Synthesis of four enantiomers of 2-acetamido-1-hydroxypropylphosphonates

Article abstract of DOI:10.1016/j.tetasy.2007.04.021

Enantiomerically pure diethyl 2-acetamido-1-hydroxypropylphosphonates were synthesised from N-[(R)-(1-phenylethyl)]aziridine-(2S)- and N-[(S)-(1-phenylethyl)]aziridine-(2R)-carboxaldehydes via phosphonylation followed by acetylation of the hydroxy groups

Full text of DOI:10.1016/j.tetasy.2007.04.021

Tetrahedron: Asymmetry 18 (2007) 1134–1141
Synthesis of four enantiomers of 2-acetamido-1-
hydroxypropylphosphonates
*
´
Andrzej E. Wroblewski and Joanna Drozd
Bioorganic Chemistry Laboratory, Faculty of Pharmacy, Medical University of Ło´dz´, 90-151 Ło´dz´, Muszyn´skiego 1, Poland
Received 29 March 2007; accepted 23 April 2007
Available online 1 June 2007
Abstract—Enantiomerically pure diethyl 2-acetamido-1-hydroxypropylphosphonates were synthesised from N-[(R)-(1-phenylethyl)]azi-
ridine-(2S)- and N-[(S)-(1-phenylethyl)]aziridine-(2R)-carboxaldehydes via phosphonylation followed by acetylation of the hydroxy
groups and the simultaneous hydrogenolytic cleavage of the aziridine rings and the removal of the chiral auxiliaries. In addition, enan-
tiomerically pure diethyl (1S,2R)- and (1R,2S)-2-amino-1-hydroxypropylphosphonates (the phosphonate analogues of isothreonine)
were separated.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
The most straightforward approach to substituted
2-amino-1-hydroxyphosphonates relies on the addition of
dialkyl phosphites to N-protected a-amino aldehydes (the
Abramov reaction).27 However, depending on the protec-
tive groups at the nitrogen atom and structural features
of a-amino aldehydes, the N-protected a-amino aldehydes
undergo racemisation in the presence of basic catalysts
commonly employed in the Abramov reaction.28–30
For this reason enantiomerically pure 2-amino-1-hydroxy-
propylphosphonic acids 1 (phosphonate analogues of
isothreonine) were first prepared by different strategies,
that is, (1R,2R)-1 from fosfomycin,31 and (1S,2R)-1 from
2-Aminophoshonates can be considered as isosteres of
b-amino acids. Although they are less known than 1-amino-
phoshonates,1 their chemistry has recently been reviewed.2–6
Interest in 2-aminophoshonates was stimulated by the
isolation of 2-aminoethylphosphonic acid from Celiate
protozoa7 and other 2-aminophosphonic acids from diverse
species.8 Furthermore, substituted 2-aminophosphonic
acids display an array of biological properties. For example,
they act as NMDA9 or GABAB receptor10 antagonists,
inhibit aminopeptidase A,11 glutationylspermidine synthe-
tase,12 a-L-fucosidase13 and imidazole glycerol phosphate
dehydratase,14,15 and also show antifungal activity.16
2-Amino-3-phosphonopropionic acid (AP3) and its deriva-
tives have been extensively studied and their activity as a
metabotropic glutamate receptor antagonist17 and inhibi-
tors of several enzymes18,19 was discovered. Tripeptides con-
taining 2-aminophosphonates substituted at C-1 with the
hydroxy, oxo or fluorine groups at a C-terminus were found
to be inhibitors of human rennin,20 HIV protease,21 dipep-
tidyl peptidase IV,22 norstatine,23 human calpain I24 and
cathepsin E.25 Furthermore, 2-amino-1-hydroxy-3-phenyl-
propylphosphonic acid showed significant herbicidal
activity.26
diisopropyl
(1S,2S)-2-benzyloxy-1-hydroxypropylphos-
phonate in a multi step procedure,32 while only (1S,2S)-1
was obtained from N-Boc-(S)-alaninal in a KF-catalysed
addition of dimethyl phosphite followed by hydrolysis.33
But for the synthesis of diethyl ester (1S,2S)-2 cate-
cholborane reduction of diethyl (S)-1-oxo-2-(N-phthalo-
yl)aminopropylphosphonate was successfully employed34
(Fig. 1).
Herein, we report the asymmetric synthesis of all four
enantiomerically pure diethyl esters 2 via (aziridin-2-
yl)hydroxymethylphosphonates 3 and 4, employing the
esters (2S,10S)- and (2R,10S)-5 as the starting materials
(Scheme 1). The synthesis and separation of aziridines 535
and their enantiomers36 were described several years ago.
The respective aldehydes 737 are configurationally stable
and can serve as synthetic equivalents of serinals in the
Abramov reaction.
*
Corresponding author. Tel.: +48 42 677 92 33; fax: +48 42 678 83 98;
e-mail: aewplld@ich.pharm.am.lodz.pl
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.04.021

A. E. Wro´blewski, J. Drozd / Tetrahedron: Asymmetry 18 (2007) 1134–1141
1135
NH2
NH2
NH2
NH2
P(O)(OR)2
P(O)(OR)2
P(O)(OR)2
P(O)(OR)2
Me
Me
Me
Me
OH
OH
OH
OH
(1R,2R)-1
(1R,2R)-2
(1R,2S)-1
(1R,2S)-2
(1S,2R)-1
(1S,2R)-2
(1S,2S)-1
(1S,2S)-2
R = H
R = Et
Figure 1. Enantiomers of the phosphonate analogue of isothreonine.
