Asymmetric synthesis of α-amino phosphonic acids by diastereoselective addition of trimethyl phosphite onto chiral oxazolidines

Article abstract of DOI:10.1021/jo960020c

A simple and general asymmetric synthesis of α-amino phosphonic acids is described. The method involves the highly selective addition of trialkyl phosphite onto various chiral oxazolidines. Oxazaphosphorinanes thus obtained with an excellent diastereoselectivity furnish the corresponding (S)-α-substituted amino phosphonic acids in good overall yields and high ee (77→97%) after simple deprotection.

Full text of DOI:10.1021/jo960020c

J . Org. Chem. 1996, 61, 3687-3693
3687
Asym m etr ic Syn th esis of r-Am in o P h osp h on ic Acid s by
Dia ster eoselective Ad d ition of Tr im eth yl P h osp h ite on to Ch ir a l
Oxa zolid in es1
Catherine Maury, Tawfik Gharbaoui, J acques Royer,* and Henri-Philippe Husson
Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette, France
Received J anuary 2, 1996X
A simple and general asymmetric synthesis of R-amino phosphonic acids is described. The method
involves the highly selective addition of trialkyl phosphite onto various chiral oxazolidines.
Oxazaphosphorinanes thus obtained with an excellent diastereoselectivity furnish the corresponding
(S)-R-substituted amino phosphonic acids in good overall yields and high ee (77f97%) after simple
deprotection.
In tr od u ction
(-)-phenylglycinol (2) (Scheme 1, route a). In spite of
its efficiency, this method furnished R-amino phosphonic
acids in only moderate ee. In order to improve this result,
we first envisioned the preparation of 6, a rigid analogue
of 3, and the study of its alkylation (Scheme 1, route c).
On the other hand, we decided to develop a new meth-
odology using as the key step the nucleophilic addition
of trialkyl phosphite onto chiral alkylated oxazolidines
4 as illustrated in Scheme 1 (route b).
The R-amino phosphonic acids 1 (Scheme 1) are at-
tractive substitutes for amino carboxylic acids in biologi-
cal systems such as peptides, giving rise to interesting
new properties. These amino phosphonic acids have
found applications as potent active compounds with a
large range of biological activities: antibiotics, enzyme
inhibitors, herbicides,2 .... Such an impressive array of
applications has stimulated considerable effort toward
their synthesis and, more recently, their preparation in
nonracemic form.3 Among the asymmetric syntheses
recently reported, very few are both efficient and general,
so novel procedures are still needed to enlarge the organic
chemist’s synthetic potential.
Resu lts
We first investigated the preparation of oxazaphos-
phorinane 65 and its alkylation (Scheme 2). A number
of routes toward 6 were studied. One of these consisted
of the opening of the oxazolidine ring of the previously
described N-(phosphonomethyl)oxazolidine 34 by an or-
ganometallic reagent, followed by an intramolecular
transesterification of the phosphonate moiety. Indeed,
treatment of 3 (prepared from (R)-(-)-phenylglycinol and
dimethyl phosphite4 or trimethyl phosphite as reported
in this paper) with phenylmagnesium chloride and in the
presence of TiCl4 gave directly the expected oxazaphos-
phorinane 6 but in a low yield (Scheme 2).
It was eventually found that such oxazaphosphori-
nanes could be obtained more efficiently by including as
a key step the nucleophilic attack of the oxazolidine ring
by a trialkyl phosphite. As NH oxazolidines are known
to be unstable and frequently found in equilibrium with
the imine form,6 we focused on the preparation of
N-alkylated oxazolidines, and among them the N-benzy-
loxazolidines were chosen in order to facilitate N-depro-
tection at the end of the synthesis.
We recently reported a general method4 involving a
diastereoselective alkylation of the anion of a chiral
N-(phosphonomethyl)oxazolidine 3 derived from (R)-
X Abstract published in Advance ACS Abstracts, May 1, 1996.
(1) Reported in part at the “J ourne´es de Chimie Organique” of the
Socie´te´ Franc¸aise de Chimie, Sept 12-15, 1995, Palaiseau, France.
(2) (a) Kafarski, P.; Lejczak, B.; Mastalerz, P. Beitr. Wirkt. Forsh.
1985, H25. (b) Kafarski, P.; Lejczak, B.; Mastalerz, P. Beitr. Wirkt.
Forsh., 1984, H21. (c) Neuzil, E.; Cassaigne, A. Exp. Ann. Biochim.
Med. 1980, 34, 165-210.
(3) For recently reported asymmetric syntheses see: (a) Smith, A.
B., III; Yager, K. M.; Taylor, C. M. J . Am. Chem. Soc.,1995, 117,
10879-10888;. (b) Sasai, H.; Arai, S.; Tahara, Y.; Shibasaki, M. J . Org.
Chem. 1995, 60, 6656-6657. (c) Hamilton, R.; Walker, B.; Walker, B.
J . Tetrahedron Lett. 1995, 36, 4451-4454. (d) Cabella, G.; J ommi, G.;
Pagliarin, R.; Sello, G.; Sisti, M. Tetrahedron 1995, 51, 1817-1826.
(e) Bongini, A.; Camerini, R.; Hofman, S.; Panunzio, M. Tetrahedron
Lett. 1994, 35, 8045-8048. (f) Yager, K. M.; Taylor, C. M.; Smith, A.
B., III. J . Am. Chem. Soc. 1994, 116, 9377-9378. (g) Song, Y.; Niederer,
D.; Lane-Bell, P. M.; Lam, L. K. P.; Crawley, S.; Palcic, M. M.; Pickard,
M. A.; Pruess, D. L.; Vederas, J . C. J . Org. Chem. 1994, 59, 5784-
5793. (h) Hanessian, S.; Bennani, Y. L. Synthesis 1994, 1272-1274.
(i) Gajda, T. Tetrahedron: Asymm. 1994, 5, 1965-1972. (j) Groth, U.;
Lehmann, L.; Richter, L.; Scho¨llkopf, U. Liebigs Ann. Chem. 1993,
427-431. (k) Kukhar, V. P.; Svistunova, N. Y.; Solodenko, V. A.;
Soloshonok, V. A. Russ. Chem. Rev. 1993, 62, 261-278. (l) J acquier,
R.; Lhassani, M.; Petrus, C.; Petrus, F. Phosphorus, Sulfur Silicon
1993, 81, 83-87. (m) Hanessian, S.; Bennani, Y. L.; Herve´, Y. Synlett
1993, 35-36. (n) J ommi, G.; Miglierini, G.; Pagliarin, R.; Sello, G.;
Sisti, M. Tetrahedron 1992, 48, 7275-7288. (o) Denmark, S. E.;
Chatani, N.; Pansare, S. V. Tetrahedron 1992, 48, 2191-2208. (p)
Dumy, P.; Escale, R.; Girard, J .-P.; Parello, J .; Vidal, J .-P. Synthesis
1992, 1226-1228. (q) Groth, U.; Richter, L.; Scho¨llkopf, U. Liebigs Ann.
Chem. 1992, 903-909. (r) Yokomatsu, T.; Shibuya, S. Tetrahedron:
Asymm. 1992, 3, 377-378. (s) Groth, U.; Richter, L.; Scho¨llkopf, U.
