Stereoselective synthesis of 1,4,2-oxazaphosphorines as precursors of chiral α-aminophosphonic acids by intramolecular heterocyclization of β-aldiminoalkylphosphites

Article abstract of DOI:10.1002/hc.10054

The intramolecular version of nucleophilic addison of phosphites to imines was carried out for the first time taking as an example β-aldimino-alkylphosphites, formed from chlorophosphites and β-aldiminoalcohols [N-(benzylidene)-2-aminoethanol and R-(+)-N-(benzylidene)-2-aminobutanol-1]. In these reactions, stereoisomeric 1,4,2-oxazaphospho-rines were obtained in good yields. R-(+)-N-(benzylidene)-2-aminobutanol-1 being used as a precursor, nucleophilic attack by P(III) atone on electrophilic C atom of the C=N group proceeds stereospecifically with participation of only re-face of the two possible diastereotopic faces of the imine double bond to give the epimeric at phosphorus (3R, 5R)-2-(β-chloroethyl)-2-oxo-3-phenyl-5-ethyl-1,4,2-oxazaphosphorines as precursors of nonracemic α-aminophosphonic acids.

Full text of DOI:10.1002/hc.10054

Heteroatom Chemistry
Volume 14, Number 1, 2003
Stereoselective Synthesis
of 1,4,2-Oxazaphosphorines as Precursors
of Chiral α-Aminophosphonic Acids
by Intramolecular Heterocyclization
of β-Aldiminoalkylphosphites
Mudaris N. Dimukhametov, Eugenija V. Bajandina, Elena Yu.
Davydova, Igor A. Litvinov, Aidar T. Gubaidullin, Alexey B. Dobrynin,
Tatyana A. Zyablikova, and Vladimir A. Alfonsov
A.E. Arbuzov Institute of Organic and Physical Chemistry, Arbuzov Str. 8, 420088, Kazan,
Russian Federation
Received 22 June 2001; revised 19 October 2001
INTRODUCTION
ABSTRACT: The intramolecular version of nucleo-
philic additon of phosphites to imines was carried
out for the first time taking as an example ꢀ-aldimino-
alkylphosphites, formed from chlorophosphites and
ꢀ-aldiminoalcohols [N-(benzylidene)-2-aminoethanol
and R-(+)-N-(benzylidene)-2-aminobutanol-1]. In
these reactions, stereoisomeric 1,4,2-oxazaphospho-
rines were obtained in good yields. R-(+)-N-(ben-
zylidene)-2-aminobutanol-1 being used as a precursor,
nucleophilic attack by P(III) atom on electrophilic
C atom of the C N group proceeds stereospecifically
with participation of only re-face of the two possible
diastereotopic faces of the imine double bond to give
the epimeric at phosphorus (3R,5R)-2-(ꢀ-chloroethyl)-
2-oxo-3-phenyl-5-ethyl-1,4,2-oxazaphosphorines as
precursors of nonracemic ꢁ-aminophosphonic
The ꢁ-amino phosphonic acids, the phosphonic acid
analogs of ꢁ-amino carboxylic acids, are interesting
compounds because of their biological activity, par-
ticularly in connection with the design of enzyme
inhibitors [1,2]. It is well known and is not surpris-
ing that the absolute configuration of a stereogenic
ꢁ-carbon atom attached to phosphorus strongly
influences the biological properties of derivatives
of ꢁ-amino phosphonic acids [3]. Although several
methods (the first synthesis of an optically active
ꢁ-amino phosphonic acid was reported by Gilmore
and McBride in 1972 [4]) for the synthesis of non-
racemic ꢁ-aminophosphonates have been reported
[5–8], there still exists a requirement for new meth-
ods which have greater simplicity and generality.
The analysis of literature data shows that the most
significant results in this field are obtained on the
basis of stereoselective addition, including the cat-
alytic one [9] of dialkyl or trialkyl phosphite deriva-
tives to compounds, containing a C N double bond
(imines, nitrones). However, only intermolecular re-
actions were considered in terms of this approach
(Scheme 1, route a). To develop a new, more effective
ꢀ
C
acids.
2003 Wiley Periodicals, Inc. Heteroatom Chem
14:56–61, 2003; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.10054
Correspondence to: Mudaris N. Dimukhametov; e-mail:
mudaris@iopc.knc.ru.
c
ꢀ
2003 Wiley Periodicals, Inc.
56