Ph
H
Me
H
N
N
P(O)(OEt)2
OH
Ph
3a
3b
1'
H
Me
H
COOMe
(2R,1'S)-5
N
Ph
H
Me
H
P(O)(OEt)2
OH
NH2
Ph
H
P(O)(OEt)2
+
BrCH2CHBrCOOMe
NH2
Me
Me
OH
2
Ph
H
H
N
P(O)(OEt)2
P(O)(OEt)2
Me
Ph
OH
1'
H
Me
H
4a
4b
N
Ph
COOMe
H
H
(2S,1'S)-5
N
Me
OH
Scheme 1. Retrosynthesis of P-isothreonine.
2. Results and discussion
a 1:1 ratio (Scheme 2). These were then separated on a
silica gel column to afford 3a and 3b as slightly yellowish
oils in 29% and 37% yield, respectively.
Aziridines (2S,10S)- and (2R,10S)-5 were prepared as de-
scribed in the literature35 in 42% and 40% yield, respec-
tively. The ester groups were reduced with a sodium
borohydride–lithium chloride mixture38 to provide the cor-
responding alcohols (2S,10S)- and (2R,10S)-6, both in 87%
yield, after column chromatography. Swern oxidation of
(2R,10S)-6 gave the respective aldehyde (2R,10S)-7, which
was subjected to the NEt3-catalysed addition of diethyl
phosphite to afford 1-hydroxyphosphonates 3a and 3b in
When aldehyde (2S,10S)-7 was subjected to phosphonyl-
ation (Scheme 3), a 1:1 mixture of the oily hydroxyphosph-
onates 4a and 4b was produced almost quantitatively,
although several attempts at separating them on a silica
gel column failed. However, a few fractions partially solid-
ified over 48 h and after recrystallisation, phosphonate 4b
was separated in 14% yield.
Ph
Ph
Ph
1'
H
H
R
H
H
H
H
c
N
+
N
P(O)(OEt)2
N
P(O)(OEt)2
Me
Me
Me
OH
OH
(2R,1'S)-5 R = COOMe
(2R,1'S)-6 R = CH2OH
(2R,1'S)-7 R = CHO
3a
3b
a
b
Scheme 2. Reagents and conditions: (a) NaBH4–LiCl, 0 ꢁC to rt, 16 h, 87%; (b) DMSO, (COCl)2, ꢀ78 ꢁC, 1 h, TEA, ꢀ78 ꢁC to rt, 15 min; (c)
(EtO)2P(O)H, NEt3 10 mol %, rt, 3 d.

1136
A. E. Wro´blewski, J. Drozd / Tetrahedron: Asymmetry 18 (2007) 1134–1141
Ph
Ph
Ph
1'
H
H
R
H
H
H
H
c
N
N
P(O)(OEt)2
+
N
P(O)(OEt)2
Me
Me
Me
OH
OH
(2S,1'S)-5 R = COOMe
(2S,1'S)-6 R = CH2OH
(2S,1'S)-7 R = CHO
4a
4b
a
b
Scheme 3. Reagents and conditions: (a) NaBH4–LiCl, 0 ꢁC to rt, 16 h, 87%; (b) DMSO, (COCl)2, ꢀ78 ꢁC, 1 h, TEA, ꢀ78 ꢁC to rt, 15 min;
(c) (EtO)2P(O)H, NEt3 10 mol %, rt, 3 d.
Ph
Ph
Ph
1'
Me
H
H
R
Me
H
Me
H
H
H
c.
N
N
P(O)(OEt)2
OH
11a (ent-3a)
+
N
P(O)(OEt)2
OH
11b (ent-3b)
(2S,1'R)-8 R = COOMe
(2S,1'R)-9 R = CH2OH
(2S,1'R)-10 R = CHO
a
b
Scheme 4. Reagents and conditions: (a) NaBH4–LiCl, 0 ꢁC to rt, 16 h, 78%; (b) DMSO, (COCl)2, ꢀ78 ꢁC, 1 h, TEA, ꢀ78 ꢁC to rt, 15 min;
(c) (EtO)2P(O)H, NEt3 10 mol %, rt, 3 d.
For this reason, aldehyde (2S,10R)-10 was prepared from
aziridine (2S,10R)-8 [via alcohol (2S,10R)-9] and was re-
acted with diethyl phosphite to give hydroxyphosphonates
11a (ent-3a) and 11b (ent-3b) in 43% and 35% yield, respec-
tively (Scheme 4).
In a similar fashion, aziridine phosphonates 11a (ent-3a)
and 11b (ent-3b) were acetylated to give the respective
acetates 13a (ent-12a) and 13b (ent-12b). Catalytic hydro-
genation of 13a led to a 1:1 mixture of (1R,2S)-14 and
(1R,2S)-2, while from 13b, only 2-acetamidophosphonate
(1S,2S)-14 was produced.
The aziridine ring cleavage and removal of the N-(1-phen-
ylethyl) group was observed when the respective aziridine
alcohols were subjected to hydrogenolysis leading to a vari-
ety of chiral amino alcohols.37,38 Under similar conditions,
hydrogenolyses of aziridine hydroxyphosphonates 3a and
3b gave complex reaction mixtures. However, after trans-
formation into acetates 12a and 12b (Schemes 5 and 6)
their hydrogenolyses were accomplished quantitatively. A
1:1 mixture of the 2-acetamidophosphonate (1S,2R)-14
and 2-aminophosphonate (1S,2R)-2 was formed from
12a. On the other hand, acetate 12b furnished the 2-acet-
amidophosphonate (1R,2R)-14 as a single product.