Tetrahedron 1992, 48, 117-122. (t) Laschat, S.; Kunz, H. Synthesis
1992, 90-95. (u) Ouazzani, F.; Roumestant, M.-L.; Viallefont, P.; El
Hallaoui, A. Tetrahedron: Asymm. 1991, 36, 913-917. (v) Hanessian,
S.; Bennani, Y. L. Tetrahedron Lett. 1990, 31, 6465-6468. (w) Sting,
M.; Steglich, W. Synthesis 1990, 132-134.
The overall synthesis of 6 starting from (R)-(-)-
phenylglycinol (2) is described in Scheme 3. The N-
benzylphenylglycinol (7) was prepared from 2 by ben-
zoylation followed by LiAlH4 reduction and was then
condensed with formaldehyde to afford the oxazolidine
8 in 86% overall yield.
Treatment of 8 with trimethyl phosphite in the pres-
ence of 1 equiv of SnCl4 gave the expected oxazaphos-
(5) The conception of this compound was inspired by the asymmetric
synthesis of carboxylic acids described some years ago: (a) Dellaria,
J . F.; Santarsiero, B. D. J . Org. Chem. 1989, 54, 3916-3926. (b)
Sinclair, P. J .; Zhai, D.; Reibenspies, J .; Williams, R. M. Tetrahedron
Lett. 1988, 29, 6075-6078.
(6) (a) Wu, M. J .; Pridgen, L. N. J . Org. Chem. 1991, 56, 1340-
1344. (b) Fu¨lo¨p, F.; Berna´th, G.; Mattinen, J .; Pihlaja, K. Tetrahedron
1989, 45, 4317-4334. (c) Astudillo, M.; Chokotho, N.; J arvis, T.;
J ohnson, C.; Lewis, C.; McDonell, P. Tetrahedron 1985, 41, 5919-5928.
(4) Maury, C.; Royer, J .; Husson, H.-P. Tetrahedron Lett. 1992, 33,
6127-6130.
S0022-3263(96)00020-5 CCC: $12.00 © 1996 American Chemical Society

3688 J . Org. Chem., Vol. 61, No. 11, 1996
Maury et al.
Sch em e 1
13C NMR spectra the C-5 chemical shift was only slightly
affected by epimerization at the phosphorus center.
We were not able to find conditions which could
deprotonate oxazaphophorinane 6, and we thus tried to
generalize the above synthetic route for the synthesis of
alkylated oxazaphophorinanes 5 using alkylated oxazo-
lidines 4 and studied the stereochemistry of this reaction
in order to get a new asymmetric access to R-amino
phosphonic acids. The overall synthesis is outline in
Scheme 4.
Sch em e 2
Oxazolidines 4a -e were easily prepared in high yields
and diastereomeric excesses9 (see Table 2) from N-
benzylphenylglycinol (7) and then converted into oxaza-
phosphorinanes 5a -e by treatment with trimethyl phos-
phite in the presence of SnCl4 for 12-16 h.
Sch em e 3
Oxazaphosphorinanes were obtained in good to excel-
lent yield and consisted of a mixture of diastereomers.
Two new chiral centers at C-3 and at phosphorus were
created in the reaction, and the ratios of diastereomers
as determined by 1H, 13C, and 31P NMR spectra are
reported in Table 2. Four isomers were found to be
formed for R ) Me and (CH2)3CO2Me (5a and 5e) and
only two for R ) Et, Pr, and Bn (5b, 5c, 5d ).
The different data found in the NMR and IR spectra
of these mixtures suggested, by analogy with the above-
described study of 6, that the two major (or the two
exclusive) compounds were epimers at the phosphorus
center. In other words, formation of the phosphorus-
carbon bond is highly to totally diastereoselective. This
assertion had to be carefully checked, so we transformed
oxazaphosphorinane esters 5 into acids 9, in which the
phosphorus atom was no longer chiral, by treatment with
trimethylsilyl bromide (Scheme 5).
HPLC and 31P NMR analysis of oxazaphosphorinanes
9 confirmed our hypothesis showing the presence of only
one isomer for 9b-d and two isomers in the case of 9a
and 9e. Furthermore, the diastereomeric ratios for 9a
and 9e were in full agreement with those of 5a and 5e
(see Table 2). Thus, the addition of trialkyl phosphite
onto chiral oxazolidines is a highly to totally diastereo-
selective process leading to the formation of a major S
configuration at C-3 (vide infra) with a de varying from
72% up to 95%.
phorinane 6 in 81% yield. This transformation involved
a Lewis acid-mediated opening of the oxazolidine ring,
followed by an Arbusov-type reaction and an intramo-
lecular transesterification. Compound 6 consisted of a
mixture of two diastereomers in a 4:1 ratio and was fully
analyzed. Assignment of structure 6a for the major
component and 6b for the minor one was made on the
basis of the 1H NMR and IR spectra data reported in
Table 1. Compared to its epimer, the major compound
3
6a , with an equatorial PdO bond, has smaller J P/H-6ax
3
and larger J P/H-6eq coupling constants, more shielded
1
protons at C-6 in the H NMR spectrum, and a higher
PdO bond IR frequency.7,8 On the other hand, in the
(7) (a) Finocchiaro, P.; Recca, A.; Bentrude, W. G.; Tan, H.-W.; Yee,
K. C. J . Am. Chem. Soc. 1976, 98, 3537-3541. (b) Majoral, J .-P.;
Bergounhou, C.; Navech, J .; Maria, P. C.; Elegant, L.; Azzaro, M. Bull.
Soc. Chim. Fr. 1973, 3142-3145. (c) Bentrude, W. G.; Tan, H.-W.; Yee,
K. C. J . Am. Chem. Soc. 1972, 94, 3264-3266. (d) Majoral, J .-P.; Pujol,
R.; Navech, J . C. R. Acad. Sc. Paris Ser. C 1972, 274, 213-216. (e)
Buys, H. R. Rec. Trav. Chim. Pays-Bas 1970, 89, 1244-1252.
(8) (a) Majoral, J .-P.; Bergounhou, C.; Navech, J . Bull. Soc. Chim.
Fr 1973, 3146-3149. (b) Bergesen, K.; Vikane, T. Acta Chem. Scand
1972, 26, 1794-1798. (c) Bergesen, K. Acta Chem. Scand. 1967, 21,
578-579.
