New highly diastereoselective synthesis of phosphoramidates. A route to chiral methyl p-nitrophenyl alkylphosphonates

Article abstract of DOI:10.1055/s-1998-1560

A new, efficient and highly enantioselective synthesis of methyl p-nitrophenyl alkylphosphonates 4a-c is described. Alkylphosphonic dichloride 1a-d reacted successively with L-proline ethyl ester and p-nitrophenol to afford phosphoramidates 3a-d in 97% de. Boron trifluoride catalysed methanolysis gave 4a-c with 93% ee. Absolute configurations of compounds 4c and 3c were established by correlation with the X-ray structure of HPL-colipase-(-)-4c complex. ³¹P NMR studies indicates that monochloro phosphoramidates (R_p)-and (S_p)-2c undergo fast epimerisation. The observed diastereoselectivity in favour of (S_p)-3c results from a faster reaction of (R_p)-2c as compared to its epimer, according to the Curtin-Hammett principle.

Full text of DOI:10.1055/s-1998-1560

January 1998
SYNLETT
73
New Highly Diastereoselective Synthesis of Phosphoramidates. A Route to Chiral Methyl
p-Nitrophenyl Alkylphosphonates
Jean-François Cavalier, Frédéric Fotiadu, Robert Verger, Gérard Buono *
a
a
b
a
a
ENSSPICAM, UMR 6516, "Synthèse, Catalyse et Chiralité", Avenue Escadrille Normandie-Niemen, F-13397 Marseille Cedex 20
Fax (+33) 491 027 776; buono@spi-chim.u-3mrs.fr
b
Laboratoire de Lipolyse Enzymatique, UPR 9025, IFR 1 du CNRS, 31, Chemin Joseph Aiguier, F-13402 Marseille Cedex 20
Fax (+33) 491 715 857; verger@ir2cbm.cnrs-mrs.fr
Received 2 October 1997
Abstract
: A new, efficient and highly enantioselective synthesis of
4a-c
methyl p-nitrophenyl alkylphosphonates
is described.
1a-d
Alkylphosphonic dichloride
ethyl ester and p-nitrophenol to afford phosphoramidates
4a-c
reacted successively with L-proline
3a-d
in 97%
with 93% ee.
were established by
de. Boron trifluoride catalysed methanolysis gave
4c 3c
Absolute configurations of compounds
and
(-)-4c
correlation with the X-ray structure of HPL-colipase-
complex.
31
(R )-
P NMR studies indicates that monochloro phosphoramidates
p
(S )-2c
and
undergo fast epimerisation. The observed
p
(S )-3c
diastereoselectivity in favour of
results from a faster reaction of
p
(R )-2c
as compared to its epimer, according to the Curtin-Hammett
p
principle.
Scheme 1
Phosphonate compounds mimic in both their charge distribution and
geometry the first transition state occurring during enzymatic
carboxyester hydrolysis. They are thus efficient inhibitors of lipases by
1
formation of a covalent bond between the nucleophilic Oγ of the active
2
serine of the enzyme and the phosphorus atom. Recently, we resolved
by X-ray diffraction the three-dimensional structures of Human
Pancreatic Lipase (HPL)-colipase complexes covalently bound to each
enantiomer of a chiral phosphonate inhibitor, the O-methyl-O-(p-
3
4c.
nitrophenyl) n-undecylphosphonate
The two enantiomers, that were
separated by chiral HPLC, exhibited distinct inhibitory activities. The
absolute configuration of the phosphorus atom of the most active
(-)-4c
levorotatory enantiomer
bound to the active serine 152 was found
R
to be
. The need to study various analogous compounds in both
p
enantiomeric forms as lipase inhibitors prompted us to focus our
attention on synthetic methods towards optically pure
alkylphosphonates.
Koizumi et al. reported the synthesis of chiral alkyl
4,5
6
phenylphosphonates and dialkyl phenyl phosphates, starting from
phosphonic dichloride compounds. Successive additions of L-proline
3a-c
yield and with 73 to 98% de (Table 1). Finally, the alcoholysis of
7
ethyl ester, used as chiral auxiliary, and various alcohols afforded
by boron trifluoride-methanol complex gave the corresponding
4a-c 4b-c
intermediate phosphoramidates in poor chemical yields (~ 35%), with
diastereomeric excess (de) ranging from 25 to 36%. After separation of
the diastereomers, substitution of the proline group on each of them by
acid-catalysed alcoholysis afforded the corresponding phosphonates and
enantiomers
in 89% yield and 92-93% ee for
.
4a-c
All the phosphonate enantiomers
obtained by using this procedure
were levorotatory, just like the most active inhibitor of HPL, compound
4-6
phosphates in fair to good yields with high enantiomeric excess (ee).
3
(-)-4c
.
Providing that the nucleophilic substitution of the p-
In the present paper we wish to report a new, general, efficient and
highly enantioselective synthetic method of chiral p-nitrophenyl
nitrophenoxy group by the serine oxygen in the lipase active site
proceeds with an inversion of the phosphorus configuration, according
to previous studies on organophosphorus stereochemistry, inhibitor
10
1a-d
alkylphosphonates. Starting from the alkylphosphonic dichloride
in CH Cl at -5°C, the substitution of one chlorine atom by 1 equivalent
2
2
(-)-4c
R
p
bound to the HPL active site exhibiting
a
absolute
of L-proline ethyl ester in the presence of
N-methylimidazole (NMI) led to a diastereomeric mixture of the
2a-d
1 equivalent of
configuration, the original configuration of this compound should be
11
S
4c
proceeds from methanolysis
.
p
Moreover, since compound
corresponding monochloro alkylphosphoramidates
isolated (Scheme 1). P NMR spectroscopy of the crude reaction
mixture at 20°C revealed a 13% de in favour of the less shielded
, that were not
3c
reaction of
with BF −MeOH, that is known to occur with complete
3
8
31
12
3c
inversion of the phosphorus centre, absolute configuration of
13
S
should be
.
p
Assuming that substitution of chlorine by p-nitrophenol
47.7
diastereomer (δ
/47.2 ppm).
p
proceeds with inversion of configuration in a classical SN2 mechanism,
2c (S )-3c
R
should be . However, we
p
the configuration of
that led to
p
(R )-2c
could not determine whether
observed in P NMR.
is the major or the minor epimer
Next, addition of 1 equivalent of p-nitrophenol to 1 equivalent of NMI
3a-d
p
31
afforded the alkylphosphoramidate p-nitrophenyl esters
in 40-76%

