Regio- and stereoselective synthesis of 2-amino-1-hydroxy-2-aryl ethylphosphonic esters

Article abstract of DOI:10.1016/S0040-4039(00)01722-6

A highly regio- and diastereoselective synthesis of 2-amino-1-hydroxy-2-aryl ethylphosphonic esters was achieved by opening trans 1,2-epoxy-2-aryl ethylphosphonic esters with 28% NH(3(aq.)) in methanol. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01722-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9781–9785
Regio- and stereoselective synthesis of
2-amino-1-hydroxy-2-aryl ethylphosphonic esters
Henri-Jean Cristau,a,* Jean-Luc Pirat,a,* Marcin Draga,b and Pawel Kafarskib
aLaboratoire de Chimie Organique, UMR 5076 du CNRS, Ecole Nationale Supe´rieure de Chimie de Montpellier,
8 Rue de l’Ecole Normale, 34296 Montpellier Cedex 5, France
bInstitute of Organic Chemistry, University of Technology, Wybrzeze Wyspianskiego 27, 50-370 Wroclaw, Poland
Received 29 August 2000; accepted 29 September 2000
Abstract
A highly regio- and diastereoselective synthesis of 2-amino-1-hydroxy-2-aryl ethylphosphonic esters was
achieved by opening trans 1,2-epoxy-2-aryl ethylphosphonic esters with 28% NH3(aq.) in methanol. © 2000
Published by Elsevier Science Ltd.
Keywords: 2-amino-1-hydroxy-2-aryl ethylphosphonic esters; b-aminophosphonic esters; a-hydroxyphosphonic esters;
ammonolysis; 1,2-epoxyphosphonic esters.
Phosphonic acids with heteroatoms in the a and/or b positions have attracted considerable
interest because of their use as inhibitors of proteolytic enzymes, such as renin1 and human
immunodeficiency virus (HIV) protease,2 as agents affecting the growth of plants3 or as haptens
in the development of catalytic antibodies.4
The preparation of b-amino-a-hydroxyalkylphosphonic esters 4 can be accomplished in
different ways,5 but there are only two reports that mention the possibility of obtaining
2-amino-1-hydroxyethylphosphonic acids by the opening of 1,2-epoxyethylphosphonic esters6
and no papers record the opening of 1,2-epoxy-2-aryl ethylphosphonic esters.
Herein we report a quite general synthetic approach to compounds 4 starting from various
types of alkenylphosphonic esters 2, which are prepared in two ways according to the desired Z
or E stereochemistry (Scheme 1).
Standard Horner–Wittig reaction of the tetraethyl methylenebisphosphonate with aromatic
aldehydes carried out in an aqueous two-phase system affords the pure (E)-isomers of
vinylphosphonates 2 in good yields7 (Table 1). The same reaction carried out with alkyl or
cycloalkyl aldehydes in toluene with sodium hydride also gave the desired (E)-isomer of 28
(Table 1).
* Corresponding authors. Fax: 33-(0)4-67-14-43-19; e-mail: cristau@cit.enscm.fr; pirat@cit.enscm.fr
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01722-6

9782
Scheme 1. Preparation of compounds 2, 3 (Table 1) and 4 (Table 2)
Table 1
Preparation of alkenylphosphonic esters 2 and 1,2-epoxyethylphosphonic esters 3a
Alkenylphosphonates esters 2
31P NMR
1,2-Epoxyethylphosphonic esters 3
R
Compound Yield (%)
Compound Yield (%)
31P NMR
3JHH
(CDCl3,
ppm)
(CDCl3, ppm)
(HC-HCP,
Hz)
Phenyl
2a (E)
2b (E)
2c (E)
2d (E)
2e (E)
68
87
70
92
80
83
70
68
63
58
20.1
20.0
20.2
20.6
21.1
20.2
16.5
17.7
19.4
20.4
3a (trans)
3b (trans)
3c (trans)
3d (trans)
3e (trans)
3f (trans)
3a (cis)
3g (cis)
–
75
76
64
85
78
63
73
58
–
17.2
17.2
17.3
17.4
18.1
17.2
17.5
19.6
–
2.4
2.5
2.3
2.3
2.4
2.3
4.6
4.5
–
o-Tolyl
m-Tolyl
p-Tolyl
o-Anisyl
a-Naphtyl 2f (E)
Phenyl
n-Butyl
n-Butyl
c-Hexyl
2a (Z)
2g (Z)
2g (E)
2h (E)
–
–
–
–
a All alkenylphosphonic esters 2 and 1,2-epoxyethylphosphonic esters 3 were identified satisfactorily by their 1H and
13C NMR and also by comparison with literature data.
