JCP = 4.3 Hz),
58.0 (d, JCP = 6.8 Hz), 50.0 (d, JCP = 89.5 Hz), 37.3, 26.9, 25.5 (d,
JCP = 6.8 Hz), 21.5, 19.3 (d, JCP = 11.2 Hz), 16.5 (d, JCP = 5.6 Hz),
15.4, 15.1; 31P NMR (122 MHz, CDCl3) d: 40.75; IR (neat) 3114,
1335, 1159, 1025 cmꢀ1; MS m/z 530 (MH+); HRMS calcd for
AcOEt) to give (SP)-20 (324 mg, 95%). Colorless oil; ½a D29
¼ ꢀ68:3
ꢁ
(c 0.27, CHCl3); 1H NMR (300 MHz, CDCl3) d: 7.73 (2H, d,
J = 8.2 Hz), 7.33 (2H, d, J = 8.2 Hz), 4.20–4.00 (3H, m), 3.47–3.37
(2H, m), 2.70–2.62 (2H, m), 2.44 (3H, s), 2.41–2.27 (2H, m), 1.46
(9H, s), 1.32 (3H, t, J = 7.0 Hz); 13C NMR (75 MHz, CDCl3) d: 171.7,
144.1–127.6 (aromatic), 80.8, 61.8 (d, JCP = 6.8 Hz), 57.4 (d,
JCP = 116.2 Hz), 49.5, 28.1, 28.0 (d, JCP = 3.1 Hz), 25.3, 24.6, 21.6,
21.2 (d, JCP = 91.3 Hz), 16.7 (d, JCP = 5.6 Hz); 31P NMR (122 MHz,
CDCl3) d: 53.14; IR (neat) 1728, 1348, 1156, 1032 cmꢀ1; MS m/z
446 (MH+); HRMS calcd for C20H33NO6PS: 446.1766 (MH+). Found:
446.1788.
C
20H37NO9PS2: 530.1647 (MH+). Found: 530.1679.
4.6. (1R,RP)-Ethyl 1,1-diethoxyethyl{[1-(4-methylphenyl)sulfonyl]-
2-pyrrolidinyl}phosphinate (RP)-18
To a solution of (RP)-17 (727 mg, 1.37 mmol) in DMF (8.2 mL)
was added K2CO3 (947 mg, 6.85 mmol) and the mixture was 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 column chromatography (Hexane/
AcOEt = 1:1 to AcOEt) to give (RP)-18 (546 mg, 92%). Colorless oil;
4.9. (1R,SP,2R)-tert-Butyl 2-benzyl-3-[ethoxy(1-{[(4-methylphenyl)
sulfonyl]-2-pyrrolidinyl})phosphoryl]propanoate (SP)-210
To a stirred solution of (SP)-20 (120 mg, 0.27 mmol) in THF
(3.4 mL) was added a 1.06 M THF solution of LHMDS (0.76 mL,
0.81 mmol) at ꢀ78 °C. After stirring for 30 min at the same tem-
perature, BnBr (0.10 mL, 0.81 mmol) was added to the mixture
and stirred for 2 h at the same temperature. The mixture was di-
luted with an aqueous saturated NH4Cl solution 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 1:5) to give a mixture of (SP)-21 and (SP)-210
(117 mg, 81%). The major isomer (SP)-210 was isolated by pre-
½
a 2D7
ꢁ
¼ ꢀ82:5 (c 0.05, CHCl3); 1H NMR (300 MHz, CDCl3) d: 7.78
(2H, d, J = 8.0 Hz), 7.30 (2H, d, J = 8.0 Hz), 4.39 (1H, ddd, J = 3.8,
3.8, 9.7 Hz), 4.29–4.12 (2H, m), 3.89–3.69 (4H, m), 3.55 (1H, ddd,
J = 4.6, 8.1, 12.3 Hz), 3.40 (1H, ddd, J = 7.8, 7.8, 12.3 Hz), 2.43 (3H,
s), 2.24–2.13 (1H, m), 2.00–1.80 (1H, m), 1.80–1.36 (2H, m), 1.72
(3H, d, J = 11.5 Hz), 1.32 (3H, t, J = 7.0 Hz), 1.24 (6H, t, J = 7.0 Hz);
13C NMR (75 MHz, CDCl3) d: 143.9–127.8 (aromatic), 102.0 (d,
JCP = 137.3 Hz), 62.0 (d, JCP = 6.8 Hz), 58.3 (d, JCP = 5.0 Hz), 58.0 (d,
JCP = 7.4 Hz), 56.5 (d, JCP = 103.7 Hz), 49.2, 25.8, 24.0, 21.5, 20.3 (d,
JCP = 12.4 Hz), 16.6 (d, JCP = 5.0 Hz), 15.5, 15.2; 31P NMR
(122 MHz, CDCl3) d: 41.25; IR (neat) 1348, 1158, 1030 cmꢀ1; MS
m/z 434 (MH+); HRMS calcd for C19H33NO6PS: 434.1766 (MH+).