The R-amino phosphonic acids 1a -e were finally
obtained in two steps from oxazaphosphorinanes 5a -e
(Scheme 4). The hydrogenolysis of 5a -e at 60 psi and
(9) (a) Arseniyadis, S.; Huang, P. Q.; Morellet, N.; Belœil, J .-C.;
Husson, H.-P. Heterocycles 1990, 31, 1789-1799. (b) Agami, C.; Rizk,
T. Tetrahedron 1985, 41, 537-540.

Synthesis of R-Amino Phosphonic Acids
J . Org. Chem., Vol. 61, No. 11, 1996 3689
Ta ble 1. Sp ectr oscop ic Da ta for th e Mixtu r e of Oxa za p h osp h or in a n es 6
Sch em e 4
Ta ble 2. P r ep a r a tion a n d Dia ster eoselectivity of Oxa zolid in es 4 a n d Oxa za p h osp h or in a n es 5 a n d 9
oxazolidines 4
oxazaphosphorinanes 5
comp 9
yield (%)
R
yield (%)
dra (%)
yield (%)
dra (%)
3S/3R
3S/3Rc
a: Me
b: Et
c: Pr
d: Bn
e: (CH2)3CO2Me
92
92
99
86
70
>98:2
92:8
>98:2
>98:2
90:10
64
92
72
56
77
64:21:8:7
80:20:0:0
79:21:0:0
60:40:0:0
60:33:6:1
85:15
100:0
100:0
100:0
93:7
91
93
92
89
91
86:14
100:0
100:0
100:0
90:10
a
b
Ratios determined by 1H and 13C NMR. Ratios determined by 1H, 13C, and 31P NMR. c Ratios determined by HPLC and 31P NMR.
modification11 swhich could also introduce possible
Sch em e 5
racemizationswere not successful. Comparison of optical
rotations with those of the literature gave ee values in
very good agreement with the de values found for 5 (and
9) in the case of 1a , 1b, and 1d (Table 3). Amazingly,
the values reported in the literature for 1c and 1e were
very different from those we determined. The coherence
of the optical rotations we have found in this series,
together with the good chemical purity of these amino
acids (microanalyses, see the Experimental Section) and
high diastereomeric purity of oxazaphosphorinanes 5,
gave credence to the authenticity of our findings.
in the presence of Pearlman’s catalyst gave amino
phosphonates 10a -e in high yield. This reaction allowed
the complete N-debenzylation and monohydrolysis of the
phosphonate. The second ester function was finally
cleaved in acidic medium (5 N HCl) and led to the free
amino acids 1a -e in good overall yield after treatment
with propylene oxide.
Discu ssion
The key step of this R-amino phosphonic acid asym-
metric synthesis was the insertion of a phosphorus atom
into the C-O linkage of the oxazolidine. This process
gave rise to a new chiral carbon center in a highly
diastereoselective fashion. The absolute configuration of
the target molecules indicates that the phosphorus
insertion occurred with invertion of configuration at C-2
suggesting a SN2 mechanism. Although this mechanism
could not be ruled out, it appears to be rather improbable
All the R-amino phosphonic acids we have prepared
had been already described in the literature,10 which
allowed us to determine their absolute configuration as
S. Enantiomeric excesses of these acids would be the
same as the diastereomeric excesses of oxazaphosphori-
nanes 5 if we suppose complete absence of racemization
in the last two steps. Our attempts to determine the
enantiomeric excesses of 1 without any further chemical
(10) Dhawan, B.; Redmore, D. Phosphorus Sulfur 1987, 32, 119-
144.
(11) Huber, R.; Vasella, A. Helv. Chim. Acta 1987, 70, 1461-1476.

3690 J . Org. Chem., Vol. 61, No. 11, 1996
Ta ble 3. F or m a tion a n d Ch a r a cter iza tion of r-Am in o P h osp h on ic Acid s 1a -e
Maury et al.
[R]578
(c ) 1, 1 N NaOH)
lit.10 [R]578
(c ) 1, 1 N NaOH)
R
yield (%)
config
ee 1 (%)
de 5 (%)
a: Me
b: Et
c: Pr
d: Bn
e: (CH2)3CO2H
96
87
82
70
81
+13.1
+19.3
+17.1
+50.3
+27.1
+17.0
+21.0
-8.3
+52.0
+13
S
S
S
S
S
77
92
70
>95
>95
>95
86
97
(-)-phenylglycinol (2) (commercially available or prepared
according to the literature procedure) (137 mg, 1 mmol),
trimethyl phosphite (1.2 mmol), and freshly distilled toluene
(10 mL). Paraformaldehyde 95% (3.2 mmol) was added in
small portions. After 2 h of refluxing, the solvent was
evaporated under vacuum and the crude oil purified by flash
chromatography on silica gel (ether/ethyl acetate 1:1) to leave
to the desired N-(phosphonomethyl)oxazolidine 3 in 75% yield.
Sch em e 6
White crystalline solid: mp 79 °C (Et2O); IR (cm-1) 1272
(PdO st), 1033 (POC st); 1H NMR: 7.40-7.25 (m, 5H), 4.94 (d,
1H, J ) 3.6 Hz), 4.31 (d, 1H, J ) 3.6 Hz), 4.25 (t, 1H, J ) 7.5
3
Hz), 3.86 (t, 1H, J ) 7.5 Hz), 3.72 and 3.64 (2 × d, 6H, J P-H
) 10.7 Hz), 3.69 (t, 1H, J ) 7.5 Hz), 3.09 (dd, 1H, J ) 15.2,
2
2J P-H ) 17.0 Hz), 2.80 (dd, 1H, J ) 15.2, J P-H ) 7.0 Hz); 13
C
)
)
3
NMR: 138.4, 128.7, 128.0, 127.6, 87.8, 73.0, 69.1 (d, J P-C
2
1
16 Hz), 53.1 and 52.6 (2 × d, J P-C ) 7 Hz), 46.8 (d, J P-C
164 Hz); MS (EI) m/ z 271 (11) 162 (100), 161 (54), 148 (100),
132 (38), 104 (100), 103 (37), 91 (63); [R]25 ) -118.7 (c ) 1,
since the de’s of oxazaphosphorinanes 5 or 9 are in some
cases different from those of the starting oxazolidines 4.
This is illustrated in the case of 4b, which exhibited a
84% de and gave 5b in 92% chemical yield and with a de
> 99% (Table 2).
D
CHCl3). Anal. Calcd for C12H18NO4P: C, 53.13; H, 6.69; N,
5.16. Found: C, 52.94; H, 6.43; N, 5.21%.
(R)-2-(Ben zyla m in o)-2-p h en yleth a n ol (7). (R)-(-)-Phe-
nylglycinol (1.37 g, 10 mmol) was dissolved in water (5 mL)
in the presence of potassium carbonate (1.93 g, 14 mmol).
Dichloromethane (20 mL) was introduced, and the mixture was
vigorously stirred at room temperature. Benzoyl chloride was
then added dropwise. After 5 h, the white solid was filtered
off, washed with water and CH2Cl2, and dried under vacuum
(0.2 mmHg) at 50 °C and in the presence of P2O5 for 1 night.
The amide was isolated in quantitative yield (2.41 g) and used
without further purification.
Furthermore, the use of a Lewis acid in this reaction
is compatible with a prior opening of the oxazolidine ring
to generate a much more reactive iminium salt.
We tried to rationalize our results using a working
model depicted in Scheme 6 and established the follow-
ing. We propose the formation of (Z)-iminium salt I
resulting from the simultaneous transesterification of
trimethyl phosphite12 and opening of the oxazolidine.
The geometry of the double bond of this intermediate
depends upon the configuration of the starting oxazoli-
dine. The major oxazolidine possesses a N-benzyl group
trans relative to both phenyl and alkyl substituents at
C-2 and C-4. The formation of the iminium salt occurred
through a trans-antiperiplanar process to give (Z)-I. In
the minor component, the nitrogen lone-pair exchanged
rapidly, and both geometries of the iminium could be a
priori formed. Diastereofacial selectivity to give the
major S isomer of 5 could be explained by a less
constrained transition state A compared to B with all
substituents in axial position.