Stereoselective Synthesis of 1,4,2-Oxazaphosphorines 57
SCHEME 2
refluxing benzene, accompanied by simultaneous re-
moval of water by azeotropic distillation (Scheme 2).
The compounds 2 were found to be in equilibrium
SCHEME 1
with 1,3-oxazolidines 2ꢀ. The 1H NMR spectra of the
strategy of stereoselective synthesis of ꢁ-amino phos-
phonates we found it attractive to study reactions, al-
lowing an intramolecular type of interaction of P(III)
atom and an imino C N unit (Scheme 1, route b).
The following transformation of a cyclic intermedi-
ate, in particular via the Arbuzov reaction, could lead
to nonracemic ꢁ-aminophosphonates. As the realiza-
tion of such a process requires a strictly definite rel-
ative position of the P(III) atom to the imino group,
possessing nonequivalent diastereotopic faces, one
can anticipate a significant increase of diastereo-
meric excess of reaction products in terms of this
approach.
To study the possibilities provided by this ap-
proach, we have chosen ꢀ-aldiminoalkylphosphites
as model systems. The choice is explained by the fact
that in this case potential cyclization will proceed
via a six-membered intermediate which is most fa-
vorable for the stereodifferentiaton of diastereotopic
faces of the C N double bond. Possible products
of the reaction—1,4,2-oxazaphosphorines, as it was
shown by Royer and co-workers [10], can be easily
converted into free ꢁ-amino phosphonic acids.
For the preparation of ꢀ-aldiminoalkylphos-
phites, we have focused our attention on the study
of the reaction of monochlorophosphites with chi-
ral ꢀ-aldiminoalcohols. However, to the best of our
knowledge, no attempts have been made to investi-
gate the reaction of halogen P(III) derivatives with
ꢀ-iminoalcohols. We started our studies using N-
(benzilydene)-2-aminoethanol (2a) as a model com-
pound. In order to investigate the stereochemistry
of the potentially possible intramolecular cycliza-
tion and to obtain optically active title compounds,
we chose R-(+)-N-(benzylidene)-2-aminobutanol-1
(2b), which is easily preparable from commer-
cially available R-(−)-2-aminobutanol-1 (1b) and
benzaldehyde.
ꢀ
ꢁ
compounds 2
2ꢀ exhibit a sharp singlet of the
CH N moiety at δ = 8 [11] and minor signals of the
protons at the C-2 position of cyclic forms 2ꢀ at δ =
5–6 with the following ratios –2a:2ꢀa = 10:1(CCl4),
2b:2ꢀb = 5.5:1(CCl4).
We have chosen to study the reactions of ꢀ-
aldimines 2 with ethylene chlorophosphite 3 and
bis(ꢀ-chloroethyl) chlorophosphite 4.
Slow addition of a chloroformic solution of 2a to
a stirred solution of 3 in chloroform at room tempe-
rature, according to a decoupled 31P NMR spectrum
of the crude reaction mixture, leads to the formation
of unequal amounts of two reaction products A and B
with ꢂ = 12.7 (A) and 16.8 (B). The ratio of A and B is
2.8:1. Both reaction products were isolated from the
reaction mixture by column chromatography (see
Experimental). They are crystalline compounds sta-
ble to moisture and air. Recrystallization of A from
benzene–ether (1:3) and B from acetone gave sin-
gle crystals suitable for X-ray diffraction studies. It
was found that these compounds are stereoisomeric
1,4,2-oxazaphosphorines 5, shown in Scheme 3 and
Figs. 1 and 2. Thus, the products of the reaction be-
tween 2a and 3 are diastereomers A and B, which
are distinguished from one another by the phospho-
rus atom configuration. (Each diastereomer is the
racemic mixture of two enantiomers.)
The reaction between 2b and 3, conducted in
a similar fashion, results in the formation of a
RESULTS AND DISCUSSION
ꢀ-Aldiminoalcohols 2 were prepared by the conden-
sation of ꢀ-aminoalcohols 1 with benzaldehyde in
SCHEME 3