Found: 434.1761.
parative TLC (CHCl3/AcOEt = 1:3). Colorless oil; ½a D29
¼ ꢀ72:8 (c
ꢁ
0.24, CHCl3); 1H NMR (300 MHz, CDCl3) d: 7.73 (2H, d,
J = 8.4 Hz), 7.32 (2H, d, J = 8.4 Hz), 7.27–7.19 (5H, m), 4.19–3.98
(3H, m), 3.50–3.34 (2H, m), 3.18–3.11 (1H, m), 3.04 (1H, dd,
J = 5.5, 13.4 Hz), 2.89 (1H, dd, J = 9.2, 13.4 Hz), 2.54–2.41 (1H,
m), 2.44 (3H, s), 2.22–2.06 (2H, m), 1.96–1.88 (1H, m), 1.67–
1.46 (2H, m), 1.34–1.27 (3H, m), 1.30 (9H, s); 13C NMR
(75 MHz, CDCl3) d: 173.2 (d, JCP = 5.0 Hz), 144.0–126.4 (aromatic),
80.6, 61.0 (d, JCP = 6.8 Hz), 57.0 (d, JCP = 114.3 Hz), 49.6, 41.8 (d,
JCP = 3.7 Hz), 40.3 (d, JCP = 12.4 Hz), 27.9 (d, JCP = 89.4 Hz), 27.8,
25.1, 24.4, 21.4, 16.6 (d, JCP = 5.0 Hz); 31P NMR (122 MHz, CDCl3)
d: 51.99; IR (neat) 1724, 1348, 1156, 1032 cmꢀ1; MS m/z 536
(MH+); HRMS calcd for C27H39NO6PS: 536.2236 (MH+). Found:
536.2259.
4.7. (1R,SP)-Ethyl {[1-(4-methylphenyl)sulfonyl]-2-pyrrolidinyl}
phosphinate (SP)-19
To a solution of (RP)-18 (114 mg, 0.26 mmol) in CH2Cl2 (2.6 mL)
was added TMSCl (0.23 mL, 1.79 mmol) and EtOH (0.11 mL) at
room temperature. After stirring for 2 h at the same temperature,
the mixture was concentrated to give a residue, which was purified
by column chromatography (AcOEt) to give (SP)-19 (70 mg, 84%).
White crystals; mp 91–92 °C; ½a D27
ꢁ
¼ ꢀ109:0 (c 0.19, CHCl3); 1H
4.10. (1R⁄,RP⁄)-Ethyl 1,1-diethoxyethyl(1-{[(4-methylphenyl)sulfo
nyl]amino}-4-tert-butyl{diphenyl}silyloxybutyl)phosphinate 22
NMR (300 MHz, CDCl3) d: 7.73 (2H, d, J = 8.1 Hz), 7.33 (2H, d,
J = 8.1 Hz), 7.31 (1H, d, J = 573.5 Hz), 4.27–4.10 (2H, m), 3.82–
3.79 (1H, m), 3.44 (1H, ddd, J = 5.1, 7.0, 10.3 Hz), 3.28–3.23 (1H,
m), 2.43 (3H, s), 2.28–2.21 (1H, m), 2.08–1.98 (1H, m), 1.80–1.71
To
a solution of 16 (1.01 g, 2.23 mmol) in DMF (2 mL)
were added a solution of imidazole (318 mg, 4.68 mmol) in

1638
T. Yamagishi et al. / Tetrahedron: Asymmetry 23 (2012) 1633–1639
DMF (4 mL) and a solution of TBDPSCl (673 mg, 2.45 mmol) in
DMF (4 mL) and the mixture was stirred for 12 h at room tem-
perature. 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 column chromatography (Hexane/AcOEt = 2:1 to
1:2) to give 22 (1.51 g, 98%). White crystals; mp 121–122 °C;
1H NMR (300 MHz, CDCl3) d: 7.75–7.20 (14H, m), 5.50–5.43
(1H, m), 4.22–4.09 (2H, m), 3.92–3.80 (1H, m), 3.79–3.59 (4H,
m), 3.53–3.39 (2H, m), 2.33 (3H, s), 1.95–1.43 (4H, m), 1.50
(3H, d, J = 11.5 Hz), 1.26 (3H, t, J = 7.1 Hz), 1.22 (3H, t,
J = 7.1 Hz), 1.19 (3H, t, J = 7.1 Hz), 1.00 (9H, s); 13C NMR
(75 MHz, CDCl3) d: 143.1–126.9 (aromatic), 102.5 (d,
JCP = 140.4 Hz), 63.4, 62.3 (d, JCP = 7.5 Hz), 58.8 (d, JCP = 4.3 Hz),
57.9 (d, JCP = 7.4 Hz), 50.6 (d, JCP = 89.9 Hz), 29.0 (d, JCP = 6.8 Hz),
27.3, 26.7, 21.4, 19.8 (d, JCP = 11.8 Hz), 19.1, 16.5 (d, JCP = 4.9 Hz),
15.4, 15.1; 31P NMR (122 MHz, CDCl3) d: 41.39; IR (neat) 3135,
1336, 1159, 1027 cmꢀ1; MS m/z 690 (MH+); HRMS calcd for
C35H53NO7PSSi: 690.3050 (MH+). Found: 690.3080.