The relative configurations of the diastereoisomeric diethyl
2-acetamido-1-hydroxypropylphosphonates have already
been established.28 Based on the comparison of the pub-
lished NMR spectral data28 and these described herein,
the relative configurations in phosphonates (1R,2R)-14
and (1S,2S)-14 as well as in (1R,2S)-14 and (1S,2R)-14
could be assigned. The absolute configurations at C-2 in
the 2-acetamidophosphonates (1R,2R)-14 and (1S,2R)-14
are the same as that in the starting aziridine ester
(2R,10S)-5,35,36 which without traces of epimerisation,
was transformed into the corresponding aldehyde
(2R,10S)-7 and later into aziridinephosphonates 3b and 3a
(Scheme 2), precursors to (1R,2R)-14 and (1S,2R)-14,
respectively.
Ph
NHAc
H
H
b
P(O)(OEt)2
OH
(1R,2R)-14
N
P(O)(OEt)2
Me
Me
OR
In addition, the absolute configuration at C-1 in phospho-
nate 3a can be independently assigned, based on the follow-
ing arguments. The vicinal H1–H2, H2–P and P–C3
couplings, 2.7, 1.2 and 3.1 Hz, respectively, could only be
observed, when phosphonate 3a adopts the antiperiplanar
conformation (Fig. 2), which is stabilised by a strong intra-
3b
R = H
a
12b
R = Ac
Scheme 6. Reagents and conditions: (a) Ac2O, NEt3, DMAP, rt, 16 h,
98%; (b) H2, 20% Pd(OH)2–C, methanol, 4 d.
Ph
NHAc
P(O)(OEt)2
NH2
H
H
b
P(O)(OEt)2
OH
(1S,2R)-2
N
P(O)(OEt)2
+
Me
Me
Me
OH
OR
3a
R = H
(1S,2R)-14
a
12a
R = Ac
Scheme 5. Reagents and conditions: (a) Ac2O, NEt3, DMAP, rt, 16 h, 89%; (b) H2, 20% Pd(OH)2–C, methanol, 4 d.

A. E. Wro´blewski, J. Drozd / Tetrahedron: Asymmetry 18 (2007) 1134–1141
1137
molecular H-bond (Nꢁ ꢁ ꢁH–O). This conclusion is further
supported by the observation of a large vicinal PCOH cou-
pling (22.2 Hz), which arises from the almost antiperipla-
nar disposition of the hydrogen and phosphorus atoms in
the P–C–O–H unit. In this conformation, the bulky dieth-
oxyphosphoryl group is located far away from the 1-phen-
ylethyl moiety. Furthermore, analyses of the vicinal H–H,
H–P and C–P coupling constants led us to conclude that
(1R,2R)-14 and (1S,2R)-14 exist in preferred conforma-
tions, which are stabilised by strong intramolecular H-
bonds (Fig. 2).
The absolute configuration at C-1 in phosphonate 4b was
assigned in the following way. After acetylation of 4b,
the hydrogenolysis of the crude acetate 16b gave 2-acet-
amidophosphonate (1S,2S)-14 as a single product (Scheme
9). This could only happen, if acetate (1S,2S)-15b was
formed as an intermediate in the intramolecular acetyl
transfer.
O
H
Ph
H
N
O
H
H
4b
N
P(O)(OEt)2
OAc
16b
(1S,2S)-14
Me
H
Me
H
P(O)(OEt)2
O
OEt
OEt
O
EtO
EtO
O
EtO
EtO
Me
(1S,2S)-15b
H
N
H
N
Me
O
Me
P
P
H
P
H
H
C
H
C
Scheme 9. Configurational assignment of phosphonate 4b.
C
H
O
O
H
O
H
H
O
H
H
∗
N
R
Me
H
3. Conclusions
Figure 2. The preferred conformations of phosphonates 3a, (1R,2R)-14
and (1S,2R)-14.
The reaction of aziridine aldehyde (2R,10S)-7 with diethyl
phosphite led to a separable mixture of the respective aziri-
dine hydroxyphosphonates 3a and 3b, while from aldehyde
(2S,10S)-7, only small quantities of the crystalline phospho-
nate 4b were isolated. For this reason phosphonylation of
the aziridine aldehyde (2S,10R)-10 was undertaken to pro-
vide enantiomers of 3a and 3b, phosphonates 11a and 11b.
Acetylation of hydroxyphosphonates 3b or 11b furnished
the corresponding acetates 12b or 13b, which were sub-
jected to hydrogenolysis to give cleanly 2-acet-
amidophosphonates (1R,2R)-14 or (1S,2S)-14. Acetates
12a or 13a obtained from hydroxyphosphonates 3a or
11a were transformed hydrogenolytically into mixtures of
2-acetamidophosphonates (1S,2R)-14 or (1R,2S)-14 and
2-aminophosphonates (1S,2R)-2 or (1R,2S)-2.
Hydrogenolyses of acetates 12b or 13b led exclusively to 2-
acetamidophosphonates (1R,2R)-14 or (1S,2S)-14. On the
other hand, from acetates 12a or 13a mixtures of 2-acet-
amidophosphonates (1S,2R)-14 or (1R,2S)-14 and 2-amino-
phosphonates (1S,2R)-2 or (1R,2S)-2 were formed.
Undoubtedly, acetate 12b was first transformed into O-ace-
tate (1R,2R)-15b (Scheme 7), in which the intramolecular
acetyl transfer is energetically highly favourable due to lack
of spatial interactions of the methyl and O,O-diethylphos-
phoryl groups. However, this is not the case for the
O-acetate (1S,2R)-15a (Scheme 8), in which severe repul-
sions of the bulky groups are expected to make the intra-
molecular transacetylation less feasible. The formation of
significant amounts of (1S,2R)-2 can be explained by
assuming that the acetyl group is transferred in an intermo-
lecular process, in which methanol acts as a competing
nucleophile.
