New phosphine oxide aziridinyl phosphonates as chiral Lewis bases for the Abramov-type phosphonylation of aldehydes

Article abstract of DOI:10.1016/j.tetasy.2013.04.005

A series of Lewis bases were screened for Abramov-type phosphine additions to aldehydes. A novel phosphine oxide aziridinyl phosphonate POAP-A was found to be better than the others in forming the product in 96% yield and with 42% ee. The absolute configu

Full text of DOI:10.1016/j.tetasy.2013.04.005

Tetrahedron: Asymmetry 24 (2013) 562–567
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Tetrahedron: Asymmetry
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New phosphine oxide aziridinyl phosphonates as chiral Lewis bases
for the Abramov-type phosphonylation of aldehydes
Özdemir Dogan a, , Muhammet Isci a, Muhittin Aygun b
⇑
a Middle East Technical University, Department of Chemistry, 06800 Ankara, Turkey
b Dokuz Eylül University, Department of Physics, Buca-Izmir, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 February 2013
Accepted 30 March 2013
A series of Lewis bases were screened for Abramov-type phosphine additions to aldehydes. A novel phos-
phine oxide aziridinyl phosphonate POAP-A was found to be better than the others in forming the prod-
uct in 96% yield and with 42% ee. The absolute configuration of the newly synthesized POAP Lewis bases
was determined by single-crystal X-ray analysis.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
5a and 5b in 90% and 85% yields, respectively. Finally, phosphory-
lation by displacement with KPPh2 and then treatment with hydro-
Optically active
a
-hydroxy phosphonates are biologically
gen peroxide provided POAP-A and POAP-B. The absolute
stereochemistry of POAP-B was determined by single crystal X-
ray analysis (Fig. 1).7
After synthesizing the chiral Lewis bases, their performance
was tested for the Abramov-type enantioselective trialkyl phos-
phite additions to aldehydes. By adopting a literature procedure,4
triethyl phosphite was reacted with anisaldehyde in the presence
of chiral Lewis bases (LB) and SiCl4. The results of the optimization
studies are summarized in Table 1.
important compounds.1 The phosphonylation of aldehydes with
dialkyl (Pudovic-type) or trialkyl phosphites (Abramov-type) is a
useful method for the synthesis of these compounds.2 Although
the asymmetric addition of dialkyl phosphites to aldehydes has
been successfully studied by different groups,3 the first asymmet-
ric addition of trialkyl phosphites to aldehydes was reported by
Nakajima et al. in 2008 with the highest ee of 49%.4 In a recent
study, the same group reported a new catalyst system that pro-
vided
a
-hydroxy phosphonates with modest selectivity.5 These re-
Lewis base screening experiments performed using the previ-
ously synthesized 4a, 4b, AP,6 POFAM,8 and the newly synthesized
POAP compounds showed that POAP-A gave the best results (Ta-
ble 1, entries 2–10). The reaction was then repeated with this LB
at ꢀ90 °C hoping to increase the ee, but the result did not change
(entry 11). Next, the effect of additives was investigated. Screening
of HMPA, TMEDA, Bu4NI, and Et3N–iPr2NEt mixtures did not give
the expected results; the ee remained low (entries 12ꢀ15). There-
sults show that new and more effective catalysts need to be
developed for highly enantioselective trialkyl phosphite additions
to aldehydes. In this respect, we have recently synthesized new
phosphine oxide aziridinyl phosphonates POAP and investigated
their organocatalytic activity as Lewis bases for SiCl4 mediated
Abramov-type enantioselective trialkyl phosphite additions to
aldehydes. Herein we report the results of our studies.
i
fore, Pr2NEt was used as the additive for the rest of the optimiza-
tion studies. While studying the additive concentration, 0.2 equiv
were found to be the optimum amount (entries 16ꢀ18). In previ-
ous literature studies, the slow addition (over 2 h) of SiCl4 was re-
ported to be important.4 In our studies, adding SiCl4 in either 2 h or
10 min showed no effect on the ee and a very minor effect on the
yield (entries 10 and 19). Lowering, or increasing, the amount of
both (EtO)3P and SiCl4 had no significant effect on ee (entries 22–
24) either. Finally with the optimum additive amount in hand,
the reactions were repeated at ꢀ98 °C using three different condi-
tions (entries 25ꢀ27). In all the cases, the ee was approximately
the same. In addition to DCM, the reaction was also carried out
in toluene, THF, and acetonitrile. In these solvents, the product
was formed in 98%, 77%, and 71% yields with enantioselectivities
of 13%, 14% and 19%, respectively. Therefore, DCM was determined
2. Results and discussion
The synthesis of phosphine oxide aziridinyl phosphonates
POAP was achieved using a Gabriel–Cromwell reaction starting
from a vinyl phosphonate. Bromination of this compound provided
1, which was reacted with Et3N to yield compound 2 by HBr elim-
ination. The reaction of this compound with (R)-2-amino-1-buta-
nol provided aziridinyl phosphonates 4a and 4b in a total yield
of 90%. These compounds were also synthesized by starting from
easily available acetyl phosphonate as shown in Scheme 1.6 In
the next step, 4a and 4b were tosylated individually to provide
⇑
Corresponding author. Tel.: +90 312 210 5134.