74
LETTERS
SYNLETT
Starting from n-undecylphosphonic dichloride 1c, we then performed
the synthetic sequence changing either the para substituent of phenol or
the nature of the L-proline derivative (Scheme 2, Table 2).
The fast epimerisation of the phosphorus atom of 2c should proceed
through a chlorine atom exchange catalysed by the presence of NM•HCl
14
as the substitution coproduct in the reaction medium. This exchange
should then occur via the formation of
a pentacoordinated
organophosphorus intermediate in a trigonal bipyramidal structure with
the chlorine atoms in apical position.
Remarkably, this equilibrium between (R )- and (S )-2c is affected by
p
p
the presence of the reaction product 3c. Indeed, addition of 0.25
equivalent of p-nitrophenol and NMI to the former reaction mixture of
2c at 20°C led immediately and quantitatively to phosphoramidate (S )-
p
3c in 98% de (vide supra). At the same time, de of the remaining
monochloro phosphoramidate 2c raised from 13% to 45% in favour of
the same diastereomer, whose configuration at the phosphorus atom
remains unknown. This enhanced diastereomeric excess remained
constant after addition of a new portion of 0.25 equivalent of reactants
and no significant variation was observed within 1 hour. On the other
Scheme 2
hand, addition of 10 mol% of (S )-3c (98% de) in the crude reaction
p
mixture of 2c in 13% de, displaced the thermodynamic equilibrium to
the same extend (45% de) as previously. Although we do not understand
at this time the origin of such effect, some specific interaction between
one epimer of 2c (probably the major one) and phosphoramidate (S )-3c
p
should take place.
In conclusion, the remarkable diastereoselectivity observed in the
formation of (S )-3c must result from a dynamic kinetic resolution
p
process, in which one diastereomer of 2c, the S epimer, undergoes the
p
substitution by the p-nitrophenate much faster than the other one (k >>
2S
k
k
, Scheme 3). The two epimers of 2c being in fast equilibrium (k ,
1R
2R
>> k ), this reaction obeys the Curtin-Hammett principle and the
1S
2S
high diastereoselectivity in favour of (S )-3c depends only on the ratio
p
of the substitution rate constants (k / k ).
2S
2R
The chemical selectivity of the second substitution was highly
dependent on the nature of the phenol derivative. As seen previously, p-
nitrophenol gave only the desired phosphoramidate 3c in good yield and
high diastereoselectivity, without any trace of disubstitution (entry 5). In
all the other cases, extensive disubstitution was observed (entries 1-4).
Compound 3c was thus obtained in very poor yields, but without notable
loss of the diastereoselectivity. In contrast, the nature of the alkoxy
group in the L-proline ester derivatives affected neither the chemical
selectivity nor the diastereoselectivity of the reaction (entries 5-8).
However, 2-methoxymethyl-1-pyrrolidine (entry 9) gave a slightly
lower de and an unexpected poor yield, indicating that the
alkoxycarbonyl group has a favourable influence on the reaction.
In order to understand the origin of the high diastereoselectivity
observed for the first time in such reactions, we finally performed a
31
mechanistic study. First, dynamic P NMR spectroscopy experiments
between 20 and 100°C on the crude reaction mixture of the monochloro
phosphoramidates 2c in toluene-d showed that the two diastereomers
8
(R )- and (S )-2c were in rapid thermodynamic equilibrium. The
Scheme 3
p
p
diastereomeric excess varied from 13% at 20°C to 0% at 100°C, in
favour of the less shielded compound (δ = 47.7 ppm). The equilibrium
constant values K were measured at each temperature by P NMR
signal integration, and linear regression on Ln K = f(1/T) allowed to
deduce the differences of enthalpy (∆H) and entropy (∆S) of formation
between these two diastereomers:
p
Acknowledgements. We thank the Conseil Régional de la Région
PACA for a PhD financial support. This research was carried out under
the BIOTECH G-Lipase Program of the European Union.
31