To a mixture of dry THF (10 mL) and LAH (0.75 g, 19.7
mmol) heated at 65 °C, was carefully added a solution of
benzamide (2.05 g, 8.5 mmol) in dry THF. After complete
addition (30-45 min), the mixture was refluxed for 24 h. The
reaction was quenched at 0 °C by careful, dropwise addition
of 0.8 mL of water, followed by 0.8 mL of aqueous 15% NaOH
solution, and finally 1.6 mL of water. The thick mixture was
then filtered through a Celite pad, and the filtrate was
concentrated under reduced pressure. The crude mixture was
purified by crystallization from ether to give 1.75 g (91%) of
the pure N-benzylamino alcohol.
White needles: mp 88 °C (Et2O); IR (cm-1) 3445 and 3433
(NH and OH st); 1H NMR 7.45-7.20 (m, 10H), 3.80 (dd, 1H, J
) 4.2, 8.7 Hz), 3.70 (d, 1H, J ) 13.0 Hz), 3.66 (dd, 1H, J )
4.2, 11.0 Hz), 3.55 (d, 1H, J ) 13.0 Hz), 3.53 (dd, 1H, J ) 8.7,
11.0 Hz), 2.75 (bs, 2H); 13C NMR 140.5, 140.0, 128.7-127.1,
66.8, 63.9, 51.2; MS (CI-isobutane) m/ z 228 (100); [R]25
)
Exp er im en ta l Section
D
-82.5 (c ) 1, CHCl3). Anal. Calcd for C15H17NO: C, 79.26;
Gen er a l Meth od s. Tetrahydrofuran (THF) and diethyl
ether were distilled from sodium/benzophenone ketyl im-
mediately prior to use. Diisopropylamine was distilled from
and stored over KOH. Final solutions before rotary evapora-
tion were dried over Na2SO4, and flash chromatography was
carried out using 230-400 mesh silica gel. Melting points are
uncorrected. Optical rotations were recorded at 20 °C in a 1
dm cell. Microanalyses were carried out at the Service de
Microanalyse at the Institut de Chimie des Substances Na-
turelles.
H, 7.54; N, 6.16. Found: C, 79.36; H, 7.59; N, 6.04.
(4R)-3-Ben zyl-4-p h en yloxa zolid in e (8). In a dry round-
bottomed flask equipped with a Dean-Stark apparatus, a
solution of amino alcohol 7 (1 mmol) and paraformaldehyde
(5 mmol) in toluene (2.5 mL) was refluxed for 16 h. The
solvent was removed under vacuum, and the crude oil was
purified by flash chromatography on silica gel (ether/heptane
2:8) to afford the oxazolidine 8 in 95% yield.
Oil: 1H NMR 7.45-7.20 (m, 10H), 4.56 (d, 1H, J ) 3.4 Hz),
4.24 (t, 1H, J ) 7.5 Hz), 4.16 (d, 1H, J ) 3.4 Hz), 3.88 (d, 1H,
J ) 13.4 Hz), 3.85 (t, 1H, J ) 7.5 Hz), 3.70 (t, 1H, J ) 7.5 Hz),
3.41 (d, 1H, J ) 13.4 Hz); 13C NMR 139.7, 138.7, 128.6-127.2,
86.9, 73.5, 67.2, 56.4; MS (EI) m/ z 239 (51), 209 (42), 208 (26),
162 (16), 148 (52), 118 (99), 104 (34), 103 (19), 91 (100), 77
(23).
(4R)-(4-P h en yloxa zolid in -3-yl)m eth ylp h osp h on ic Acid
Dim eth yl Ester (3). In a dry round-bottomed flask equipped
with a Dean-Stark apparatus was refluxed a mixture of (R)-
(12) Watanabe, Y.; Maehara, S.-I.; Ozaki, S. J . Chem. Soc., Perkin
Trans. 1 1992, 1879-1880.
(13) Abiko, A.; Masamune, S. Tetrahedron Lett. 1992, 33, 5517-
5518.
Typ ica l Exp er im en ta l P r oced u r es for th e Con d en sa -
t ion of Ald eh yd es w it h a n N-Mon op r ot ect ed Am in o

Synthesis of R-Amino Phosphonic Acids
J . Org. Chem., Vol. 61, No. 11, 1996 3691
Alcoh ol. P r oced u r e A. Freshly distilled aldehyde (3 mmol)
was added dropwise, with stirring and under an argon
atmosphere, to a refluxing solution of N-benzylamino alcohol
(1 mmol) in dry CH2Cl2 (3 mL) and in the presence of molecular
sieves (4 Å). The mixture was refluxed for 8-16 h. After being
cooled to room temperature and filtered, the mixture was
concentrated under reduced pressure to afford the desired
oxazolidine as a viscous colorless oil which was purified by
flash chromatography on silica gel (ether/heptane 9:1).
P r oced u r e B. See the typical experimental procedure
described below (yield 81%).
White crystalline solid: mp 156 °C (Et2O); dr 80:20; IR
(cm-1) 1258 (PdO eq st), 1239 (PdO ax st), 1035 and 1011
1
(POC st); H NMR data for the (2R)-isomer (80%) 7.50-7.20
3
(m, 10H), 4.25 (ddd, 1H, J ) 10.5, 11.5 Hz, J P-H ) 2.8 Hz),
3
4.09 (ddd, 1H, J ) 3.1, 11.5 Hz, J P-H ) 22.0 Hz), 3.83 (dd,
4
3
1H, J ) 13.3 Hz, J P-H ) 7.5 Hz), 3.77 (d, 3H, J P-H ) 10.7
Hz), 3.68 (dd, 1H, J ) 3.1, 10.5 Hz), 3.19 (dd, 1H, J ) 14.8
2
Hz, J P-H ) 19.2 Hz), 2.95 (d, 1H, J ) 13.3 Hz), 2.50 (dd, 1H,
P r oced u r e B. To a stirred solution of N-benzylamino
alcohol (1 mmol) in dry THF (3 mL) was added anhydrous
magnesium sulfate (≈650 mg) under an argon atmosphere,
followed by freshly distilled aldehyde (5 mmol). The mixture
was stirred at room temperature for 24 h. The magnesium
sulfate was filtered off, and the filtrate was concentrated under
reduced pressure to afford the desired oxazolidine as a viscous
colorless oil which was then purified by flash chromatography
on silica gel (ether/heptane 9:1).
2
J ) 14.8 Hz, J P-H ) 9.0 Hz); data for the (2S)-isomer (20%)
3
7.50-7.25 (m, 10H), 4.53 (ddd, 1H, J ) 7.9, 11.6 Hz, J P-H
)
3
7.8 Hz), 4.30 (ddd, 1H, J ) 3.1, 11.6 Hz, J P-H ) 16.6 Hz),
3.80 (d, 3H, 3J P-H ) 10.8 Hz), 3.77 (dd, 1H, J ) 13.3 Hz, 4J P-H
) 7.0 Hz), 3.71 (dd, 1H, J ) 3.1, 7.9 Hz), 3.22 (d, 1H, J ) 13.3
Hz), 3.13 (dd, 1H, J ) 14.0 Hz, 2J P-H ) 15.0 Hz), 2.57 (dd, 1H,
J ) 14.0 Hz, J P-H ) 11.4 Hz; 13C NMR data for the (2R)-
2
isomer (80%) 136.8, 129.1-127.5, 73.0 (d, 2J P-C ) 6 Hz), 66.6,
3
2
1
60.6 (d, J P-C ) 18 Hz), 51.9 (d, J P-C ) 6 Hz), 46.9 (d, J P-C
) 143 Hz); data for the (2S)-isomer (20%) 136.4, 129.1-127.0,
(2R,4R)-3-Ben zyl-2-m eth yl-4-p h en yloxa zolid in e (4a ):
yield 92%; oil; dr >98:2. Data for the major product: 1H NMR
7.45-7.20 (m, 10H), 4.40 (q, 1H, J ) 7.0 Hz), 4.15 (t, 1H, J )
7.5 Hz), 3.90 (t, 1H, J ) 7.5 Hz), 3.82 (d, 1H, J ) 14.0 Hz),
3.72 (t, 1H, J ) 7.5 Hz), 3.50 (d, 1H, J ) 14.0 Hz), 1.14 (d, 3H,
J ) 7.5 Hz); 13C NMR 140.5, 138.3, 129.1-127.1, 93.5, 73.0,
68.3 (C4), 54.8, 21.4; MS (EI) m/ z 253 (9), 252 (4), 238 (100),
91 (70).