4.13. (1R⁄,SP⁄,2S⁄)-tert-Butyl 2-benzyl-3-[ethoxy(1-{[(4-methyl
phenyl)sulfonyl]amino}-4-tert-butyl{diphenyl}silyloxybutyl)phos
phoryl]propanoate 25
To a stirred solution of 24 (140 mg, 0.20 mmol) in THF (2.5 mL)
was added a 1.06 M THF solution of LHMDS (0.57 mL, 0.60 mmol)
at ꢀ78 °C. After stirring for 30 min at the same temperature, BnBr
(71 lL, 0.60 mmol) was added to the mixture and stirred for 3 h at
the same temperature. The mixture was then diluted with aqueous
saturated NH4Cl solution 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 chro-
matography (Hexane/AcOEt = 3:1 to 1:1) to give 25 (32.3 mg, 20%).
Colorless oil; 1H NMR (300 MHz, CDCl3) d: 7.73–7.13 (19H, m),
5.55–5.38 (1H, m), 4.13–3.98 (2H, m), 3.59–3.51 (1H, m), 3.44–
3.40 (2H, m), 3.10–2.94 (1H, m), 2.88–2.74 (2H, m), 2.33 (3H, s),
2.14–1.74 (4H, m), 1.60–1.37 (2H, m), 1.32 (9H, s), 1.25 (3H, t,
J = 7.0 Hz), 1.00 (9H, s); 13C NMR (75 MHz, CDCl3) d: 173.7,
143.4–126.5 (aromatic), 80.9, 63.0, 61.7 (d, JCP = 6.8 Hz), 52.9 (d,
JCP = 103.7 Hz), 42.0 (d, JCP = 4.3 Hz), 40.2 (d, JCP = 11.8 Hz), 28.7
(d, JCP = 8.0 Hz), 28.3 (d, JCP = 88.8 Hz), 27.8, 26.8, 25.6, 21.4, 19.1,
16.5 (d, JCP = 5.6 Hz); 31P NMR (122 MHz, CDCl3) d: 50.85; IR (neat)
3055, 1719, 1365, 1156, 1029 cmꢀ1; MS m/z 792 (MH+); HRMS
calcd for C43H59NO7PSSi: 792.3519 (MH+). Found: 792.3539.
4.11. (1R⁄,SP⁄)-Ethyl (1-{[(4-methylphenyl)sulfonyl]amino}-4-
tert-butyl{diphenyl}silyloxybutyl)phosphinate 23
To a solution of 22 (1.51 g, 2.19 mmol) in CH2Cl2 (6.6 mL)
were added TMSCl (0.42 mL, 3.28 mmol) and EtOH (0.5 mL) at
room temperature. After stirring for 3 h at the same tempera-
ture, the mixture was concentrated to give a residue, which
was purified by column chromatography (Hexane/AcOEt = 1:1
to 0:1) to give 23 (899 mg, 71%). White crystals; mp 141–
142 °C; 1H NMR (300 MHz, CDCl3) d: 7.74–7.24 (14H, m), 6.90
(1H, d, J = 558.7 Hz), 5.30–5.20 (1H, m), 4.17–4.07 (2H, m),
3.53–3.46 (3H, m), 2.37 (3H, s), 1.92–1.88 (1H, m), 1.69–1.50
(2H, m), 1.45–1.40 (1H, m), 1.32 (3H, t, J = 7.1 Hz), 1.02 (9H,
s); 13C NMR (75 MHz, CDCl3) d: 143.4–126.9 (aromatic), 63.1
(d, JCP = 7.4 Hz), 62.4, 51.6 (d, JCP = 109.9 Hz), 28.0 (d, JCP = 9.9 Hz),
26.7, 23.2, 21.4, 19.0, 16.2 (d, JCP = 6.2 Hz); 31P NMR (122 MHz,
CDCl3) d: 33.91; IR (neat) 3066, 1333, 1158, 1051 cmꢀ1; MS m/
z 574 (MH+); HRMS calcd for C29H41NO5PSSi: 574.2212 (MH+).