58 Dimukhametov et al.
SCHEME 4
to assign the structure of 1,4,2-oxazaphosphorine
6 as the product D, shown in Scheme 4 with the
absolute configurations of chiral centers (2R, 3R,
5R); that is, structure D is an analog of structure B
(Scheme 3). Thus, the products C and D are epimers
distinguished by the configuration of the phosphorus
atom.
FIGURE 1 ORTEP drawing of A with atom numbering.
The above conclusions were additionally veri-
fied by the comparison of the H NMR spectra of
two-component product 6 (C and D) with ꢂ = 12.4
(C) and 16.8 (D) (Scheme 4) according to the de-
coupled 31P NMR spectrum in CHCl3 of the crude
reaction mixture. The ratio of C and D is 2.4:1. Pure
product C was isolated by column chromatography
and was a crystalline solid stable towards the ac-
tion of moisture and air. Single crystals of C suit-
able for X-ray diffraction studies were obtained by
its recrystallization from benzene. It was found that
1,4,2-oxazaphosphorine 6 was formed (Scheme 4
and Fig. 3). The absolute configuration of all chi-
ral centers C (2S, 3R, 5R) was determined by X-ray
diffraction using the Hamilton test ratio, and was
confirmed by the comparison with the known con-
figuration of the C-5 atom.
1
products A,B and C,D. One of the arguments is that
the axial proton at C-3 in compounds A,B,C and
the same proton in compound D have close values
of chemical shifts and spin–spin coupling constants
2
2
δ (ppm) and JHP (Hz): A (δ 4.33, JHP − 12.4), B
(δ 4.50, 2 JHP − 11.4), C (δ 4.25, 2 JHP − 12.5), D (δ 4.10,
2 JHP − 10.7). According to the literature [10,12], the
proton at C-3 in 1,4,2-oxazaphosphorines has the
2
values of JHP = −15.0 to −19.2 Hz for an equato-
rial proton and 2 JHP = −8.0 to −11.4 Hz for an axial
one. Other proofs are given by the comparison of the
NMR spectra of compounds C and D. The proton at
the endocyclic atom C-5 is axial in both compounds
C and D, and the Et group is equatorial. This is
proved by the large values of the spin–spin coupling
It appeared to be impossible to isolate individual
product D because of the close values of Rf of prod-
ucts C and D. The eluate fraction with the C:D ratio
equal to 1:10 was obtained for spectral analysis. This
mixture was a colorless oil.
The comparison of the structures A,B and C,D,
and analysis of their NMR spectra gave us the basis
FIGURE 2 ORTEP drawing of B with atom numbering.
FIGURE 3 ORTEP drawing of C with atom numbering.