E-mail address: dogano@metu.edu.tr (Ö. Dogan).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.04.005

Özdemir Dogan et al. / Tetrahedron: Asymmetry 24 (2013) 562–567
563
EtO OEt
OEt
EtO
OEt
O
OEt
Br2
Et3N
P
P
P
Et
Et
Br
O
OH
OH
(-HBr)
0 °C
Et
O
Br
Br
OH
NH2
N
N
O
O
2
1
+
H
OEt
OEt
P
P
4b
40%
4a
50%
OEt
OEt
O
EtO
OEt
O
OEt
DBU
TsCl
OEt
P
Et3N, TsCl
P
O
OTs
Et
Et
3
OTs
OTs
N
N
O
O
OEt
OEt
P
P
5a
90%
5b
85%
OEt
OEt
1. KPPh2, -78°C
2. H2O2
O
O
P
Et
Et
P
Ph
Ph
Ph
Ph
N
N
O
O
P
OEt
OEt
P
POAP-A
POAP-B
OEt
OEt
90%
90%
Scheme 1. Synthesis of POAP chiral Lewis bases.
Figure 1. X-ray crystal structure of POAP-B.
to be the solvent of choice for the reaction. Although the optimal
catalyst POAP-A did not provide exceptionally high ee values un-
der different reaction conditions, the aldehyde screening was car-
ried out using procedure A in order to determine whether the
catalyst was substrate dependent. The results of these studies are
summarized in Table 2.
From the aldehyde screening experiments, we could see that
the products were formed in good to excellent yields except in
the case of p-tolualdehyde (Table 2, entry 7). In terms of enantiose-
lectivity, the results of anisaldehyde, benzaldehyde, and 1-naph-
thaldehyde were very similar, with the ee being 38–44% (entries
1, 2, and 8). For crotonaldehyde, m-nitrobenzaldehyde, p-tolualde-
hyde, 2-naphthaldehyde, and ferrocenecarboxaldehyde, the
enantioselectivity was approximately 30% (entries 3, 5, 7, 9, and
10). The remaining two aldehydes, m-anisaldehyde and m-bromo-
benzaldehyde, gave the lowest ees of 17% and 13%, respectively
(entries 4 and 6).
3. Conclusion
A series of different chiral Lewis bases 4a, 4b, AP, POFAM
series, and POAP were screened for enantioselective Abramov-
type triethyl phosphite additions to aldehydes. Among them
newly synthesized POAP-A, with phosphate and phosphine oxide
groups, was found to be better than the others. Although differ-
ent reaction conditions (SiCl4 addition, temperature, concentra-
tion, solvents, and so on) were tried, the ee could not be
increased above 44%. The slow addition of SiCl4, previously re-
ported to be important for this reaction, was found not to be sig-
nificant for our catalyst. In terms of enantioselectivity, our
results resemble the literature results where the highest ee
was reported to be approximately 50% for the same reaction.
The low enantioselectivity of the reaction can be attributed to
the background reaction, which takes place without the chiral
Lewis base.

564
Özdemir Dogan et al. / Tetrahedron: Asymmetry 24 (2013) 562–567
Table 1
Triethyl phosphite addition to anisaldehyde
O
OH
*
SiCl4 (1.5 equiv)
OEt
OEt
iPr2NEt
H
(EtO)3P
P
+
−78°C, DCM
LB (10 mol%)
O
(1.5 equiv)
H3CO
H3CO
O
P
O
O
O
P
Me
Ph
Et
OH
Et
H
Et
OH
Et
H
Ph
Ph
P
Ph
Ph
P
Ph
Ph
Ph
Ph
N
LB :
N
O
P
N
N
N
Fc
Fc
HO
Fc
Fc
HO
OEt
OEt
H
AP
H
POFAM1
POFAM2
POFAM3
POFAM4
Entry
LB
Method
Additive (equiv)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
—
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
A
B
C
A
iPr2NEt (1.5)
iPr2NEt (1.5)
iPr2NEt (1.5)
iPr2NEt (1.5)
iPr2NEt (1.5)
iPr2NEt (1.5)
iPr2NEt (1.5)
iPr2NEt (1.5)
iPr2NEt (1.5)
iPr2NEt (1.5)
iPr2NEt (1.5)
HMPA (1.5)
TMEDA (1.0)
72
84
85
55
74
73
70
80
70
91
80
56
51
93
47
86
91
92
95
62
91
76
51
50
41
56
76
52
—
10
5
7
11
2
4
5
2
34
35
rac
11
11
7
35
37
42
34
36
39
34
31
32
43
41
40
—
POFAM1
POFAM2
POFAM3
POFAM4
AP
4a
4b
9
POAP-B
POAP-A
POAP-A
POAP-A
POAP-A
POAP-A
POAP-A
POAP-A
POAP-A
POAP-A
POAP-A
POAP-A
POAP-A
POAP-A
POAP-A
POAP-A
POAP-A
POAP-A
POAP-A
—
10
11c
12
13
14
15
16
17
18
19
20
21
22d
23e
24f
25c
26c
27c
28
Bu4NI (1.5)
i
Et3N (1.5) Pr2NEt (0.75)
iPr2NEt (1.0)
iPr2NEt (0.5)
iPr2NEt (0.2)
iPr2NEt (1.5)
iPr2NEt (0.1)
iPr2NEt (0.35)
iPr2NEt (0.2)
iPr2NEt (0.35)
iPr2NEt (0.35)
iPr2NEt (0.2)
iPr2NEt (0.2)
iPr2NEt (0.2)
iPr2NEt (0.2)
A—SiCl4 was added over 2 h to a solution of LB, P(OEt)3, and additive in DCM; stirring was continued for another hour and hydrolyzed.