Found: 574.2218.
4.14. (1R⁄,SP⁄,2S⁄)-tert-Butyl 2-benzyl-3-[ethoxy(1-{[(4-methyl
phenyl)sulfonyl]amino}-4-hydroxybutyl)phosphoryl]propanoate
26
To a solution of 25 (70.5 mg, 0.09 mmol) in THF (1.6 mL) was
added a 1.0 M THF solution of TBAF (0.27 mL, 0.27 mmol) and
the mixture was stirred for 1 h at room temperature. The mixture
was poured into H2O and extracted with AcOEt. The combined ex-
tracts were washed with brine and dried over MgSO4. Removal of
the solvent gave a residue, which was purified by preparative
TLC (CHCl3/MeOH = 30:1) to give 26 (41.3 mg, 84%). Colorless oil;
1H NMR (300 MHz, CDCl3) d: 7.77 (2H, d, J = 8.1 Hz), 7.30–7.12
(7H, m), 6.88–6.67 (1H, m), 4.10–4.04 (2H, m), 3.67–3.45 (2H,
m), 3.12–2.96 (2H, m), 2.93–2.77 (2H, m), 2.40 (3H, s), 2.20–1.95
(2H, m), 1.72–1.46 (4H, m), 1.31 (9H, s), 1.27 (3H, t, J = 7.0 Hz);
13C NMR (75 MHz, CDCl3) d: 173.5, 143.4–126.5 (aromatic), 81.0,
62.1, 61.8 (d, JCP = 6.2 Hz), 52.4 (d, JCP = 106.8 Hz), 42.0 (d,
JCP = 4.3 Hz), 40.2 (d, JCP = 13.0 Hz), 28.4 (d, JCP = 8.0 Hz), 28.2 (d,
JCP = 89.4 Hz), 27.8, 26.0, 21.5, 16.5 (d, JCP = 5.6 Hz); 31P NMR
(122 MHz, CDCl3) d: 52.26; IR (neat) 3271, 2975, 1723, 1331,
4.12. (1R⁄,SP⁄)-tert-Butyl 3-[ethoxy(1-{[(4-methylphenyl)sulfonyl]amino}-
4-tert-butyl{diphenyl}silyloxybutyl)phosphoryl]propanoate 24
To a stirred solution of 23 (597 mg, 1.04 mmol) and tert-butyl
acrylate (187 mg, 1.46 mmol) in THF (4 mL) were added a solu-
tion of t-BuOMgBr in THF (2.2 mL) at 0 °C, prepared from t-BuOH
(77 mg, 1.04 mmol) and 0.99 M THF solution of MeMgBr (1.05 mL,
1.04 mmol) in situ. After stirring for 7 h at the same temperature,
to the mixture was slowly added H2O 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 give 24
(237 mg, 33%). White crystals; mp 117–118 °C; 1H NMR
(300 MHz, CDCl3) d: 7.72–7.20 (14H, m), 5.35–5.25 (1H, m),
4.13–4.03 (2H, m), 3.64–3.42 (3H, m), 2.51 (1H, dd, J = 7.7,
7.7 Hz), 2.47 (1H, dd, J = 7.6, 7.6 Hz), 2.33 (3H, s), 2.02–1.83 (3H,
m), 1.59–1.31 (3H, m), 1.45 (9H, s), 1.26 (3H, t, J = 7.1 Hz), 1.00
(9H, s); 13C NMR (75 MHz, CDCl3) d: 171.5 (d, JCP = 14.2 Hz),
143.0–126.7 (aromatic), 80.7, 62.8, 61.4 (d, JCP = 6.8 Hz), 51.4 (d,
JCP = 106.8 Hz), 28.5 (d, JCP = 8.7 Hz), 28.0, 27.7 (d, JCP = 3.7 Hz),
26.7, 24.8, 21.3, 21.0 (d, JCP = 91.3 Hz), 19.0, 16.5 (d, JCP = 5.6 Hz);
31P NMR (122 MHz, CDCl3) d: 52.37; IR (neat) 3070, 1726, 1326,
1153, 1030 cmꢀ1
C
;
MS m/z 554 (MH+); HRMS calcd for
27H41NO7PS: 554.2341 (MH+). Found: 554.2365.