2
3
71.9 (d, J P-C ) 5 Hz), 65.0, 60.3 (d, J P-C ) 17 Hz), 52.6 (d,
2J P-C ) 6 Hz), 46.4 (d, J P-C ) 143 Hz); MS (CI-isobutane)
1
m/ z 318 (100).
Typ ica l Exp er im en ta l P r oced u r e for th e Ad d ition of
Tr im eth ylp h osp h or u s Com p ou n d s to Oxa zolid in es. Dis-
tilled trimethyl phosphite (0.5 mL, 4.5 mmol) was added under
an argon atmosphere to a solution of oxazolidine (1 mmol) in
dry CH2Cl2 (10 mL). A 1 M solution of SnCl4 (1 mL, 1 mmol)
in CH2Cl2 was then added dropwise with stirring. The mixture
was stirred at room temperature and monitored by TLC. After
completion of the reaction (12-16 h) , the solvent was
evaporated under vacuum to leave a viscous oil which was
purified by chromatography on silica gel (ether) to afford the
desired compound as a colorless oil.
(2R,4R)-3-Ben zyl-2-eth yl-4-ph en yloxazolidin e (4b): yield
92%; oil; dr 92:8. Data for the major product: 1H NMR 7.50-
7.20 (m, 10H), 4.31 (dd, 1H, J ) 3.7, 6.6 Hz), 4.13 (t, 1H, J )
7.5 Hz), 3.90 (t, 1H, J ) 7.5 Hz), 3.85 (d, 1H, J ) 13.8 Hz),
3.69 (t, 1H, J ) 7.5 Hz), 3.52 (d, 1H, J ) 13.8 Hz), 1.40 (m,
2H), 0.90 (t, 3H, J ) 7.3 Hz); 13C NMR 140.1, 138.3, 129.1-
126.9, 97.7, 73.3, 68.2, 55.4, 27.7, 21.4; MS (EI) m/ z 267 (1),
239 (43), 238 (100), 210 (4), 104 (15), 91 (100).
Cyclic phosphorus compounds were obtained as mixtures
of two or four diastereomers.
(2R,4R)-3-Ben zyl-4-p h en yl-3-p r op yloxa zolid in e (4c):
yield 99%; oil; dr >98:2. Data for the major product: 1H NMR
7.50-7.20 (m, 10H), 4.35 (dd, 1H, J ) 2.8, 5.6 Hz), 4.12 (t,
1H, J ) 7.5 Hz), 3.89 (t, 1H, J ) 7.5 Hz), 3.85 (d, 1H, J ) 13.8
Hz), 3.68 (t, 1H, J ) 7.5 Hz), 3.53 (d, 1H, J ) 13.8 Hz), 1.62
(m, 2H), 1.40 (m, 2H, CH2CH2CH3), 0.92 (t, 3H, J ) 7.3 Hz);
13C NMR 139.5, 139.9, 138.0, 129.0-126.7, 96.5, 73.0, 67.9,
55.2, 36.9, 17.4, 13.8; MS (CI-isobutane) m/ z 282 (100).
(5R)-4-Ben zyl-2-m et h oxy-3-m et h yl-5-p h en yl-1,4,2-ox-
a za p h osp h in a n e 2-oxid e (5a ): yield 64%; oil; dr 64:21:8:7;
1H NMR data for the (2R,3S)-isomer (64%) 7.45-7.20 (m, 10H),
4.40-4.05 (m, 3H), 3.80 (m, 5H), 3.35 (m, 1H), 1.40 (dd, 3H, J
3
) 7.2 Hz, J P-H ) 14.0 Hz); data for the (2S,3S)-isomer (21%)
7.45-7.20 (m, 10H), 4.70-4.40 (m, 3H), 3.80 (m, 5H), 3.20 (m,
1H), 1.35 (dd, 3H, J ) 7.2 Hz, 3J P-H ) 14.0 Hz); 13C NMR data
for the (2R,3S)-isomer (64%) 137.1, 136.5, 128.3-126.6, 72.2
(2R,4R)-2,3-Diben zyl-4-p h en yloxa zolid in e (4d ): yield
86%; oil; dr >98:2. Data for the major product: 1H NMR 7.40-
7.15 (m, 15H), 4.60 (t, 1H, J ) 4.8 Hz), 4.08 (t, 1H, J ) 7.7
Hz), 3.93 (t, 1H, J ) 7.7 Hz), 3.91 (d, 1H, J ) 13.3 Hz), 3.60
(t, 1H, J ) 7.7 Hz), 3.59 (d, 1H, J ) 13.3 Hz), 2.67 (d, 2H, J )
4.8 Hz); 13C NMR 139.5, 139.2, 137.7, 129.9-126.0, 97.1, 72.6,
67.7, 55.6, 41.8; MS (CI-isobutane) m/ z 330 (100).
2
3
(d, J P-C ) 8 Hz), 58.2 (d, J P-C ) 4 Hz), 51.4 , 51.0, 45.6 (d,
1J P-C ) 142 Hz), 5.0; data for the (2S,3S)-isomer (21%) 137.8,
2
3
136.7, 128.3-126.6, 69.3 (d, J P-C ) 8 Hz), 57.6 (d, J P-C ) 4
1
Hz), 52.2), 51.0, 47.7 (d, J P-H ) 138 Hz), 8.9. It has to be
noted that for (2S,3R) and (2R,3R) diastereomers only the
carbon C6 could be detected: data for the (2S,3R)-isomer (8%)
2
70.3 (d, J P-C ) 4 Hz); data for the (2R,3R)-isomer (7%) 71.2
4-[3-Ben zyl-4-ph en yloxazolidin -2-yl]bu tyr ic acid m eth -
yl ester (4e): yield 70%; oil; dr 90:10. Data for the major
product: 1H NMR 7.50-7.30 (m, 10H), 4.36 (dd, 1H, J ) 2.8
Hz, 5.8 Hz), 4.13 (t, 1H, J ) 7.5 Hz), 3.90 (t, 1H, J ) 7.5 Hz),
3.86 (d, 1H, J ) 14.0 Hz), 3.68 (t, 1H, J ) 7.5 Hz), 3.63 (s,
3H), 3.50 (d, 1H, J ) 14.0 Hz), 2.20 (t, 2H, J ) 7.5 Hz), 1.75
(m, 2H), 1.40 (m, 2H); 13C NMR 173.5, 139.5, 137.7, 128.8-
126.6, 95.9, 72.8, 67.8, 54.9, 50.9, 33.6, 19.3; MS (CI-isobutane)
m/ z 340 (100).