B—SiCl4 was added over 10 min to a solution of LB, P(OEt)3, and additive in DCM; the reaction mixture was stirred for 2 h.
C—SiCl4 was added directly at once to a solution of LB, P(OEt)3, and additive in DCM; the reaction mixture was stirred for 2 h.
a
Isolated yields.
Determined by chiral HPLC.
b
c
Reaction was carried out at ꢀ98 °C.
d
P(OEt)3 and SiCl4 were used in 1.05 equiv.
e
P(OEt)3 was used in 2.0equiv.
SiCl4 was used in 2.0 equiv.
f
search Analytical Autopol III Polarimeter was used to measure
optical rotations.
4. Experimental
4.1. General
4.1.1. (R)-2-((R)-2-(Diethoxyphosphoryl)aziridin-1-yl)butyl 4-
methylbenzenesulfonate 5a
All asymmetric reactions were performed under an inert atmo-
sphere in dry glassware. DCM was dried and distilled from calcium
hydride prior to use. P(OEt)3 was distilled from sodium. Diisopro-
pylethylamine was distilled from calcium hydride.
The products were purified by flash column chromatography on
Silica Gel 60 (Merck, 230–400 mesh ASTM). TLC analyses were per-
Diethyl
((R)-1-((R)-1-hydroxybutan-2-yl)aziridin-2-yl)phos-
phonate 4a (502 mg, 2.00 mmol) was dissolved in DCM (4 mL) at
room temperature. Then Et3N (0.42 mL, 3.00 mmol) was added.
To this stirred solution was added p-toluenesulfonyl chloride
(570 mg, 3 mmol). Next, the reaction mixture was stirred at room
temperature overnight at which point TLC showed no starting
material. To the reaction flask, water (15 mL) was added. The
two layers were separated and the aqueous layer was extracted
with DCM (15 mL ꢁ 2). The combined organic layers were dried
over Na2SO4, filtered and concentrated. The crude pale yellow vis-
cous liquid was purified by flash column chromatography on silica
gel using EtOAc as the eluent. After purification, 2-(2-(diethoxy-
formed on 250 lm Silica Gel 60 F254 plates. Enantiomeric excess
(ee) was determined by chiral HPLC. Melting points were taken
in open-end capillary tubes and are uncorrected. IR spectra are re-
ported in reciprocal centimeters (cmꢀ1). 1H, 13C, and 31P NMR spec-
tra were reported on a Brucker spectrospin Avance DPX-400 Ultra
shield instrument at 400, 100, and 162 MHz, respectively relative
to TMS for 1H and 13C NMR and H3PO4 for 31P NMR. A Rudolph Re-

Özdemir Dogan et al. / Tetrahedron: Asymmetry 24 (2013) 562–567
565
Table 2
Aldehyde screening studies
layers were dried over Na2SO4 and concentrated under reduced
pressure to give the crude product as a colorless oil. Then it was dis-
solved in acetone (120 mL) and stirred with H2O2 (30% aq, 1.74 mL,
18.5 mmol) at rt. After 1 h, TLC showed no starting material. The
reaction mixture was quenched with a saturated solution of Na2S2O3
(4 mL). The extraction was performed by adding DCM (25 mL ꢁ 2).