4.15. (1R⁄,SP⁄,2S⁄)-tert-Butyl 2-benzyl-3-[ethoxy(1-{[(4-methyl
phenyl)sulfonyl]-2-pyrrolidinyl})phosphoryl]propanoate 21
To a solution of 26 (41.3 mg, 0.07 mmol) in CH2Cl2 (0.25 mL)
were added Et3N (15 lL, 0.11 mmol) and a solution of MsCl
(10.3 mg, 0.09 mmol) in CH2Cl2 (0.5 mL) at 0 °C and the mixture
was stirred for 1 h at room temperature. The mixture was poured
into H2O and extracted with CHCl3. After the combined extracts
were washed with brine and dried over MgSO4, removal of the sol-
vent gave a residue. To a solution of this residue in DMF (1.5 mL)
was added K2CO3 (51.8 mg, 0.37 mmol) and the mixture was stir-
red for 6 h at room temperature. The mixture was poured into
H2O 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 preparative TLC (AcOEt) to
give 21 (18.6 mg, 46%). Colorless oil; 1H NMR (300 MHz, CDCl3)
1155, 1024 cmꢀ1
C
;
MS m/z 702 (MH+); HRMS calcd for
36H53NO7PSSi: 702.3050 (MH+). Found: 702.3057.

T. Yamagishi et al. / Tetrahedron: Asymmetry 23 (2012) 1633–1639
1639
6. For selected examples of stereoselective syntheses of PDIs, see: (a) Bartley, D.
M.; Coward, J. K. J. Org. Chem. 2005, 70, 6757; (b) Liu, X.; Hu, X. E.; Tian, X.;
Mazur, A.; Ebetino, F. H. J. Organomet. Chem. 2002, 646, 212–222; (c) Cristau, H.-
J.; Coulombeau, A.; Genevois-Borella, A.; Pirat, J.-L. Tetrahedron Lett. 2001, 42,
4491; (d) Chen, H.; Noble, F.; Mothe, A.; Meudal, H.; Coric, P.; Danascimento, S.;
Roques, B. P.; George, P.; Fournie-Zaluski, M.-C. J. Med. Chem. 2000, 43, 1398; (e)
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9. Yuan et al. independently reported on the preparation of 4 and the related
compounds by addition of phosphorus nucleophiles to imines, see: (a) Zhang,
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d: 7.72 (2H, d, J = 8.1 Hz), 7.32 (2H, d, J = 8.1 Hz), 7.28–7.19 (5H, m),
4.19–4.06 (2H, m), 4.00 (1H, ddd, J = 3.7, 3.7, 9.3 Hz), 3.49–3.32
(2H, m), 3.23–3.12 (1H, m), 3.06 (1H, dd, J = 5.7, 13.4 Hz), 2.91
(1H, dd, J = 9.2, 13.4 Hz), 2.43 (3H, s), 2.39–2.32 (2H, m), 2.11–
1.88 (2H, m), 1.76–1.45 (2H, m), 1.33–1.25 (3H, m), 1.30 (9H, s);
13C NMR (75 MHz, CDCl3) d: 173.7 (d, JCP = 5.0 Hz), 144.0–126.3
(aromatic), 80.5, 61.2 (d, JCP = 7.4 Hz), 58.5 (d, JCP = 114.9 Hz),
49.4, 42.2 (d, JCP = 4.3 Hz), 40.4 (d, JCP = 12.4 Hz), 28.1 (d,
JCP = 89.4 Hz), 27.8, 25.2, 24.5, 21.5, 16.7 (d, JCP = 5.6 Hz); 31P
NMR (122 MHz, CDCl3) d: 51.11; IR (neat) 1722, 1347, 1157,
1031 cmꢀ1; MS m/z 536 (MH+); HRMS calcd for C27H39NO6PS:
536.2236 (MH+). Found: 536.2259.
Acknowledgment
10. Haruki, T.; Yamagishi, T.; Yokomatsu, T. Tetrahedron: Asymmetry 2007, 18,
2886.
11. Yamagishi, T.; Mori, J.; Haruki, T.; Yokomatsu, T. Tetrahedron: Asymmetry 2011,
22, 1358.
The authors thank Ohu University for their generous financial
support.
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