2
(d, J P-C ) 5 Hz); 31P NMR data for the (2R,3S)-isomer (64%)
22.3; data for the (2S,3S)-isomer (21%) 20.9; data for the
(2S,3R)-isomer (8%) 21.6; data for the (2R,3R)-isomer (7%)
25.4; MS (CI-isobutane) m/ z 332 (100). Anal. Calcd for
C18H22NO3P + 0.25 H2O: C, 64.37; H, 6.75; N, 4.17. Found:
C, 64.51; H, 6.91; N, 4.19.
(5R)-4-Ben zyl-3-eth yl-2-m eth oxy-5-p h en yl-1,4,2-oxa za -
p h osp h in a n e 2-oxid e (5b): yield 92%; oil; dr 80:20; IR (cm-1
)
1258 (PdO eq st), 1230 (PdO ax st), 1040 and 1012 (POC st);
1H NMR data for the (2R,3S)-isomer (80%) 7.50-7.20 (m, 10H),
4.60 (m, 2H), 4.20 (m, 1H), 3.85-3,65 (m, 2H), 3.80 (d, 3H,
(5R)-4-Ben zyl-2-m eth oxy-5-p h en yl-1,4,2-oxa za p h osp h i-
n a n e 2-Oxid e (6). P r oced u r e A. To a solution of N-
(phosphonomethyl)oxazolidine 3 (1.36 g, 5 mmol) in freshly
distilled CH2Cl2 (20 mL) was added a 1 M solution of TiCl4 (5
ml, 5 mmol) in CH2Cl2 dropwise under an argon atmosphere
and at room temperature. After 1 h, the reaction mixture was
diluted into ether (80 ml), and a 2 M solution of PhMgCl (2.5
mL, 5 mmol) in THF was added. After an additional 2 h, the
mixture was poured into a NH4Cl-saturated solution, and
organic compounds were extracted with ether (4 × 25 mL).
The combined organic extracts were dried (MgSO4) and
concentrated by evaporation under reduced pressure to lead
to the desired oxazaphosphorinane 6 after purification by flash
chromatography on silica gel (ether/ethyl acetate 1:1). This
heterocycle was obtained as a white solid (480 mg, 30% yield)
and a mixture of 2 diastereomers in a ratio of 2:1.
2
3J P-H ) 10.7 Hz), 2.90 (td, 1H, J ) 7.2 Hz, J P-H ) 16.5 Hz),
1.90 (m, 2H), 1.00 (t, 3H, J ) 7.4 Hz); data for the (2S,3S)-
isomer (20%) 7.50-7.20 (m, 10H), 4.80 (m, 2H), 4.20 (m, 1H),
3.85-3,65 (m, 2H), 3.78 (d, 3H, 3J P-H ) 11.0 Hz), 3.15 (m, 1H),
1.90 (m, 2H), 1.00 (t, 3H, J ) 7.4 Hz); 13C NMR data for the
(2R,3S)-isomer (80%) 137.8, 137.1, 128.4-127.0, 70.0 (d, 2J P-C
1
2
) 7 Hz), 57.4, 53.0 (d, J P-C ) 131 Hz), 51.5 (d, J P-C ) 6 Hz),
3
3
51.1 (d, J P-C ) 5 Hz), 18.6, 11.4 (d, J P-C ) 7 Hz); data for
the (2S,3S)-isomer (20%) 138.3, 137.4, 128.4-127.0, 66.7, 56.0,
1
2
54.2 (d, J P-C ) 128 Hz), 51.5 (d, J P-C ) 6 Hz), 50.1, 17.2,
3
10.6 (d, J P-C ) 12 Hz); MS (EI) m/ z 345 (11), 330 (7), 316
(32), 220 (61), 205 (93), 149 (94), 110 (100), 109 (52), 104 (61),
91 (94). Anal. Calcd for C19H24NO3P + 0.25H2O: C, 65.22;
H, 7.05; N, 4.00. Found: C, 65.48; H, 7.21; N, 3.74.

3692 J . Org. Chem., Vol. 61, No. 11, 1996
Maury et al.
(5R)-4-Ben zyl-2-m et h oxy-5-p h en yl-3-p r op yl-1,4,2-ox-
a za p h osp h in a n e 2-oxid e (5c): yield 72%; oil; dr 79:21 ; IR
(cm-1) 1265 (PdO eq st), 1246 (PdO ax st), 1035 and 1010
(POC st); 1H NMR data for the (2R,3S)-isomer (79%) 7.50-
7.10 (m, 10H), 4.60 (m, 2H), 4.20 (m, 1H), 3.80 (dd, 1H), 3.77
isomer (86%) 9.0; data for the (3R)-isomer (14%) 10.0; HPLC
86.05%-13.95%; MS (CI-isobutane) m/ z 318 (100). Anal.
Calcd for C17H20NO3P + 0.9HBr: C, 52.34; H, 5.40; N, 3.59.
Found: C, 52.25; H, 5.92; N, 3.45.
(3S,5R)-4-Ben zyl-3-et h yl-2-oxo-5-p h en yl-2λ5-1,4,2-ox-
a za p h osp h in a n -2-ol (9b): yield 93%; white solid; dr 100:0;
1H NMR (CD3OD) 7.80-7.40 (m, 10H), 5.20 (m, 1H), 4.70 (m,
1H), 4.40 (m, 2H), 4.05 (d, J ) 12.5 Hz), 3.25 (m, 1H), 2.30 (m,
2H), 0.90 (t, 1H, J ) 7.0 Hz); 13C NMR (CD3OD) 132.2-129.9,
3
(d, 3H, J P-H ) 10.8 Hz), 3.59 (d, 1H), 3.00 (td, 1H, J ) 7.2
2
Hz, J P-H ) 16.5 Hz), 1.90 (m, 2H), 1.40 (m, 2H), 0.80 (t, 3H,
J ) 7.4 Hz); data for the (2S,3S)-isomer (21%) 7.50-7.10 (m,
10H), 4.80 (m, 2H), 4.00-3.70 (m, 6H), 3.25 (m, 1H), 1.90 (m,
2H), 1.40 (m, 2H), 0.80 (t, 3H, J ) 7.4 Hz); 13C NMR data for
the (2R,3S)-isomer (79%) 138.2, 137.3, 128.8-127.3, 70.2 (d,
3
1
67.7 (d, J P-C ) 4 Hz), 65.4, 59.1 (d, J P-C ) 131 Hz), 56.6 (d,
3J P-C ) 5 Hz), 18.5, 12.4; 31P NMR (CD3OD) 9.5; HPLC 100%;
MS (CI-isobutane) m/ z 332 (100). Anal. Calcd for C18H22
3
2
2J P-C ) 7 Hz), 57.6 (d, J P-C ) 5 Hz), 51.8 (d, J P-C ) 5 Hz),
-
1
3
NO3P + HBr: C, 52.44; H, 5.62; N, 3.39. Found: C, 52.61; H,
51.7, 51.3 (d, J P-C ) 131 Hz), 26.4, 19.9 (d, J P-C ) 8 Hz),
13.6; data for the (2S,3S)-isomer (21%) 138.6, 137.7, 128.8-
5.90; N, 3.29.