4. Experimental
1H NMR spectra were recorded with a Varian Mercury-
300 spectrometer; chemical shifts d in ppm with respect
to TMS; coupling constants J in Hz. 13C and 31P NMR
spectra were recorded on a Varian Mercury-300 machine
at 75.5 and 121.5 MHz, respectively. IR spectral data were
measured on an Infinity MI-60 FT-IR spectrometer. Melt-
ing points were determined on a Boetius apparatus and are
uncorrected. Elemental analyses were performed by the
Microanalytical Laboratory of this Faculty on a Perkin
Elmer PE 2400 CHNS analyser. Polarimetric measure-
ments were conducted on a Perkin Elmer 241 MC
apparatus. The following absorbents were used: column
chromatography, Merck silica gel 60 (70–230 mesh);
O
H
H
N
O
(1R,2R)-14
12b
H
P(O)(OEt)2
Me
H
(1R,2R)-15b
Scheme 7. Intermediate for the intramolecular acetyl transfer in (1R,2R)-
12b.
analytical TLC, Merck TLC plastic sheets silica gel 60 F254
.
O
H
H
4.1. Diethyl (S)- and (R)-hydroxy{(R)-1-[(S)-1-phenylethyl]-
aziridin-2-yl}methylphosphonates 3a and 3b
N
O
+
(1S,2R)-2
12a
(1S,2R)-14
H
H
Me
P(O)(OEt)2
A mixture of the crude aldehyde (2R,10S)-6 (0.787 g,
4.49 mmol) and diethyl phosphite (0.550 mL, 4.27 mmol)
containing triethylamine (0.063 mL, 0.45 mmol) was left
at room temperature for 3 days. The crude product was
(1S,2R)-15a
Scheme 8. Intermediate for the intramolecular acetyl transfer in (1S,2R)-
12a.

1138
A. E. Wro´blewski, J. Drozd / Tetrahedron: Asymmetry 18 (2007) 1134–1141
chromatographed on a silica gel column with chloroform–
methanol (100:1 to 50:1, v/v) to give phosphonates 3a
(0.393 g, 29%) and 3b (0.499 g, 37%), both as slightly yel-
lowish oils.
1H, HCCH3), 2.15 (dddd, J = 6.6, 3.6, 3.6, 3.3 Hz, 1H,
HCN), 1.78 (dd, J = 3.6, 0.9 Hz, 1H, HaCHb), 1.50 (d,
J = 6.6 Hz, 3H, HCCH3), 1.44 (d, J = 6.6 Hz, 1H, HaCHb),
1.39 and 1.38 (2 · t, J = 7.1 Hz, 6H, CH3CH2OP). 13C
NMR (75.5 MHz, CDCl3): d = 144.2, 128.5, 127.3, 126.8,
69.0, 67.3 (d, J = 163.8 Hz, CP), 63.0 and 62.9 (2 · d,
J = 7.6 Hz, CH3CH2OP), 39.0 (d, J = 5.3 Hz, CCP), 30.3
(d, J = 6.8 Hz, CCCP), 23.7, 16.9 and 16.9 (2 · d,
J = 5.4 Hz, CH3CH2OP). 31P NMR (121.5 MHz, CDCl3):
d = 22.54. Anal. Calcd for C15H24NO4P: C, 57.50; H,
7.72; N, 4.47. Found: C, 57.71; H, 8.00; N, 4.66.
4.1.1. Diethyl (S)-hydroxy{(R)-1-[(S)-1-phenylethyl]aziridin-
2-yl}methylphosphonate 3a. IR (film): m = 3293, 3061,
2980, 2930, 1449, 1237, 1027, 756, 702 cmꢀ1
.
20
½aꢂD ¼ ꢀ15:2 (c 1.46, CHCl3). 1H NMR (300 MHz,
CDCl3): d = 7.35–7.23 (m, 5H), 4.20–4.08 (m, 4H,
CH2OP), 3.96 (dd, J = 5.4, 2.7 Hz, 1H, HCP), 3.56 (br d,
J = 22.2 Hz, 1H, HO), 2.72 (q, J = 6.6 Hz, 1H, HCCH3),
2.18 (d, J = 3.6 Hz, 1H, HaCHb), 1.97 (dddd, J = 6.3,
3.6, 2.7, 1.2 Hz, 1H, HCN), 1.59 (d, J = 6.3 Hz, 1H,
HaCHb), 1.43 (d, J = 6.6 Hz, 3H, HCCH3), 1.32 and 1.31
(2 · t, J = 7.1 Hz, 6H, CH3CH2OP). 13C NMR
(75.5 MHz, CDCl3): d = 143.8, 128.6, 127.4, 126.5, 69.0,
64.1 (d, J = 170.4 Hz, CP), 63.0 and 62.6 (2 · d,
J = 6.9 Hz, CH3CH2OP), 37.2 (d, J = 3.7 Hz, CCP), 29.8
(d, J = 3.1 Hz, CCCP), 23.3, 16.8 and 16.7 (2 · d,
J = 6.0 Hz, CH3CH2OP). 31P NMR (121.5 MHz, CDCl3):
d = 22.77. Anal. Calcd for C15H24NO4P: C, 57.50; H,
7.72; N, 4.47. Found: C, 57.21; H, 8.01; N, 4.29.
4.3. Diethyl (R)- and (S)-hydroxy{(S)-1-[(R)-1-phenylethyl]-
aziridin-2-yl}methylphosphonates 11a and 11b
A mixture of crude aldehyde (2S,10R)-6 (1.34 g, 7.66 mmol)
and diethyl phosphite (0.938 mL, 7.28 mmol) containing
triethylamine (0.107 mL, 0.766 mmol) was left at room
temperature for 3 days. The crude product was chromato-
graphed on a silica gel column with chloroform–methanol
(100:1 to 50:1, v/v) to give phosphonates 11a (0.973 g, 43%)
and 3 b (0.790 g, 35%), both as colourless oils.
