Scheme 4 Synthesis of monoesters 9–12 from P–H spirophosphoranes 2–3
and aldimines 4–6
Scheme 3 Synthesis of chiral monoester 8 by stereoselective Pudovik
addition between chiral P–H spirophosphorane 1 and aldimine 4.
in both enantiopure forms and both enantiomers of monoesters
9–12 can be prepared.
The enantiopure monoesters 8–12 were then converted in
80% yield into the corresponding enantiopure free (a-ami-
no)alkylphosphonic acids 13–15 by drastic hydrolysis with
concentrated hydrochloric acid under reflux7 (Scheme 5). The
P–C bond was very stable under these conditions and racemiza-
tion did not occur.
NMR; no further changes were observed after this time.
Therefore, hydrolysis of these different mixtures afforded 8A
and 8B in totally different ratios, as a function of the timing of
water addition to the crude reaction mixture (Table 1).
This observation shows that the equilibrium between the
diastereoisomers 7 is not only due to simple pseudorotations but
also requires the lability of the P–C bond. This phenomenon
involves also an equilibrium between the two diastereoisomers
of the P–H spirophosphorane 1. This equilibrium was not
observed previously and seems to be catalysed by the imine.
This property is very interesting because the ratio of 8A and 8B
and the sense of diastereoselectivity can be easily controlled by
simply changing the time of hydrolysis. The diastereoisomers of
8 were separated and purified by selective crystallization,
yielding enantiopure forms, with moderate yields: 8A in 13%
and 8B in 44% (starting with 8A : 8B = 15 : 85).
Scheme 5 Synthesis of enantiomerically pure a-aminophosphonic acids
13–15 by acidic treatement of monoesters 8–12
The Pudovik addition reactions between P–H spirophosphor-
anes 2–3 and long-chain aldimines 4 (n = 18), 5 (n = 16) or 6
(n = 12) were very slow, since they needed at least 10 days.
During the reaction, the spiranic P–C adducts (d 31P ~ 211)
decomposed slowly, leading first to P–C monocyclic phospho-
nates (d 31P ~ +45) then the desired monoesters 9–12 (d 31P ~
+8) started to accumulate. When the NMR signal of the P–H
spirophosphoranes decreased below 5%, the crude mixture was
then mixed with water to complete the hydrolysis reaction
(Scheme 4). Monoesters 9–12 were obtained in a high yield
( > 75%) as monitored by 31P NMR of the crude mixture.
However, no significant stereoselectivity was observed: the
monoesters 9–12 were formed as two diastereoisomers 9A–12A
and 9B–12B (A having a more deshielding NMR signal than B),
in a A : B = 55 : 45 ratio in all cases. This lack of
diastereoselectivity, comparedto the reaction with compound 1,
might be due to the structural lability of spirophosphoranes 2–3.
The absence of the carbonyl intracyclic group may also reduce
the acidity and the reactivity of the P–H bond. The ster-
eochemistry of monoesters 9–12 had a very strong influence on
their physico-chemical properties. Diastereoisomers A precipi-
tated in a pure form (isolated yields about 40% from A : B = 55
: 45) in the presence of Et2O or acetone, whereas isomers B
remained soluble in most organic solvents or precipitated with
all the impurities in polar solvents; they were not purified.
Although only one diastereoisomer of the monoester was
readily obtained with tartrates, they are commercially available
In conclusion, we described the asymmetric synthesis of a-
aminophosphonic acid amphiphiles, via Pudovik addition
reaction between chiral P–H spirophosphoranes and long-chain
aldimine. Since the chirality could play a crucial role on the
supramolecular properties, self-organization of these chiral
amphiphiles is now actively studied.
Notes and references
1 V. P. Kukhar and H. R. Hudson, Aminophosphonic and Aminophos-
phinic Acids, J. Wiley & Sons, New York, 2000.
2 For reviews see: B. Dhawan and D. Redmore, Phosphorus Sulfur, 1987,
32, 119; P. Kafarski and B. Lejczak, Phosphorus Sulfur, 1991, 63, 193;
R. A. Chersakov and V. I. Galkin, Russ. Chem. Rev., 1998, 67, 857.
3 C. Y. Yuan, S. S. Li, J. B. Xiao, S. H. Cui and G. Q. Wang, Phosphorus,
Sulfur, Silicon Relat. Elem., 2002, 177, 1731; H. R. Hudson and M.
Pianka, Phosphorus, Sulfur, Silicon Relat. Elem., 1996, 109–110, 345;
L. Maier and P. J. Diel, Phosphorus, Sulfur, Silicon Relat. Elem., 1994,
90, 259.
4 R. B. Nazarski, J. A. Lewkowski and R. Skowronski, Heteroat. Chem.,
2002, 13, 120.
5 M. J. Rosen, Surfactants and Interfacial Phenomena, J. Wiley & Sons,
New York, 1989 and reference therein.
6 C. Déjugnat, F. Al Ali, K. Vercruysse-Moreira, G. Etemad-Moghadam
and I. Rico-Lattes, Langmuir, 2002, 18, 10168.
7 K. Vercruysse, C. Déjugnat, A. Munoz and G. Etemad-Moghadam, Eur.
J. Org. Chem., 2000, 281.
Table 1 Influence of time on the ratio between the diastereoisomers of 7 and
on the ratio of 8A to 8B obtained by hydrolysis of 7
8 The racemic spirophosphorane was described by A. Munoz, B.
Garrigues and M. Koenig, Tetrahedron, 1980, 36, 2467.
9 N. A. Van Draanen, S. Arseniyadis, M. T. Crimmins and C. H.
Heathcock, J. Org. Chem., 1991, 56, 2499.
Diastereoisomers of 7
8A and 8B
10 They were prepared without AcONa by M. Koenig, A. Munoz, B.
Garrigues and R. Wolf, Phosphorus Sulfur, 1979, 6, 435.
11 R. Burgada, Bull. Soc. Chim. Fr., 1975, 1–2, 407.
12 R. S. Berry, J. Chem. Phys., 1960, 32, 933; R. Burgada and R. Setton,
The Chemistry of Organophosphorous Compounds, ed. F. R.Hartley,
Wiley & Sons, New York, 1994, vol. 3, 185–272.
d 31Pa
% after 5 min
% after 1 h
226.3
227.3
10
83
227.7
228.3
10.8
65
15
9.3
35
85
55
4
26
1
8
12
a In CDCl3 for 7, in CHCl3–AcOH for 8
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