(Z)-Isomers of vinylphosphonate esters were obtained by hydrogenation of appropriate
alkynylphosphonate 1a catalyzed by Pd (Lindlar) in MeOH9 (Table 1).
Phosphonic esters 2E and 2Z were converted into the corresponding trans or cis isomers of
1,2-epoxyethylphosphonic esters 3 by the reaction of 2 with dioxirane in a two-phase system
according to a previously developed procedure10 (Table 1). Unfortunately, this method gave no
satisfactory results for the (E)-isomers of b-alkylsubstituted vinylphosphonates 2g and 2h.
Reaction of 3 trans with an 84-fold excess of ammonia (28% NH3(aq.)) in MeOH11 gave
practically always only one diastereoisomer of the desired product 4,12 as established by 31P
NMR.

9783
We have observed high regioselectivity (usually about 95%) for compounds 4 as well.13 The
position of the hydroxy group in the a position and the amino group in the b position was
confirmed by comparison of chemical shifts and coupling constants in 13C NMR spectra with
the data given in the literature for derivatives of compound 4a and some analogs,5 and
additionally with simulated values by an ACD-CNMR program.
Concerning the diastereoselectivity, the compounds 4, obtained from the 3 trans isomer, are
probably the unlike diastereoisomers, in agreement with the expected SN2 opening of the oxirane
by NH3, corroborated by the literature data of compounds 4.5
We have noticed also that the maximum conversion (usually 50–65%) into 4 (Table 2) was
reached after about 24 hours, as established by 31P NMR monitoring of the crude reaction
mixture. Prolongation of the reaction time because of uncompleted conversion of substrate 3
induces the decomposition of compound 4, so the reaction should be monitored by 31P NMR
and interrupted at the appropriate moment.
Table 2
Preparation of 2-amino-1-hydroxyethylphosphonic esters 4a
4
Reaction time (h)
Conversion (%) Yield (%)
31P NMR (CDCl3, ppm)
Stereoselectivity (u/l)
a
b
c
d
e
f
24
23
32
22
23
22
57
52
54
65
66
59
42
44
47
59
53
53
23.0
23.4
22.8
23.4
23.5/23.8
23.0
100:0
100:0
100:0
98:2
10:90
100:0
a All compounds were identified satisfactorily by their 1H and 13C NMR (comparing with simulated values of
chemical shifts using the ACD-CNMR program), IR and MS FAB (+).
The same procedure was applied toward (cis)-1,2-epoxyethylphosphonic esters 3, but the
reaction was very slow (more than 50 hours), not regioselective, and resulted in poor yields.14
In conclusion the ammonolysis of trans 1,2-epoxyethylphosphonic esters appears to be a
valuable synthetic method for the preparation of b-amino-a-hydroxy arylalkylphosphonic
derivatives in consideration of its simplicity, applicability and selectivity. The application of this
method towards trisubstituted 1,2-epoxyethylphosphonic esters is under investigation.
Acknowledgements
Marcin Drag is grateful to the Erasmus Program for the Ph.D. scholarship at the laboratory
of Professor H. J. Cristau at Ecole Nationale Superieure de Chimie de Montpellier.
References
1. (a) Dellaria Jr., F.; Maki, R. G.; Stein, H. H.; Cohen, J.; Whittern, D.; Marsh, K.; Hoffman, D. J.; Plattner, J.
J.; Perun, T. J. J. Med. Chem. 1990, 534–542. (b) Kafarski, P.; Lejczak, B. Phosphorus Sulfur Silicon 1991, 63,
193–215; Dhawan, B.; Redmore, D. Phosphorus Sulfur Silicon 1987, 32, 119–144.