4.3.1. Diethyl (R)-hydroxy{(S)-1-[(R)-1-phenylethyl]aziri-
20
4.1.2. Diethyl (R)-hydroxy{(R)-1-[(S)-1-phenylethyl]aziri-
din-2-yl}methylphosphonate 3b. IR (film): m = 3305,
din-2-yl}methylphosphonate 11a. ½aꢂD ¼ þ16:5 (c 1.5,
CHCl3). Anal. Calcd for C15H24NO4P: C, 57.50; H, 7.72;
N, 4.47. Found: C, 57.28; H, 7.85; N, 4.40.
3059, 2981, 2929, 1449, 1233, 1052, 757, 701 cmꢀ1
.
20
½aꢂD ¼ ꢀ42:7 (c 1.27, CHCl3). 1H NMR (300 MHz,
CDCl3): d = 7.39–7.23 (m, 5H), 4.11–3.92 (m, 4H,
CH2OP), 3.47 (ddd, J = 7.2, 6.3, 5.1 Hz, 1H, HCP), 2.60
(q, J = 6.6 Hz, 1H, HCCH3), 2.15 (dd, J = 14.7, 5.1 Hz,
1H, HO), 1.98 (d, J = 3.3 Hz, 1H, HaCHb), 1.95 (dddd,
J = 6.6, 6.3, 6.3, 3.3 Hz, 1H, HCN), 1.64 (d, J = 6.3 Hz,
1H, HaCHb), 1.44 (d, J = 6.6 Hz, 3H, HCCH3), 1.26
and 1.23 (2 · t, J = 7.1 Hz, 6H, CH3CH2OP). 13C NMR
(75.5 MHz, CDCl3): d = 143.9, 128.7, 127.6, 127.1, 69.5
(d, J = 165.3 Hz, CP), 69.2, 62.8 and 62.6 (2 · d,
J = 6.9 Hz, CH3CH2OP), 38.8 (d, J = 6.0 Hz, CCP), 31.9
(d, J = 3.6 Hz, CCCP), 23.0, 16.7 (d, J = 5.4 Hz,
CH3CH2OP). 31P NMR (121.5 MHz, CDCl3): d = 22.20.
Anal. Calcd for C15H24NO4P: C, 57.50; H, 7.72; N, 4.47.
Found: C, 57.25; H, 8.00; N, 4.35.
4.3.2. Diethyl (S)-hydroxy{(S)-1-[(R)-1-phenylethyl]aziridin-
20
2-yl}methylphosphonate 11b. ½aꢂD ¼ þ43:8 (c 1.28,
CHCl3). Anal. Calcd for C15H24NO4P: C, 57.50; H, 7.72;
N, 4.47. Found: C, 57.21; H, 8.01; N, 4.38.
4.4. Acetylation of phosphonates 3a, 3b, 11a and 11b
(general procedure)
A mixture of the phosphonate (0.313 g, 1.00 mmol), acetic
anhydride (0.283 mL, 3.00 mmol) and triethylamine
(0.460 mL, 3.30 mmol) containing DMAP (0.012 g,
0.1 mmol) was left at room temperature for 16 h. The crude
product was diluted with methylene chloride (20 mL). A
solution was washed with water (6 · 10 mL), dried over
MgSO4, concentrated in vacuo and the residue was chro-
matographed on a silica gel column with hexanes–isopro-
panol (50:1 to 20:1, v/v) to give pure acetates.
4.2. Diethyl (R)- and (S)-hydroxy{(S)-1-[(S)-1-phenylethyl]-
aziridin-2-yl}methylphosphonates 4a and 4b
A
mixture of crude aldehyde (2S,10S)-6 (0.415 g,
2.37 mmol) and diethyl phosphite (0.290 mL, 2.25 mmol)
containing triethylamine (0.033 mL, 0.24 mmol) was left
at room temperature for 3 days. The crude product was
chromatographed on a silica gel column with chloroform–
methanol (100:1 to 50:1, v/v) to give several fractions con-
taining various mixtures of phosphonates 4a and 4b. The
fractions consisting of oil and crystals were collected and
recrystallised from methylene chloride–hexanes to give 4b
(0.097 g, 14%) as short white needles; mp 104–105 ꢁC. IR
4.4.1. Diethyl (S)-acetoxy{(R)-1-[(S)-1-phenylethyl]aziridin-
2-yl}methylphosphonate 12a. From phosphonate 3a
(0.343 g, 1.09 mmol), acetate 12a (0.346 g, 89%) was ob-
tained as a colourless oil. IR (film): m = 2980, 2928, 1751,
20
1449, 1220, 1023, 757, 701 cmꢀ1. ½aꢂD ¼ þ4:5 (c 1.3,
1
CHCl3). H NMR (300 MHz, CDCl3): d = 7.35–7.21 (m,
5H), 5.25 (dd, J = 9.9, 3.9 Hz, 1H, HCP), 4.11–3.91 (m,
4H, CH2OP), 2.52 (q, J = 6.6 Hz, 1H, HCCH3), 2.08 (d,
J = 0.3 Hz, 3H), 2.05 (d, J = 3.6 Hz, 1H, HaCHb), 1.89
(dddd, J = 6.3, 5.7, 3.9, 3.6 Hz, 1H, HCN), 1.43 (d,
J = 6.3 Hz, 1H, HaCHb), 1.37 (d, J = 6.6 Hz, 3H,
HCCH3), 1.27 and 1.22 (2 · t, J = 7.1 Hz, 6H,
CH3CH2OP). 13C NMR (75.5 MHz, CDCl3): d = 169.4
(d, J = 6.8 Hz, COCP), 143.9, 128.3, 127.1, 127.0, 70.0,
(film): m = 3274, 3065, 2979, 2931, 1455, 1242, 1017, 758,
20
706 cmꢀ1. ½aꢂD ¼ ꢀ54:7 (c 1.06, CHCl3). 1H NMR
(300 MHz, CDCl3): d = 7.37–7.24 (m, 5H), 4.29–4.19 (m,
4H, CH2OP), 3.77 (ddd, J = 7.5, 6.3, 3.6 Hz, 1H, HCP),
3.24 (dd, J = 6.9, 6.3 Hz, 1H, HO), 2.67 (q, J = 6.6 Hz,

A. E. Wro´blewski, J. Drozd / Tetrahedron: Asymmetry 18 (2007) 1134–1141
1139
66.8 (d, J = 167.6 Hz, CP), 63.1 and 62.7 (2 · d,
m = 3268, 2986, 2936, 1631, 1557, 1440, 1216, 1053 cmꢀ1
.