January 1998
SYNLETT
75
References and Notes
To a solution of 3c (0.62 mmol) in anhydrous methanol (2.5 mL)
at 0°C under N , BF -MeOH complex (3.1 mmol) was added.
After 1 h, the solution was allowed to reach r.t. and was stirred
overnight. The reaction mixture was concentrated, the crude
product was dissolved in ether, washed successively with 5%
(1) Patkar, S.; Björkling, F. "Lipases inhibitors" in Lipases. Their
Structure, Biochemistry and Application; Wooley, P. and
Petersen, S.B., Eds.: Cambridge University Press, Cambridge,
UK, 1994; p 207 and references therein.
2
3
K CO , saturated NH Cl, and brine. The organic layer was dried
2
3
4
(2) Kovach, I. M.; Bennet, A. J.; Bibbs, J. A.; Zaho, Q. J. Am. Chem.
Soc. 1993, 115, 5138. Gargouri, Y.; Ransac, S.; Verger, R.
Biochim. Biophys. Acta 1997, 1344, 6. Marguet, F.; Cudrey, C.;
Verger, R.; Buono, G. ibid 1994, 1210, 157.
over MgSO , and the solvent was removed. The crude oil was
4
purified by flash chromatography on silicagel (eluent petroleum
ether-diethyl ether 1:4) affording 4c in 82% yield.
The ee were determined on a Water HPLC system: Daicel
Chiralpack AS column 250x4.6 mm, and Waters UV detector at λ
= 234 nm. The HPLC analysis were carried out at 25°C; eluent n-
(3) Egloff, M.-P.; Marguet, F.; Buono, G.; Verger, R.; Cambillau, C.;
van Tilbeurgh, H. Biochemistry 1995, 34, 2751.
(4) Koizumi, T.; Takagi, H.; Yoshii, E. Chem. Lett. 1980, 1403.
hexane/2-propanol (90/10); flow rate 1 mL/min. Compound 4b: t
1
2
(5) Koizumi, T.; Amitani, H.; Yoshii, E. Tetrahedron Lett. 1979, 39,
= 30.5 min; t = 33.9 min (major). Compound 4c: t = 8.5 min; t
2
1
3741.
= 12.8 min (major).
(6) Koizumi, T.; Kobayashi, Y.; Amitani, H.; Yoshii, E. J. Org.
Chem. 1977, 42, 1977.
(10) Cygler, M.; Grochulski, P.; Kazlauskas, R. J.; Schrag, R. J.;
Bouthillier, J. D.; Rubin, F.; Serreqi, A. N.; Gupta, A. K. J. Am.
Chem. Soc. 1994, 116, 3180. Derewenda, U.; Brzozowski, A. M.;
Lawson, D. M.; Derewenda, Z. S. Biochemistry 1992, 31, 1532.
Corriu, R. J. P.; Lanneau, G. F.; Leclercq, D. Tetrahedron 1980,
36, 1617.
(7) Coppola, G. M.; Schuster, H. F. "The Proline family" in
Asymmetric Synthesis. Construction of chiral molecules using
amino acids; Wiley & Son, Eds.: Wiley-Interscience Publication,
New York 1987; p 267.
(11) Sequential order of the phosphorus substituents is conserved upon
substitution by the serine oxygen of the enzyme.
(8) Monochloro phosphoramidates 2a-d are highly reactive
compounds that decomposed upon concentration.
(12) Ryu, S.; Jackson, J. A.; Thompson, C. M. J. Org. Chem. 1991, 56,
4999. Kobayashi, Y.; Koizumi, T.. Chem. Pharm. Bull.1979, 27,
1641. Koizumi, T.; Kobayashi, Y.; Yoshii, E. Tetrahedron Lett.
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(9) Typical experimental procedure : To a solution of 1c (3.66
mmol) in CH Cl (10 mL) at -5°C under N , a mixture of L-
2
2
2
proline ethyl ester (3.66 mmol) and NMI (7.32 mmol) in CH Cl
2
2
(3 mL) was added and the reaction mixture was stirred for 15 min.
Compounds 2c was not isolated and a mixture of p-nitrophenol
(3.66 mmol) and, NMI (4.03 mmol) in CH Cl (3 mL) was added.
(13) In spite of the inversion of configuration, the priority rules yield
the S designation for both the starting alkylphosphoramidate 3c
2
2
p
After 15 min, the solvent was removed. The crude product was
dissolved in ether, washed successively with 5% K CO ,
and the inverted alkylphosphonate 4c.
2
3
(14) Cullis, P.M.; Iagrossi, A.; Rous, A.J.; Schilling, M.B. J. Chem.
Soc., Chem. Commun. 1987, 996.
saturated NH Cl, and brine. The organic layer was dried over
4
MgSO , and concentrated. The crude oil was purified by flash
4
chromatography on silicagel (eluent petroleum ether-diethyl ether
1:4) affording 3c in 76% yield.