2. Stowasser, B.; Budt, K.-H.; Jian-Qi, L.; Peyman, A.; Ruppert, D. Tetrahedron Lett. 1992, 33, 6625–6628.

9784
3. Kafarski, P.; Wieczorek, P.; Lejczak, B.; Gancarz, R.; Zygmunt, J. Bioorg. Med. Chem. Lett. 1996, 6, 2989–2992.
4. Smith III, A. B.; Taylor, C. M.; Benkovic, S. J.; Hirschmann, R. Tetrahedron Lett. 1994, 35, 6853–6856.
5. Thomas, A. A.; Sharpless, K. B. J. Org. Chem. 1999, 64, 8379–8385.
6. (a) Zygmunt, J.; Walkowiak, U.; Mastalerz, P. Pol. J. Chem. 1980, 54, 233–240; (b) Griffin, C. E.; Kundu, S. K.
J. Org. Chem. 1969, 34, 1532–1539.
7. Mikolajczyk, M.; Grzejszczak, S.; Midura, W.; Zatorski, A. Synthesis 1976, 396–398.
8. Waszkuc, W.; Janecki, T.; Bodalski, R. Synth. Commun. 1984, 1025–1027.
9. Lindlar, J.; Dubuis, R. Org. Synth. 1966, 46, 89–92.
10. Cristau, H. J.; Yangkou-Mbianda, X.; Gaze, A.; Beziat, Y.; Gasc, M. B. J. Organomet. Chem. 1998, 571,
189–193.
11. The synthesis of 2-amino-1-hydroxy-2-aryl ethylphosphonic esters—general procedure
Into a Schlenk flask equipped with magnetic stirrer was introduced 2 mmol of the appropriate trans 1,2-epoxy-2-
aryl ethylphosphonic ester, 10 ml (0.165 M) of 28% NH3(aq.) and 20 ml of MeOH. The flask was closed tightly
and the mixture was stirred intensively at room temperature. The progress of the reaction was monitored by 31P
NMR.
After completion of the reaction, NH3 and methanol were evaporated from the mixture and 10 ml of distilled
H2O was added to the residue. Extraction of the water phase was achieved by adding 10 ml Et2O, and then by
5×10 ml CHCl3. The combined organic layers were dried with MgSO4, filtered and the solvent was removed
under vacuum.
Column chromatography on SilicaGel (70–200 mesh/50 g) using a CH2Cl2/AcOEt gradient of 1:1 (150 ml),
followed by pure AcOEt (150 ml), and then MeOH/AcOEt (1:4) (200 ml) was used to obtain compound 4, which
was subsequently recrystallized from isopropanol.
12. Solvents and commercially available aldehydes were redistilled prior to use. Tetraethyl methylenebisphosphonate
was prepared according to the reported procedure.15 1H and 13C NMR spectra were recorded in CDCl3 at
200.132 and 50.32 MHz, respectively. 31P NMR spectra were recorded at 81.0 MHz in CDCl3. 31P NMR
chemical shifts are relative to 85% H3PO4. FT-IR spectra were recorded in the form of KBr disks using a
Perkin–Elmer 377 spectrometer. Mass spectrometry [FAB (+)] was performed at the University of Montpellier II
using a DX300-SX102 spectrometer.
1
4a: H NMR: l 1.11 (t, J=7.1 Hz, 3H), 1.26 (t, J=7.1 Hz, 3H), 2.68 (bs, 3H), 3.80–4.08 (m, 2H), 4.10–4.18 (m,
3H), 4.34 (dd, J=6.3 Hz, J=19.3 Hz, 1H), 7.25–7.46 (m, aromat., 5H); 13C NMR: l 16.37 (d, J=6.1 Hz), 16.6
(d, J=5.7 Hz), 57.49 (d, J=4.1 Hz), 62.34 (d, J=7.2 Hz), 63.06 (d, J=7.1 Hz), 71.88 (d, J=160.6 Hz), 127.9,
128.0, 128.36, 128.47, 128.61, 141.21 (d, J=5.6 Hz); MS FAB (+)=274.