Stereoselective Synthesis of 1,4,2-Oxazaphosphorines 59
constants of the axial protons at C-5 and C-6: 3 JHH
=
3
11.0 Hz for C, JHH = 10.7 Hz for D, as well as by
the close values of the NMR 13C parameters for com-
pounds C and D, being equal with respect to δ (ppm)
1
and JHP (Hz): C-3 δ 59.87, JCP137.42; C-5 δ 57.66,
2
3 JCP2.5; C-6 δ 76.00, JCP 8.1 for C and C-3 δ 59.66,
3
2
1 JCP139.32; C-5 δ 58.01, JCP0; C-6 δ 74.92, JCP 6.0
for D.
The interaction of 2b and 4 also results in forma-
tion of epimeric C,D (Scheme 4). It should be noted
that, in this case, epimer C is formed in larger quanti-
ties, the ratio C:D being equal to 4.3:1 in the reaction
mixture.
SCHEME 6
The comparison of the absolute configuration of
the reaction products C and D witnesses that the for-
mation of 1,4,2-oxazaphosphorine 6 proceeds stere-
ospecifically at the endocyclic C-3 atom. In other
words, formation of the P C bond in the course of
the reaction is totally stereoselective. This carbon
atom has the R configuration in both C and D prod-
ucts. Furthermore, the phosphorus atom configura-
tion is formed stereoselectively, which is clear from
the nonstatistical C and D epimer ratio.
imine salts 8. The latter undergo intramolecular cyc-
lization with formation of quaziphosphonium salts
9. They, in their turn, are stabilized via dealkyla-
tion following the Arbuzov reaction to give the fi-
nal stereoisomeric 1,4,2-oxazaphosphorines 5 and 6.
Though the present reaction scheme is preferable, it
is impossible to exclude the course of reaction with
the initial protonation of P(III) by HCl in phosphites
7 and with preceeding formation of dialkyl phosphite
10 (Scheme 6). However, as the basicity of the imine
nitrogen is much higher than the basicity of the P(III)
atom in phosphites, the share of this reaction di-
rection in the whole scheme is most probably very
small.
As to the stereochemistry of this process, in ac-
cordance with the above scheme, the main stereo-
controlling step is most probably heterocyclization,
taking place owing to intramolecular nucleophilic
attack on the electrophilic carbon atom of the
N CHPh fragment by the P(III) atom (Scheme 7).
Under similar conditions, the major stereodifferen-
tiating factor of the diastereotopic faces of the C N
bond is the preferable equatorial position of the Et
group for the formation of the six-membered cyclic
transition state. The R configuration of the initial 2-
aminobutanol-1 (1b) determines the re-face attack of
the C N bond by the P(III) atom generating the R
configuration at the ꢁ-C atoms to phosphorus. The
attack of the si-face is hindered, as in this case the Et
The scheme of the formation of 1,4,2-oxazaphos-
phorines 5 and 6 can be described in the following
way. The first step involves nucleophilic substitution
of the chlorine atom at P(III) in compounds 3 and 4
by ꢀ-aldiminoalcohols 2, with formation of ꢀ-aldi-
minoalkylphosphites 7 (Scheme 5). Most probably,
the acyclic form of ꢀ-aldiminoalcohols 2 partici-
pates in the reaction because no products of 1,3-
oxazolidines 2ꢁ are detected in the reaction mixtures.
Obviously, in the course of the reaction of 2 with
3 and 4, upon the consumption of 2 the equilibrium
ꢀ
ꢁ ꢀ
2
2 is gradually shifted to the right until 2 com-
ꢁ
pletely disappears. Phosphites 7, possessing a strong
basic center (imine nitrogen atom), can react with
hydrogen chloride, which is evolved in the course of
the reaction, with formation of the corresponding
SCHEME 5
SCHEME 7