20
J = 6.6 Hz, CH3CH2OP), 36.5 (d, J = 4.5 Hz, CCP), 30.5
(d, J = 4.5 Hz, CCCP), 23.6, 20.9, 16.7 and 16.6 (2 · d,
J = 5.7 Hz, CH3CH2OP). 31P NMR (121.5 MHz, CDCl3):
d = 19.11. Anal. Calcd for C17H26NO5P: C, 57.46; H,
7.37; N, 3.94. Found: C, 57.17; H, 7.13; N, 3.69.
½aꢂD ¼ þ37:8 (c 1.04, CHCl3). 1H NMR (300 MHz,
CDCl3): d = 6.49 (d, J = 7.2 Hz, 1H, HN), 4.80 (dd,
J = 7.5, 7.2 Hz, 1H, HO), 4.36 (dddq, J = 20.7, 7.2, 2.4,
6.9 Hz, 1H, HCCP), 4.24–4.13 (m, 4H, CH2OP), 4.00
(ddd, J = 9.3, 7.5, 2.4 Hz, 1H, HCP), 2.01 (s, 3H), 1.36
and 1.34 (2 · t, J = 7.2 Hz, 6H, CH3CH2OP), 1.33 (d,
J = 6.9 Hz, 3H, CH3CH). 13C NMR (75.5 MHz, CDCl3):
d = 171.4, 71.6 (d, J = 158.6 Hz, CP), 63.5 and 62.8
(2 · d, J = 6.8 Hz, CH3CH2OP), 48.6 (d, J = 4.5 Hz,
CCP), 23.4, 16.7 and 16.7 (2 · d, J = 6.0 Hz, CH3CH2OP),
16.5 (s, CCCP). 31P NMR (121.5 MHz, CDCl3): d = 22.18.
Anal. Calcd for C9H20NO5P: C, 42.69; H, 7.96; N, 5.53.
Found: C, 42.41; H, 7.80; N, 5.27.
4.4.2. Diethyl (R)-acetoxy{(R)-1-[(S)-1-phenylethyl]aziridin-
2-yl}methylphosphonate 12b. From phosphonate 3b
(0.428 g, 1.37 mmol), acetate 12b (0.485 g, 98%) was ob-
tained as a colourless oil. IR (film): m = 2980, 2929, 1745,
20
1450, 1224, 1029, 759, 702 cmꢀ1. ½aꢂD ¼ ꢀ31:2 (c 1.28,
1
CHCl3). H NMR (300 MHz, CDCl3): d = 7.33–7.21 (m,
5H), 4.76 (dd, J = 10.5, 9.0 Hz, 1H, HCP), 4.15–4.05 (m,
4H, CH2OP), 2.42 (q, J = 6.6 Hz, 1H, HCCH3), 2.06 (d,
J = 3.3 Hz, 1H, HaCHb), 1.87 (dddd, J = 9.0, 6.6, 3.3,
3.0 Hz, 1H, HCN), 1.69 (s, 3H), 1.67 (d, J = 6.6 Hz, 1H,
HaCHb), 1.40 (d, J = 6.6 Hz, 3H, HCCH3), 1.29 and 1.28
(2 · t, J = 7.2 Hz, 6H, CH3CH2OP). 13C NMR
(75.5 MHz, CDCl3): d = 169.2 (d, J = 5.1 Hz, COCP),
144.4, 128.4, 127.2, 127.1, 70.9 (d, J = 167.6 Hz, CP),
70.2 (d, J = 1.5 Hz, CNCCP), 63.2 and 63.0 (2 · d,
J = 6.8 Hz, CH3CH2OP), 37.8 (d, J = 7.6 Hz, CCP), 32.2
(s, CCCP), 23.2, 20.7, 16.8 and 16.7 (2 · d, J = 6.0 Hz,
CH3CH2OP). 31P NMR (121.5 MHz, CDCl3): d = 18.45.
Anal. Calcd for C17H26NO5P: C, 57.46; H, 7.37; N, 3.94.
Found: C, 57.24; H, 7.60; N, 3.73.
4.5.1.2. Diethyl (1S,2R)-2-amino-1-hydroxypropylphos-
phonate (1S,2R)-2. IR (film): m = 3322, 2985, 1625,
20
1521, 1340, 1222, 1049 cmꢀ1
.