The combined organic layer was dried over Na2SO4 and concen-
trated to give a light yellow oil. The crude product was purified by
flash column chromatography using silica gel (hexane/acetone
2:1 + 2% Et3N). Diethyl 1-(1-diphenylphosphoryl) butan-2-yl) aziri-
din-2-ylphosphonate POAP-A was isolated in 90% yield (1.45 g,
3.33 mmol) as a light yellow oil. Rf = 0.26, hexane/acetone 2:1 + 2%
SiCl4 (1.5 equiv)
OH
*
O
iPr2NEt (0.2 equiv)
OEt
OEt
(EtO)3P
(1.5 equiv)
+
R
P
R
H
-78°C, DCM
POAP-A (10 mol %)
O
6a-j
7a-j
Entry
R
Substrate
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
p-MeOC6H4
Ph
6a
6b
6c
6d
6e
6f
6g
6h
6i
92
98
99
95
97
87
62
89
90
90
42
38
29
17
32
13
30
44
30
28
(E)-PhCH@CH
m-MeOC6H4
m-NO2C6H4
m-BrC6H4
p-MeC6H4
1-Naphthyl
2-Naphthyl
Ferrocenyl
Et3N; ½a 2D5
ꢂ
¼ ꢀ8:2 (c 0.3, CH2Cl2); 1H NMR d 7.80–7.70 (m, 4H),
7.55–7.40 (m, 6H), 4.20–4.05 (m, 4H), 2.75–2.55 (m, 2H), 2.25–
2.15 (m, 1H), 1.75–1.60 (m, 4H), 1.40–1.35 (m, 1H), 1.30 (t,
J = 7.2 Hz, 3H), 1.25 (t, J = 7.0 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H); 13C
NMR d 134.0 (Cq, ArC-P), 133.8 (Cq, ArC-P), 131.7 (CH, 2C, Ph),
130.9 (CH, Ph), 130.8 (CH, Ph), 130.7 (CH, Ph), 130.6 (CH, Ph),
128.7 (CH, Ph), 128.6 (CH, Ph), 128.6 (CH, Ph), 128.5 (CH, Ph), 65.7
(CH, d, JC-P = 7.1 Hz), 62.5 (OCH2CH3, d, JC-P = 6.7 Hz), 62.4 (OCH2CH3,
d, JC-P = 6.1 Hz), 35.2 (CH2-aziridine), 33.8 (CH2, d, JC-P = 6.5 Hz), 29.8
(CH-aziridine, d, JC-P = 216.3 Hz), 28.9 (CH2CH3), 16.8 (OCH2CH3, d,
JC-P = 5.3 Hz), 16.2 (OCH2CH3, d, JC-P = 5.3 Hz), 9.70 (CH3); 31P NMR
d 23.2 (P(O)(OEt)2), 28.5 (P(O)Ph2); IR (neat, cmꢀ1) 2987, 2921,
2875, 1452, 1260, 1171, 1020, 739, 713. HRMS-EI (m/z): calcd for
10
6j
a
Isolated yields.
Determined by chiral HPLC.
b
phosphoryl)aziridin-1-yl)butyl 4-methylbenzenesulfonate 5a was
obtained as a light yellow oil in 90% yield (730 mg, 1.80 mmol).
Rf = 0.41, EtOAc; ½a D25
ꢂ
¼ ꢀ12:5 (c 0.5, CH2Cl2); 1H NMR d 7.80 (d,
C
22H32NO4P2 [M+H]+: 436.1807; found: 436.1811.
J = 8 Hz, 2H), 7.35 (d, J = 8 Hz, 2H), 4.10 (m, 4H), 4.07 (m, 2H),
2.46 (s, 3H), 2.15 (dd, J = 5.4 and 1.8 Hz, 1H), 2.03 (d, J = 4.4 Hz,
1H), 1.67 (ddd, J = 18.4, 6.8, and 4 Hz, 1H), 1.61 (t, J = 2.4 Hz, 1H)
1.58 (m, 2H), 1.32 (t, J = 7.2 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H), 0.91
4.1.4. Diethyl ((S)-1-((R)-1-(diphenylphosphoryl)butan-2-yl)
aziridin-2-yl)phosphonate POAP-B
(t, J = 7.6 Hz, 3H); 13C NMR
d 144.4 (Cq, ArC-S), 133.2 (Cq,
Starting from tosylate 5b (1.21 g, 3.00 mmol) and following the
same procedure reported for POAP-A, diethyl 1-(1-diphenylphos-
phoryl)butan-2-yl)aziridin-2-yl phosphonate POAP-B was ob-
tained in 85% yield (1.11 g, 2.55 mmol) as a white solid. Rf = 0.20,
ArC-CH3), 129.7 (CH, 2C, Ph), 127.9 (CH, 2C, Ph), 71.2 (CH2-OTs),
68.4 (CH, d, JC-P = 6.3 Hz), 61.5 (OCH2CH3, d, JC–P = 6.3 Hz), 60.7
(OCH2CH3, d, JC–P = 6.3 Hz), 30.7 (CH, aziridine, d, JC–P = 218.5 Hz),
29.3 (CH2CH3, d, JC–P = 5.2 Hz), 24.9 (CH2 aziridine), 21.6 (CH3,
Ts), 15.1 (OCH2CH3,d, JC–P = 5.3 Hz), 15.0 (OCH2CH3, d, JC–P = 5.3 Hz),
9.89 (CH3); 31P NMR d 22.31; IR (neat, cmꢀ1) 2978, 1358, 1247,
1175, 1022, 962, 812, 787, 664.