(3S,5R)-4-Ben zyl-2-oxo-5-p h en yl-3-p r op yl-2λ5-1,4,2-ox-
a za p h osp h in a n -2-ol (9c): yield 92%; white solid; dr 100:0;
1H NMR (CD3OD) 7.70-7.30 (m, 10H), 4.95 (m, 1H), 4.75 (m,
2
3
127.3, 66.8 (d, J P-C ) 8 Hz), 56.2 (d, J P-C ) 5 Hz), 52.3 (d,
1J P-C ) 127 Hz), 51.3 (d, J P-C ) 5 Hz), 50.4, 27.5, 18.9 (d,
2
3J P-C ) 12 Hz), 13.4; 31P NMR: data for the (2R,3S)-isomer
(79%) 22.2; data for the (2S,3S)-isomer (21%) 21.0; MS (CI-
isobutane) m/ z 360 (100).
3
1H), 4.42 (ddd, 1H, J ) 3, 13.0 Hz, J P-H ) 18.5 Hz), 4.25 (m,
2H), 3.07 (m, 1H), 2.05 (m, 2H), 1.7 (m, 2H), 0.96 (t, 3H, J )
7.5 Hz); 13C NMR (CD3OD) 140.2, 139.2, 132.2-129.9, 67.5,
(5R)-3,4-Diben zyl-2-m eth oxy-5-ph en yl-1,4,2-oxazaph os-
1
65.1, 57.8 (d, J P-C ) 132 Hz), 56.4, 27.5, 22.0, 14.2; 31P NMR
p h in a n e 2-oxid e (5d ): yield 56%; oil; dr 60:40; IR (cm-1) 1266
1
(CD3OD) 9.5; MS (FAB) m/ z 346 (100).
(PdO eq st), 1241 (PdO ax st), 1040 and 1011 (POC st); H
(3S,5R)-3,4-Dib en zyl-2-oxo-5-p h en yl-2λ5-1,4,2-oxa za -
p h osp h in a n -2-ol (9d ): yield 89%; white solid; dr 100:0; 1H
NMR (CD3OD) 7.40-6.90 (m, 15H), 4.80 (m, 2H), 4.20 (m, 1H),
NMR data for the (2R,3S)-isomer (60%) 7.35-7.05 (m, 15H),
4.72 (m, 2H), 4.36 (dd, 1H, J ) 4.5, 7.0 Hz), 3.86 (dd, 1H, J )
4
3
13.8 Hz, J P-H ) 4.5 Hz), 3.78 (d, 3H, J P-H ) 10.7 Hz), 3.68
(d, 1H, J ) 13.8 Hz), 3.41 (dd, 1H, J ) 6.7, 8.1 Hz), 3.25 (m,
2H); data for the (2S,3S)-isomer (21%) 7.35-7.05 (m, 15H),
4.84 (ddd, 1H, J ) 3.5, 5.0, 7.3 Hz), 3.90-3.60 (m, 4H), 3.80
(d, 3H, 3J P-H ) 10.5 Hz), 3.40 (m, 1H), 3.25 (m, 2H); 13C NMR
data for the (2R,3S)-isomer (60%) 138.0, 137.7, 137.1, 129.2-
4
4.00 (dd, 1H, J ) 15.0 Hz, J P-H ) 4.0 Hz), 3.77 (d, J ) 15.0
Hz), 3.55 (m, 1H), 3.25 (m, 2H); 13C NMR (CD3OD) 140.9,
2
140.8, 140.6, 130.4-126.8, 66.8 (d, J P-C ) 5 Hz), 58.1, 56.0
(d, 1J P-C ) 131 Hz), 51.6, 32.9; 31P NMR (CD3OD) 15.9; HPLC
100%; MS (CI-isobutane) m/ z 394 (100). Anal. Calcd for
C23H24NO3P + 0.25H2O: C, 69.42; H, 6.20; N, 3.52. Found:
C, 69.63; H, 6.96; N, 3.13.
2
3
126.3, 69.5 (d, J P-C ) 7 Hz), 56.7 (d, J P-C ) 5 Hz), 53.0 (d,
1J P-C ) 129 Hz), 51.9 (d, 2J P-C ) 7 Hz), 51.0 (d, 3J P-C ) 3 Hz),
31.5 (d, 2J P-C ) 5 Hz); data for the (2S,3S)-isomer (40%) 138.0,
137.8, 137.2, 128.4-127.0, 67.3 (d, 2J P-C ) 8 Hz), 56.0 (d, 3J P-C
4-(4-Ben zyl-2-h yd r oxy-2-oxo-5-p h en yl-2λ5-1,4,2-oxa za -
p h osp h in a n -3-yl)bu tyr ic a cid (9e): yield 91%; white solid;
dr 90:10; 1H NMR (NaOH/D2O): 7.45-7.15 (m, 10H), 4.45 (m,
2H), 3.90 (m, 2H), 3.64 (d, 1H, J ) 14 Hz), 2.80 (td, 1H, J )
1
2
) 4 Hz), 51.2 (d, J P-C ) 100 Hz), 51.9 (d, J P-C ) 6 Hz), 50.7,
31.0 (d, 2J P-C ) 5 Hz); MS (CI-isobutane) m/ z 408 (100). Anal.
Calcd for C24H26NO3P + 0.75H2O: C, 68.47; H, 6.58; N, 3.32.
Found: C, 68.72; H, 6.54; N, 3.21.
2
7.6 Hz, J P-H ) 15.0 Hz), 2.08 (t, 2H, J ) 6.7 Hz), 1.75 (m,
2H), 1.60 (m, 2H); 13C NMR (D2O/NaOH) 188.4, 139.7, 138.9,
1
128.8-127.1, 67.5, 57.7, 55.0, 50.1 (d, J P-C ) 143 Hz), 37.3,
4-(4-Ben zyl-2-m eth oxy-2-oxo-5-p h en yl-2λ5-1,4,2-oxa za -
p h osp h in a n -3-yl)bu tyr ic a cid m eth yl ester (5e): yield
77%; oil; dr 60:33:6:1; IR (cm-1) 1735 (CdO st), 1250 (b, PdO
eq and PdO ax st), 1040 and 1010 (POC st); 1H NMR data for
the (2R,3S)-isomer (60%) 7.50-7.20 (m, 10H), 4.90-4.50 (m,
2H), 4.30-4.15 (m, 1H), 4.05-3.75 (m, 2H), 3.85 (d, 3H, 3J P-H
) 11.0 Hz), 3.67 (s, 3H), 2.95 (td, 1H, J ) 6.9 Hz, 2J P-H ) 16.7
Hz), 2.20-1.50 (m, 6H); data for the (2S,3S)-isomer (33%)
7.50-7.20 (m, 10H), 4.90-4.50 (m, 2H), 4.30-4.15 (m, 1H),
4.05-3.75 (m, 2H), 3.65 (d, 3H, 3J P-H ) 10.6 Hz), 3.65 (s, 3H),
25.5, 23.4; 31P NMR (NaOD + CD3OD) data for the (3S)-isomer
(90%) 16.2; data for the (3R)-isomer (10%) 17.2; MS (FAB) m/ z
456 (100).