1
4b: H NMR: l 1.09 (t, J=7.1 Hz, 3H), 1.28 (t, J=7.1 Hz, 3H), 2.39 (s, 3H), 2.90 (bs, 3H), 3.87 (m, 2H), 4.10
(m, 3H), 4.57 (dd, J=6.7 Hz, J=20.5 Hz, 1H), 7.12–7.58 (m, aromat., 4H); 13C NMR: l 16.28 (d, J=5.9 Hz),
16.52 (d, J=5.7 Hz), 19.63, 52.67, 62.33 (d, J=7.1 Hz), 63.07 (d, J=7.0 Hz), 70.76 (d, J=162 Hz), 126.22,
126.89, 127.49, 130.4, 136.3, 138.92; MS FAB (+)=288.
1
4c: H NMR: l 1.11 (t, J=7.1 Hz, 3H), 1.22 (t, J=7.1 Hz, 3H), 2.34 (s, 3H), 3.51 (bs, 3H), 3.66–4.41 (m, 6H),
7.10–7.28 (m, aromat., 4H); 13C NMR: l 16.36 (d, J=6.1 Hz), 16.58 (d, J=5.7 Hz), 57.35 (d, J=4.6 Hz), 62.44
(d, J=7.2 Hz), 63.2 (d, J=7.2 Hz), 71.4 (d, J=162.1 Hz), 125.03, 128.22, 128.46, 128.8, 138.08, 139.86, MS FAB
(+)=288.
1
4d: H NMR: l 1.13 (t, J=7.08 Hz, 3H), 1.25 (t, J=7.1 Hz, 3H), 2.33 (s, 3H), 2.74 (bs, 3H), 3.99 (m, 5H), 4.25
(dd, J=6.2 Hz, J=17.2 Hz, 1H), 7.14 (d, aromat., 2H, J=7.9 Hz); 7.29 (d, aromat., 2H, J=8.2 Hz); 13C NMR:
l 16.12 (d, J=6.1 Hz), 16.37 (d, J=5.8 Hz), 21.04, 56.69, 62.15 (d, J=7.0 Hz), 62.70 (d, J=6.9 Hz), 71.73 (d,
J=160.7 Hz), 127.58, 128.78, 136.92, 138.17; MS FAB (+)=288.
1
4e: H NMR: l 1.01 (t, J=7.1 Hz, 3H), 1.30 (t, J=7.1 Hz, 3H), 2.18 (bs, 3H), 3.73 (m, 2H), 3.85 (s, 3H), 4.15
(quin., 2H), 4.33 (dd, J=4.4 Hz, J=6.52 Hz, 1H), 4.58 (dd, J=6.6, J=26.0 Hz, 1H), 6.84–7.47 (m, aromat., 4H);
13C NMR: l 16.03 (d, J=6.0 Hz), 16.42 (d, J=5.6 Hz), 53.02, 55.3, 61.51(d, J=7.3 Hz), 62.83 (d, J=6.9 Hz),
69.71 (d, J=159.2 Hz), 110.4, 120.54, 127.98, 128.36, 129.16, 156.86; MS FAB (+)=304.
1
4f: H NMR: l 0.95 (t, J=7.0 Hz, 3H), 1.18 (t, J=7.0 Hz, 3H), 3.17 (bs, 3H), 3.7–4.26 (m, 5H), 4.50 (dd, J=6.0
Hz, J=17.9 Hz, 1H), 7.27–7.88 (m, aromat., 7H); 13C NMR: l 16.11 (d, J=5.9 Hz), 16.38 (d, J=5.7 Hz), 57.48
(d, J=4.4 Hz), 62.27 (d, J=7.1 Hz), 62.83 (d, J=7.2 Hz), 71.72 (d, J=160.9 Hz), 125.77, 125.86, 126.15, 128.0,
128.4, 133.09 (d, J=14.2), 138.96 (d, J=6.6 Hz); MS FAB (+)=324.

9785
13. Three phosphorus by-products always accompanied the desired product 4. Two of them were recognized as di-
and monoethylesters of phosphonic acid and one because of very small yield (ꢀ5%) was unidentified.
14. Usually between 7 and 11 phosphorus by-products were observed and the yield of the desired product 4 was
about 10%.
15. Czekanski, T.; Gross, H.; Costisella, B. J. Prakt. Chem. 1982, 324, 537–544.
.