hexane/acetone 2:1 + 2% Et3N; mp: 108ꢀ109 °C;
½
a 2D5
ꢂ
¼ þ6:0
(c 1.0, CH2Cl2); 1H NMR d 7.82 (ddd, J = 11.5, 8.0, and 1.6 Hz, 2H),
7.70 (ddd, J = 11.5, 8.0, and 1.6 Hz, 2H), 7.55–7.40 (m, 6H), 4.20–
4.00 (m, 4H), 2.65–2.40 (m, 2H), 1.95–1.80 (m, 1H), 1.70–1.45
(m, 5H), 1.29 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H), 0.94 (t,
J = 7.4 Hz, 3H); 13C NMR d 131.7 (Cq, ArC-P, 2C), 130.8 (CH, 2C,
Ph), 130.4 (CH, Ph, 2C), 128.7 (CH, Ph, 3C), 128.6 (CH, Ph, 3C),
65.5 (CH, d, JC-P = 7.5 Hz), 62.4 (CH, d, JC-P = 6.3 Hz), 62.3 (OCH2CH3,
d, JC-P = 6.3 Hz), 32.5 (CH-aziridine, d, JC-P = 218.2 Hz), 31.9 (CH2,
CH2-P, d, JC-P = 5.1 Hz), 28.5 (CH2-aziridine, JC-P = 6.9 Hz), 25.2
(CH2CH3), 16.4 (O CH2CH3, d, JC-P = 9.7 Hz), 9.13 (CH3); 31P NMR d
22.90 (PO(OEt)2), 28.34 (P(O)Ph2); IR (neat, cmꢀ1) 2978, 2911,
2863, 1454, 1270, 1161, 1023, 749, 723. HRMSꢀEI (m/z): calcd
for C22H32NO4P2 [M+H]+: 436.1807; found: 436.1810.
4.1.2. (R)-2-((S)-2-(Diethoxyphosphoryl)aziridin-1-yl)butyl 4-
methylbenzenesulfonate 5b
Starting
from
((R)-1-((S)-1-hydroxybutan-2-yl)aziridin-2-
yl)phosphonate 4b (302 mg, 1.20 mmol) and following the same
procedure reported for 5a, 5b was obtained as a light yellow oil
in 85% yield (414 mg, 1.02 mmol). Rf = 0.57, EtOAc; ½a D25
¼ þ44 (c
ꢂ
2.4, CH2Cl2); 1H NMR d 7.78 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8 Hz,
2H), 4.08 (m, 4H), 4.05 (m, 2H), 2.46 (s, 3H), 2.06 (dd, J = 8.8 and
4.0 Hz, 1H), 1.75 (t, J = 7.2 Hz, 1H), 1.62 (d, J = 2.4 Hz, 1H), 1.58
(m, 2H), 1.49 (ddd, J = 19.0, 6.8, and 4 Hz, 1H), 1.31 (t, J = 7.0 Hz,
3H), 1.30 (t, J = 7.0 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H); 13C NMR d
144.7 (Cq, ArC-S), 133.2 (Cq, ArC-CH3), 129.8 (CH, 2C, Ph), 127.8
(CH, 2C, Ph), 71.8 (CH2-OTs), 69.7 (CH, d, JC-P = 7.5 Hz), 62.4
(OCH2CH3, d, JC-P = 6.5 Hz), 31.6 (CH2CH3, d, JC-P = 5.5 Hz), 30.0
(CH-aziridine, d, JC-P = 219.3 Hz), 24.7 (CH2-aziridine), 21.6 (CH3,
Ts), 16.5 (OCH2CH3, d, JC-P = 6.0 Hz), 16.4 (OCH2CH3, d, JC-
P = 6.0 Hz), 9.67 (CH3); 31P NMR d 22.70; IR (neat, cmꢀ1) 2980,
1357, 1245, 1175, 1022, 959, 812, 787, 665.
4.2. General procedure for the asymmetric triethyl phosphite
addition to aldehydes
i
Aldehyde (0.50 mmol), Pr2NEt (19
l
L, 0.10 mmol), and chiral
Lewis base (10 mol %) were mixed in dry DCM (1 mL) at
ꢀ78 °C in a flame dried Schlenk tube under a nitrogen atmo-
sphere. To this solution was added P(OEt)3 (130 lL, 0.75 mmol).