60 Dimukhametov et al.
group would have to adopt an unfavorable axial po-
sition in the transition state. It should be noted that,
in the case of the late transition state realization for
this reaction, the fact of the diequatorial position of
substituents Ph and Et in the final product suggests
the intramolecular re-face attack of the P(III) atom
on the C N bond. The attack on the si face is less
favorable, because it results in a less favorable final
product with the axial–equatorial positions of sub-
stituents Et and Ph.
The preferable formation of stereoisomers A and
C with the P O group in the equatorial position is
most probably explained by the fact that in the salts
9, the Arbuzov reaction is realized by chloride anion
attack at the carbon atom of the sterically less loaded
equatorial P O C fragment.
Though, as it was indicated above, the share
of the reaction direction starting from the proto-
nation of the phosphorus atom in phosphites 7 in
the course of the reaction of ꢀ-aldiminoalcohols 2
with chlorophosphites 3 and 4 in the overall reaction
scheme is small, in this case, similar stereochemical
considerations are also valid.
General Procedure for Reaction of P(III)
Chlorides 3,4 with ꢀ-Aldiminoalcohols 2a,b
Into a stirred solution of chlorophosphite 3 or 4
(10 mmol) in dry chloroform (10 ml), a solution
of 2a or 2b (10 mmol) in chloroform (5 ml) was
added dropwise at room temperature. Stirring was
continued for 1 h. Chloroform was evaporated and
the oily residue was submitted to a column chro-
matographic separation to give stereoisomeric 1,4,2-
oxazaphosphorines 5 or 6.
2-(ꢀ-Chloroethyl)-2-oxo-3-phenyl-1,4,2-oxazaphos-
phorine (5). Eluant, toluene–acetone 2:1; overall
yield 83%. Diastereoisomer A: colorless solid; mp
78–79◦C (from benzene–hexane, 1:1); 31P NMR
(CD3CN) δ 13.7. Anal. Calcd. for C11H15NO3PCl: C,
47.91; H, 5.44; N, 5.08; P, 11.25; Cl, 12.88. Found:
C, 47.88; H, 5.40; N, 4.91; P, 11.15; Cl, 12.79. Di-
astereoisomer B: colorless solid; mp 107–107.5◦C
(from acetone); 31P NMR (CD3CN) δ 16.9. Anal.
Found: C, 48.18; H, 5.25; N, 5.17; P, 11.41; Cl, 12.65.
2-(ꢀ-Chloroethyl)-2-oxo-3-phenyl–5-ethyl-1,4,2-
oxazaphosphorine (6) from Chlorophosphite 3.
Eluant, toluene–acetone 4:1; overall yield 88%.
Epimer C: colorless solid; mp 104–105◦C (from
EXPERIMENTAL
benzene–dichloromethane, 4:1); [αa]D = +115.9◦
20
Materials and Spectroscopy
(C, 2.71, CH3OH); 31P NMR (CD3CN) δ 13.6. Anal.
Calcd. for C13H19NO3PCl: C, 51.40; H, 6.26; N, 4.61;
P, 10.21; Cl, 11.70. Found: C, 51.49; H, 6.10; N, 4.53;
P, 10.02; Cl, 11.58. Mixture of epimers (C:D = 1:10):
All syntheses were performed under an atmosphere
of dry argon. All solvents and starting reagents
were distilled immediately prior to use. Commercial
R-(−)-2-aminobutanol-1 (1b) has [α]D = −7.01◦
20
20
20
colorless oil; nd = 1.5302; [α]D = +16.2◦ (C, 1.69,
CH3OH); 31P NMR (CD3CN) δ 17.4 (major), 13.5
(minor). Anal. Found: C, 51.55; H, 6.38; N, 4.73; P,
10.01; Cl, 11.89.
(neat). R-(+)-N-benzylidene-2-aminobutanol-1 (2b)
20
derived from benzaldehyde and 1b has [α]D
=
+28.03◦ (C, 13.25, CH3OH), lit. [13] [α]D = +39.30◦.
The optical purity of 2b is 71.3%. Column chro-
matography and TLC were performed on silica gel
L 100/160 ꢃ and on Silufol 254 plates, respectively.
31P NMR spectra were recorded with a Bruker MSL-
400 spectrometer at 162 MHz (external standard 85%
H3PO4). 1H NMR spectra were obtained in CD3CN on
a Bruker WM-250 spectrometer at 250 MHz. Optical
activity measurements were performed with a Pola-
mat A Carl–Zeiss polarimeter.
20
2-(ꢀ-Chloroethyl)-2-oxo-3-phenyl–5-ethyl-1,4,2-
oxazaphosphorine (6) from Chlorophosphite 4.
Eluant, toluene:acetone 4:1; overall yield 62%.
Physico-chemical constants, and spectral data of
the pure epimer C are identical with those derived
from chlorophosphite 3.
The X-ray diffraction data for the crystals were
collected on a CAD4 Enraf–Nonius automatic diff-
ractometer. Further details consisting of the molecu-
lar and crystal structures of the studied compounds,
as well as the crystal data, details of structure deter-
mination, atomic coordinates, and bond lengths and
angles will be published elsewhere. Crystallographic
data (excluding structure factors) for the structures
reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre. All figures
were made using the program PLATON [14].
CONCLUSIONS
Thus, we have found a new access to stereoselective
synthesis of ꢁ-aminophosphonates based on the re-
action of chiral ꢀ-aldiminoalcohols with chlorophos-
phites. The reactions take place under mild condi-
tions with good yields, and this makes it possible
to introduce a wide range of substituents at the ꢁ-
position to the phosphorus atom. The intramole-
cular pathway of the formation of the P C bond in
the P C N fragment allows maximal control of the

Stereoselective Synthesis of 1,4,2-Oxazaphosphorines 61
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diastereomeric excess of the reaction products. In
addition, the method allows us to obtain both R and
S ꢁ-aminophosphonates, depending on the absolute
configuration of the ꢀ-aminoalcohols.
At present, we continue to study the reaction of
chiral ꢀ-aldiminoalcohols with the P(III) halides for
the asymmetric synthesis of various compounds con-
taining the P C N fragment.
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The authors thank Dr. N. Azancheev and Dr. K.
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