½aꢂD ¼ þ5:9 (c 1.08,
1
CH3OH); H NMR (300 MHz, CDCl3): d = 6.2–4.8 (br s,
7H, H2N, HO, 2H2O), 4.59 (dd, J = 12.9, 2.4 Hz, 1H,
HCP), 4.28–4.16 (m, 4H, CH2OP), 3.82 (ddq, J = 2.4,
2.1, 6.9 Hz, 1H, HCCP), 1.49 (d, J = 6.9 Hz, 3H, CH3CH),
1.35 (t, J = 7.2 Hz, 6H, CH3CH2OP). 13C NMR
(75.5 MHz, CDCl3): d = 68.5 (d, J = 164.6 Hz, CP), 63.7
and 63.3 (2 · d, J = 6.8 Hz, CH3CH2OP), 49.3 (d,
J = 9.1 Hz, CCP), 16.7 and 16.7 (2 · d, J = 6.0 Hz,
CH3CH2OP), 15.5 (d, J = 2.3 Hz, CCCP). 31P NMR
(121.5 MHz, CDCl3): d = 22.76. Anal. Calcd for
C7H18NO4PÆ2H2O: C, 34.01; H, 8.97; N, 5.67. Found: C,
34.30; H, 8.67; N, 5.43.
4.4.3. Diethyl (R)-acetoxy{(S)-1-[(R)-1-phenylethyl]aziridin-
2-yl}methylphosphonate 13a. From phosphonate 11a
(0.553 g, 1.77 mmol), acetate 13a (0.525 g, 84%) was ob-
20
tained as a colourless oil. ½aꢂD ¼ ꢀ5:7 (c 1.87, CHCl3).
4.5.2. Hydrogenolysis of acetate 12b. From acetate 12b
(0.476 g, 1.34 mmol), diethyl (1R,2R)-2-acetamido-1-
hydroxypropylphosphonate (1R,2R)-14 (0.230 g, 68%)
was obtained as an amorphous solid.
Anal. Calcd for C17H26NO5P: C, 57.46; H, 7.37; N, 3.94.
Found: C, 57.31; H, 7.59; N, 3.76.
4.4.4. Diethyl (S)-acetoxy{(S)-1-[(R)-1-phenylethyl]aziridin-
2-yl}methylphosphonate 13b. From phosphonate 11b
4.5.2.1. Diethyl (1R,2R)-2-acetamido-1-hydroxypropyl-
phosphonate (1R,2R)-14. Mp 75–76 ꢁC. IR (KBr):
(0.308 g, 0.983 mmol), acetate 13b (0.299 g, 86%) was ob-
20
tained as a colourless oil. ½aꢂD ¼ þ35:3 (c 2.13, CHCl3).
m = 3340, 3239, 2986, 2924, 1648, 1541, 1378, 1221,
20
Anal. Calcd for C17H26NO5P: C, 57.46; H, 7.37; N, 3.94.
Found: C, 57.74; H, 7.62; N, 3.91.
1056 cmꢀ1. ½aꢂD ¼ þ21:5 (c 1.00, CHCl3). 1H NMR
(300 MHz, CDCl3): d = 6.73 (d, J = 7.2 Hz, 1H, HN),
5.05 (dd, J = 8.1, 5.4 Hz, 1H, HO), 4.29 (dddq, J = 10.5,
7.2, 3.6, 6.9 Hz, 1H, HCCP), 4.23–4.11 (m, 4H, CH2OP),
3.90 (ddd, J = 8.7, 8.1, 3.6 Hz, 1H, HCP), 1.98 (s, 3H),
1.35 and 1.35 (2 · t, J = 7.2 Hz, 6H, CH3CH2OP), 1.34
(d, J = 6.9 Hz, 3H, CH3CH). 13C NMR (75.5 MHz,
CDCl3): d = 170.4, 71.0 (d, J = 161.6 Hz, CP), 63.2 and
63.1 (2 · d, J = 6.8 Hz, CH3CH2OP), 46.9 (d, J = 1.5 Hz,
CCP), 23.5, 17.9 (d, J = 11.3 Hz, CCCP), 16.7 (d,
J = 5.3 Hz, CH3CH2OP). 31P NMR (121.5 MHz, CDCl3):
d = 22.81. Anal. Calcd for C9H20NO5P: C, 42.69; H,
7.96; N, 5.53. Found: C, 42.93; H, 8.20; N, 5.51.
4.5. Hydrogenolysis of acetates 12a, 12b, 13a and 13b
(general procedure)
A solution of acetates 12a, 12b, 13a or 13b (0.355 g,
1.00 mmol) in methanol (5 mL) was kept under an atmo-
spheric pressure of hydrogen over 20% Pd(OH)2–C
(20 mg) at room temperature for 3 days. The suspension
was filtered through a layer of Celite. The solution was
concentrated and chromatographed on a silica gel column
with chloroform–methanol (first, 20:1 and later 3:1, v/v).
4.5.1. Hydrogenolysis of acetate 12a. From acetate 12a
(0.313 g, 0.881 mmol), diethyl (1S,2R)-2-acetamido-1-
hydroxypropylphosphonate (1S,2R)-14 (0.077 g, 38%)
was separated as a white amorphous solid followed by
4.5.3. Hydrogenolysis of acetate 13a. From acetate 13a
(0.367 g, 1.03 mmol), diethyl (1R,2S)-2-acetamido-1-
hydroxypropylphosphonate (1R,2S)-14 (0.072 g, 31%)
was separated as a white amorphous solid followed by
diethyl
(1S,2R)-2-amino-1-hydroxypropylphosphonate
diethyl
(1R,2S)-2-amino-1-hydroxypropylphosphonate
(1S,2R)-2 (0.049 g, 24%) as a colourless oil.
(1R,2S)-2 (0.076 g, 33%) as a colourless oil.