Next, SiCl4 (86 lL, 0.75 mmol) solution in DCM (2 mL, prepared
in a different flask under dry conditions) was added to the reac-
tion flask over 2 h (method A). After stirring for another hour,
TLC analysis (hexane/acetone 2:1) showed no starting material.
The reaction mixture was hydrolyzed by adding water (2 mL)
and saturated NaHCO3 (5 mL). Next, EtOAc (5 mL) was added
and the reaction flask was stirred for approximately 1 h, after
which the mixture was filtered through a short Celite pad. The
two phases were separated and the aqueous phase was extracted
with EtOAc (3 ꢁ 5 mL). The combined organic phase was washed
with brine and dried over MgSO4. The concentrated crude prod-
4.1.3. Diethyl ((R)-1-((R)-1-(diphenylphosphoryl)butan-2-yl)
aziridin-2-yl)phosphonate POAP-A
Tosylate 5a (1.50 g, 3.70 mmol) was dissolved in dry THF (9 mL).
Then, potassium diphenylphosphide (8.88 mL, from 0.5 M THF solu-
tion) was added to the reaction flask slowly over 45 min at ꢀ78 °C.
After 4 h stirring at this temperature, TLC showed no starting mate-
rial. The reaction mixture was hydrolyzed with saturated NH4Cl
solution (25 mL). The two layers were separated and the aqueous
layer was extracted with DCM (25 mL ꢁ 2). The combined organic

566
Özdemir Dogan et al. / Tetrahedron: Asymmetry 24 (2013) 562–567
uct was purified by flash column chromatography using silica gel
(hexane/acetone 2:1). The enantioselectivity was determined by
HPLC using a chiralcel AS-H column.
4.2.6. Diethyl 1-hydroxy-(3-bromophenyl)methylphosphonate
7f9
Rf = 0.48 hexane/acetone 2:1; ½a D25
¼ ꢀ1:5 (c 1.0, CHCl3) for 13%
ꢂ
ee. 1H NMR d 1.23 (t, J = 7.2 Hz, 3H), 1.38 (t, J = 7.2 Hz, 3H), 3.05 (m,
1H), 4.01 (m, 4H), 4.97 (dd, J = 10.4 & 4.8 Hz 1H), 7.17 (b, 1H),
7.19(b, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H); 13C
NMR d 16.38 (CH3), 63.0 (OCH2CH3), 85.22 (CHOH), 122.92 (Ph,
1C), 126.99 (Ph, 1C), 129.20 (Ph, 1C), 133.20 (Ph, 1C), 157.98 (Ph,
Cq), 167.21(Ph, Cq), 31P NMR d 21.52; IR (neat, cmꢀ1) 3240, 2984,
1224, 1184, 1010, 964, 796, 687; HPLC: Chiralpak AS-H column,
UV detection at 254 nm, eluent: hexane/2-propanol 4:1, flow
1.0 mL minꢀ1, tR = 8.46 min (minor), 10.34 min (major).
4.2.1. Diethyl 1-hydroxy-1-(4-methoxyphenyl)methyl
phosphonate 7a
Rf = 0.31 hexane/acetone 1:1; ½a D25
¼ ꢀ12:0 (c 1.0, CHCl3) for
ꢂ
28% ee (S). Lit.4
½
a 1D8
ꢂ
¼ þ14:1 (c 1.01, CHCl3) for 40% ee (R); 1H
NMR d 1.22 (t, J = 7.2 Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H), 3.80 (s, 3H),
3.93–4.09 (m, 4H), 4.15 (m, 1H), 4.91 (dd, J = 9.8 and 5.4 Hz, 1H,),
6.86 (d, J = 8.8 Hz, 2H), 7.39 (dd, 8.6 and 2.2 Hz, 2H); 31P NMR: d
21.83; IR (neat, cmꢀ1) 3244, 2963, 1510, 1223, 1196, 1169, 1057,
961, 795; HPLC: Chiralpak AS-H column, UV detection at 254 nm,
eluent: hexane/2-propanol 4:1, flow 1.0 mL minꢀ1, tR = 21.0 min
(R, minor), 34.0 min (S, major).