Typ ica l Exp er im en ta l P r oced u r e for th e Obten tion of
(1-Am in oa lk yl)p h osp h on ic Acid s fr om Oxa za p h osp h o-
r in a n e Der iva tives. The heterocyclic compound (1 mmol)
was dissolved in methanol, and Pd(OH)2 on charcoal (20%) (0.2
mmol) was added. The mixture was stirred under hydrogen
(60 psi) at room temperature until the reaction was complete
(5 h). The reaction mixture was filtered through a Celite pad,
and the methanol was removed at reduced pressure. No
attempt was made to characterize the (1-aminoalkyl)phospho-
nic acid monomethyl ester which was formed.
A 5 N hydrochloric acid solution (20 mmol) was added to
the crude product, and the resultant solution was heated with
stirring under reflux for 3 h. The solvent was then evaporated
under vacuum to lead to the aminophosphonic acid as a
semisolid. This material was dissolved in refluxing ethanol
and treated with propylene oxide at 70-80 °C to precipate the
aminophosphonic acid as a white crystalline powder. The
product was filtered off, washed with diisopropyl ether, and
thoroughly dried at 50 °C under reduced pressure and in the
presence of a dehydrating agent (P2O5).
2
3.20 (td, 1H, J ) 4.4 Hz, J P-H ) 9.3 Hz), 2.20-1.50 (m, 6H);
13C NMR: data for the (2R,3S)-isomer (60%) 173.2, 137.8,
2
3
136.9, 129.6-127.1, 70.1 (d, J P-C ) 8 Hz), 57.2 (d, J P-C ) 5
Hz), 51.6 (d, 2J P-C ) 7 Hz), 51.1, 50.9 (d, 1J P-C ) 132 Hz), 50.9,
3
32.8, 23.4 (d, J P-C ) 4 Hz), 21.6; data for the (2S,3S)-isomer
(33%) 173.1, 137.1, 136.9, 129.6-127.1, 66.8 (d, 2J P-C ) 8 Hz),
3
2
1
55.9 (d, J P-C ) 5 Hz), 53.9 (d, J P-C ) 6 Hz), 51.4 (d, J P-C
)
132 Hz), 51.0, 50.1, 32.7, 24.6 (d, 3J P-C ) 4 Hz), 21.5; 31P NMR
data for the (2R,3S)-isomer (60%) 21.5; data for the (2S,3S)-
isomer (33%) 20.1; data for the (2S,3R)-isomer (6%) 19.0; data
for the (2R,3R)-isomer (1%) 25.2; MS (CI-isobutane) m/ z 418
(100).
Typ ica l Exp er im en ta l P r oced u r e for th e Mon oh y-
d r olysis of th e P h osp h on a te Gr ou p . To a solution of
oxazaphosphorinane (1 mmol) dissolved in dry CH2Cl2 (5 mL)
was added BrSiMe3 (2.4 mmol) dropwise under an argon
atmosphere. After being stirred at room temperature for 2 h,
the solvent was removed under reduced pressure. The solid
was dissolved in methanol, and the solvent was evaporated to
give a phoshonic acid monoester.
(S)-(1-Am in oeth yl)p h osp h on ic a cid (1a ): yield 96%;
white powder, mp 257 °C (EtOH); 1H NMR (D2O) 4.78 (s, 4H),
2
3.31 (qd, 1H, J ) 7.2 Hz, J P-H ) 14.5 Hz), 1.42 (dd, 3H, J )
3
7.2 Hz, J P-H ) 14.8 Hz); MS (FAB) m/ z 126 (100); [R]25
)
578
+13.1 (c ) 1, 1 N NaOH). Anal. Calcd for C2H8NO3P: C,
19.21; H, 6.45; N, 11.20. Found: C, 19.29; H, 6.35; N, 10.99.
(S)-(1-Am in op r op yl)p h osp h on ic a cid (1b): yield 87%;
white powder, mp 271 °C (EtOH); 1H NMR (D2O) 3.20 (m, 1H),
1.95 (m, 1H), 1.75 (m, 1H), 1.10 (t, 3H, J ) 8 Hz); MS (FAB)
m/ z 140 (100); [R]25578 ) +19.3 (c ) 1, 1 N NaOH). Anal. Calcd
for C3H10NO3P : C, 25.91; H, 7.25; N, 10.07. Found: C, 25.32;
H, 6.79; N, 9.23.
(3S,5R)-4-Ben zyl-3-m eth yl-2-oxo-5-p h en yl-2λ5-1,4,2-ox-
a za p h osp h in a n -2-ol (9a ): yield 91%; white solid; dr 86:14;
1H NMR (CD3OD) data for the major product (3S)-isomer (86%)
7.80-7.40 (m, 10H), 4.50-4.20 (m, 5H), 3.40 (m, 1H), 1.70 (dd,
3
1H, J ) 7.0 Hz, J P-H ) 14.0 Hz); 13C NMR (CD3OD) data for
the (3S)-isomer (86%) 132.1-130.0, 67.5, 64.2, 56.4, 53.5 (d,
(S)-(1-Am in obu tyl)p h osp h on ic a cid (1c): yield 82%;
1J P-C ) 135 Hz), 9.8; 31P NMR (CD3OD) data for the (3S)-
white powder mp 268 °C (EtOH); H NMR (NaOH/D2O) 3.15
1

Synthesis of R-Amino Phosphonic Acids
J . Org. Chem., Vol. 61, No. 11, 1996 3693
(m, 1H), 1.85-1.35 (m, 4H, m, 1H), 0.85 (t, 3H, J ) 7.5 Hz);
C8H12NO3P: C, 47.77; H, 6.01; N, 6.96. Found: C, 47.56; H,
5.80; N, 7.20.
MS (FAB) m/ z 154 (100); [R]25 ) +17.1 (c ) 1, 1 N NaOH).
578
Anal. Calcd for C4H12NO3P : C, 31.37; H, 7.89; N, 9.14.
Found: C, 30.92; H, 7.21; N, 8.68.
(S)-5-Am in o-5-p h osp h on op en ta n oic a cid (1e): yield
81%; white powder, mp 160 °C (EtOH); 1H NMR (NaOH/D2O)
3.20 (m, 1H), 2.20 (t, 2H, J ) 7.3 Hz), 1.85-1.55 (m, 4H); MS
(FAB) m/ z 234 (100); [R]25578 ) +27.1 (c ) 1, 1 N NaOH). Anal.
Calcd for C5H12NO5P + 0.5 C2H5OH: C, 32.73; H, 6.86; N, 6.36.
Found: C, 32.87; H, 6.35; N, 6.06.
(S)-(1-Am in o-2-ph en yleth yl)ph osph on ic acid (1d): yield
70%; white powder, mp 265 °C (EtOH); 1H NMR (NaOH/D2O)
7.20 (m, 5H), 3.08 (ddd, 1H, J ) 2.0, 13.0 Hz, 3J P-H ) 2.5 Hz),
2
2.73 (ddd, 1H, J ) 2.0, 11.0 Hz, J P-H ) 12.0 Hz), 2.35 (ddd,
3
1H, J ) 11.0 , 13.0 Hz, J P-H ) 6.0 Hz); MS (FAB) m/ z 202
(100); [R]25
) +50.3 (c ) 1, 1 N NaOH). Anal. Calcd for
J O960020C
578