4.5.1.1. Diethyl (1S,2R)-2-acetamido-1-hydroxypropyl-
phosphonate (1S,2R)-14. Mp 86–87 ꢁC. IR (KBr):
4.5.3.1. Diethyl (1R,2S)-2-acetamido-1-hydroxypropyl-
phosphonate (1R,2S)-14. Mp 86–87 ꢁC. ½aꢂD ¼ ꢀ38:2 (c
20

1140
A. E. Wro´blewski, J. Drozd / Tetrahedron: Asymmetry 18 (2007) 1134–1141
5. Palacios, F.; Alonso, C.; de los Santos, J. M. In Enantiose-
lective Synthesis of b-Amino Acids; Juaristi, E., Soloshonok,
V. A., Eds.; Wiley-Interscience, 2005, Chapter 13.
6. Palacios, F.; Alonso, C.; de los Santos, J. M. Curr. Org.
Chem. 2004, 8, 1481–1496.
7. Horiguchi, M.; Kandatsu, M. Nature 1959, 184, 901–902.
8. Hilderbrand, R. L. The Role of Phosphonates in Living
Systems; CRC Press: Boca Raton, 1983.
1.12, CHCl3). Anal. Calcd for C9H20NO5P: C, 42.69; H,
7.96; N, 5.53. Found: C, 42.54; H, 8.22; N, 5.53.
4.5.3.2. Diethyl (1R,2S)-2-amino-1-hydroxypropylphos-
20
phonate (1R,2S)-2. ½aꢂD ¼ ꢀ5:8 (c 1.01, CH3OH). Anal.
Calcd for C7H18NO4PÆ2H2O: C, 34.01; H, 8.97; N, 5.67.
Found: C, 34.24; H, 9.15; N, 5.59.
9. Kinney, W. A.; Lee, N. E.; Garrison, D. T.; Podlesny, E. J.,
Jr.; Simmonds, J. T.; Bramlett, D.; Notvest, R. R.; Kowal,
D. M.; Tasse, R. P. J. Med. Chem. 1992, 35, 4720–
4726.
10. Ong, J.; Kerr, D. I. B.; Abbenante, J.; Prager, R. W. Eur. J.
Pharmacol. 1991, 205, 319–322.
4.5.4. Hydrogenolysis of acetate 13b. From acetate 13b
(0.252 g, 0.709 mmol), diethyl (1S,2S)-2-acetamido-1-
hydroxypropylphosphonate (1S,2S)-14 (0.128 g, 71%) was
obtained as a white amorphous solid.
´ ´
11. Iturrioz, X.; Vazeux, G.; Celerier, J.; Corvol, P.; Llorens-
`
Cortes, C. Biochemistry 2000, 39, 3061–3068.
4.5.4.1. Diethyl (1S,2S)-2-acetamido-1-hydroxypropyl-
20
12. Verbruggen, C.; De Craecker, S.; Rajan, P.; Jiao, X.-Y.;
Borloo, M.; Smith, K.; Fairlamb, A. H.; Haemers, A. Bioorg.
Med. Chem. Lett. 1996, 6, 253–258.
13. Chevrier, C.; Le Noue¨n, D.; Defoin, A.; Tarnus, C. Eur. J.
Org. Chem. 2006, 2384–2392.
phosphonate (1S,2S)-14. Mp 75–76 ꢁC. ½aꢂD ¼ ꢀ19:4
(c 0.69, CHCl3). Anal. Calcd for C9H20NO5P: C, 42.69;
H, 7.96; N, 5.53. Found: C, 42.83; H, 8.21; N, 5.51.
4.6. Diethyl (1S,2S)-2-acetamido-1-hydroxypropylphospho-
nate (1S,2S)-14
14. Schweitzer, B. A.; Loida, P. J.; Thompson-Mize, R. L.;
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Hataye, J. M.; Wang, V. R.; Shelton, E. J.; Elrod, K.; Janc, J.
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Hydroxyphosphonate 4b (0.040 g, 0.13 mmol) was acetyl-
ated as described in Section 4.4 to give the crude acetate
16b (0.045 g, 100%). 1H NMR (300 MHz, CDCl3):
d = 7.29–7.15 (m, 5H), 4.82 (dd, J = 9.9, 9.0 Hz, 1H,
HCP), 4.17–4.05 (m, 4H, CH2OP), 2.39 (q, J = 6.6 Hz,
1H, HCCH3), 2.12 (s, 3H), 1.93 (dddd, J = 9.0, 6.3, 3.6,
2.7 Hz, 1H, HCN), 1.75 (d, J = 3.6 Hz, 1H, HaCHb), 1.45
(d, J = 6.3 Hz, 1H, HaCHb), 1.31 (d, J = 6.6 Hz, 3H,
HCCH3), 1.28 and 1.25 (2 · t, J = 7.2 Hz, 6H,
CH3CH2OP). 13C NMR (75.5 MHz, CDCl3): d = 169.3
(d, J = 4.6 Hz, COCP), 144.1, 128.4, 127.2, 126.9, 71.1 (d,
J = 166.1 Hz, CP), 69.4 (s, CNCCP), 63.1 and 63.0
(2 · d, J = 6.9 Hz, CH3CH2OP), 38.6 (d, J = 6.8 Hz,
CCP), 32.0 (s, CCCP), 23.5, 21.0, 16.8 and 16.7 (2 · d,
J = 5.4 Hz, CH3CH2OP). 31P NMR (121.5 MHz, CDCl3):
d = 18.53.
Acetate 16b was hydrogenolysed according to the general
procedure (Section 4.5) to afford phosphonate (1S,2S)-14
(0.029 g, 91%), which in all respects was identical to the
compound described in Section 4.5.4.1.
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`
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Acknowledgment
25. Bird, J. E.; Waldron, T. L.; Little, D. K.; Asaad, M. M.;
Dorso, C. R.; DiDonato, G.; Norman, J. A. Biochem.
Biophys. Res. Commun. 1992, 182, 224–231.
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2992.
´ ´
Financial support from the Medical University of Łodz
(503-3014-1) is gratefully acknowledged.
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