4.2.7. Diethyl 1-hydroxy-(4-methylphenyl)methylphosphonate
7g
Rf = 0.35 hexane/acetone 2:1; ½a D25
¼ ꢀ10:5 (c 1.0, CHCl3) for
ꢂ
30% ee. Lit.3g
½
a 2D0
ꢂ
¼ þ27:7 (c 0.22, CHCl3) for 80% ee; 1H NMR d
4.2.2. Diethyl 1-hydroxy-1-phenylmethylphosphonate 7b
1.22 (t, J = 7.2 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H), 2.34 (s, 3H), 3.02
(d, J = 10.4 Hz, 1H), 3.98–4.12 (m, 4H), 4.97 (dd, J = 10.4 and
4.4 Hz 1H), 7.17 (d, J = 8 Hz 2H), 7.37 (dd, J = 8.2 and 2.4 Hz, 2H);
31P NMR d 21.52; IR (neat, cmꢀ1) 3241, 2985, 1415, 1225, 1048,
963, 882, 797, 688; HPLC: Chiralpak AS-H column, UV detection
Rf = 0.40, hexane/acetone 1:1; ½a D25
¼ ꢀ10:1 (c 1.0, CHCl3) for
ꢂ
28% ee (S). Lit.4
½
a 2D7
ꢂ
¼ þ14:8 (c 1.01, CHCl3) for 41% ee (R); 1H
NMR d 1.22 (t, J = 7.0 Hz, 3H), 1.28 (t, J = 7.0 Hz, 3H), 4.14 (br, s,
1H), 4.04 (m, 4H), 4.98 (dd, J = 10.6 and 5.0 Hz, 1H), 7.32 (m, 3H),
7.46 (m, 2H); 31P NMR: d 21.55; IR (neat, cmꢀ1) 3250, 2991,
2097, 1448, 1224, 1045, 1019, 959, 700; HPLC: Chiralpak AS-H col-
umn, UV detection at 254 nm, eluent: hexane/2-propanol 4:1, flow
1.0 mL minꢀ1, tR = 17.0 min (R, minor), 22.0 min (S, major).
at 254 nm, eluent: hexane/2-propanol 4:1, flow 1.0 mL minꢀ1
,
tR = 8.02 min (minor), 11.03 min (major).
4.2.8. Diethyl 1-hydroxy-1-(naphthyl)methylphosphonate 7h
Rf = 0.20 hexane/acetone 2:1; ½a D25
¼ ꢀ19:0 (c 1.0, CHCl3) for
ꢂ
4.2.3. Diethyl 1-hydroxy-3-phenylprop-2-enyl-phosphonate 7c
44% ee. Lit.4
½
a 1D9
ꢂ
¼ þ11:5 (c 1.01, CHCl3) for 9% ee. 1H NMR d
Rf = 0.34, hexane/acetone 1:1; ½a D25
¼ ꢀ6:0 (c 1.0, CHCl3) for 28%
ꢂ
1.05 (t, J = 7.2 Hz, 3H), 1.25 (t, J = 7.2 Hz, 3H), 3.16 (dd, 10.8 and
5.2 Hz 1H), 3.98–4.06 (m, 4H), 5.86 (dd, J = 11.6 and 4.4 Hz, 1H),
7.48–7.56 (m, 3H), 7.82–7.90 (m, 3H), 8.10 (d, J = 8.4 Hz, 1H);
31P NMR d 21.52; IR (neat, cmꢀ1) 3217, 2978, 1392, 1199, 1024,
955, 770, 752, 634; HPLC: Chiralpak AS-H column, UV detection
ee (S). Lit.4
½
a 1D8
ꢂ
¼ þ7:7 (c 0.92, CHCl3) for 49% ee (R); mp:
99.0–99.5 °C; 1H NMR d 1.35 (t, J = 7.2 Hz, 6H), 3.15 (m, 1H),
4.18–4.26 (m, 4H), 4.63–4.69 (m, 1H), 6.29 (dt, J = 15.6 and
5.6 Hz, 1H), 6.76 (ddd, J = 16.0, 5.0, and 1.4 Hz, 1H), 7.24 (m, 1H),
7.30 (t, J = 7.4 Hz, 2H), 7.38 (d, J = 7.2 Hz, 2H); 31P NMR d 21.52;
IR (neat, cmꢀ1) 3244, 2982, 1446, 1223, 1014, 960, 756, 729; HPLC:
Chiralpak AS-H column, UV detection at 254 nm, eluent: hexane/2-
propanol 9:1, flow 1.0 mL minꢀ1, tR = 17.6 min (R, minor), 44.4 min
(S, major).
at 254 nm, eluent: hexane/2-propanol 4:1, flow 1.0 mL minꢀ1
,
tR = 10.19 min (minor), 33.51 min (major).
4.2.9. Diethyl 1-hydroxy-2-(naphthyl)methylphosphonate 7i
Rf = 0.25 hexane/acetone 2:1; ½a D25
¼ ꢀ11:0 (c 1.0, CHCl3) for
ꢂ
30% ee. Lit.4
½
a 2D2
ꢂ
¼ þ11:9 (c 1.0, CHCl3) for 33% ee; 1H NMR
4.2.4. Diethyl 1-hydroxy-(3-methoxyphenyl)methyl
phosphonate 7d
(CDCl3): d 1.21 (t, J = 7.2 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H), 3.36
(b, 1H), 3.99–4.07 (m, 4H), 5.20 (dd, J = 10.8 and 2.8 Hz 1H),
7.45–7.53 (m, 2H), 7.60 (d, J = 8.8 Hz, 1H), 7.81–7.84 (m, 3H),
7.96 (s, 1H); 31P NMR d 21.52; IR (neat, cmꢀ1) 3268, 2981, 1359,
1231, 1055, 1012, 946, 750, 641; HPLC: Chiralpak AS-H column,
UV detection at 254 nm, eluent: hexane/2-propanol 4:1, flow
1.0 mL minꢀ1, tR = 11.34 min. (minor), 15.35 min (major).
Rf = 0.36 hexane/acetone 2:1; ½a D25
¼ ꢀ3:6 (c 1.0, CHCl3) for 17%
ꢂ
ee. Lit.3g
½
a 2D0
ꢂ
¼ þ13:0 (c 0.25, CHCl3) for 71% ee; 1H NMR d 1.23 (t,
J = 7.1 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H), 3.86 (b, 1H), 3.81 (s, 3H),
4.00–4.14 (m, 4H), 5.0 (dd, J = 10.8 and 1.8 Hz, 1H), 6.85 (d,
J = 8.0 Hz, 1H) 7.07 (m, 2H), 7.27 (t, J = 7.9 Hz, 1H); 31P NMR
(CDCl3): d 21.52; IR (neat, cmꢀ1) 3266, 2982, 1601, 1229, 1018,
963, 790, 749, 693; HPLC: Chiralpak AS-H column, UV detection
4.2.10. Diethyl 1-hydroxy(ferrocenyl)methylphosphonate 7j10
at 254 nm, eluent: hexane/2-propanol 4:1, flow 1.0 mL minꢀ1
,
Rf = 0.42, hexane/acetone 2:1, yellow oily product; ½a D25
¼ þ3:5
ꢂ
tR = 13.61 min (minor), 24.78 min (major).
(c 1.0, CHCl3) for 28% ee; 1H NMR: d 1.19 (t, J = 7.0 Hz, 3H), 1.25
(t, J = 7.0 Hz, 3H), 3.44 (br, 1H), 3.95 (m, 4H), 4.10 (s, Fc, 2H), 4.15
(s, Fc, 5H), 4.21 (s, Fc, 1H), 4.35 (s, Fc, 1H), 4.50 (m, 1H); 13C
4.2.5. Diethyl 1-hydroxy-(3-nitrophenyl)methylphosphonate 7e
Rf = 0.25 hexane/acetone 2:1; ½a D25
¼ ꢀ4:0 (c 1.0, CHCl3) for 32%
ꢂ
NMR (100 MHz, CDCl3)
d 14.08 (CH3), 63.52 (CHOH), 63.72
ee. Lit.3e
½
a 2D2
ꢂ
¼ ꢀ30 (c 0.13, CHCl3) for 52% ee 1H NMR (CDCl3):
(OCH2CH3), 65.34 (Fc, CH), 65.52 (Fc, CH), 65.71 (Fc, CH), 65.76
(Fc, CH), 66.35 (Fc, 5C), 83.42 (Fc, Cq) 31P NMR (CDCl3): d 21.04;
IR (neat, cmꢀ1) 3288, 2981, 1221, 1002, 960, 809; HPLC: Chiralpak
AS-H column, UV detection at 254 nm, eluent: hexane/2-propanol
4:1, flow 1.0 mL minꢀ1, tR = 24.0 min (major), 65.0 min (minor).
d 1.26 (t, J = 7.2 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H), 4.12 (m, 4H), 4.35
(b, 1H), 5.15 (d, J = 11.2 Hz 1H), 7.54 (t, J = 8 Hz, 1H), 7.82
(d, J = 7.2 Hz, 1H), 8.18 (d, J = 7.2 Hz, 1H), 8.40 (d, J = 2.0 Hz, 1H);
13C NMR (100 MHz, CDCl3) d 16.20 (CH3), 65.58 (OCH2CH3), 86.78
(CHOH), 121.85 (Ph, 1C), 122.92 (Ph, 1C), 128.99 (Ph, 1C), 132.86
(Ph, 1C), 174.42 (Cq, Ph), 176.43 (Cq, Ph); 31P NMR (CDCl3): d
21.52; IR (neat, cmꢀ1) 3233, 2982, 1535, 1347, 1206, 1038, 1014,
951, 801, 686; HPLC: Chiralpak AS-H column, UV detection at
Acknowledgments
We thank the Scientific and Technical Research Council of Turkey
(TUBITAK, Grant No. TBAG-110T073) and the Middle East Technical
University Research Foundation for the financial support.
254 nm, eluent: hexane/2-propanol 4:1, flow 1.0 mL minꢀ1
,
tR = 47.91 min (minor), 49.49 min (major).

Özdemir Dogan et al. / Tetrahedron: Asymmetry 24 (2013) 562–567
567
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