Diastereoselective synthesis of α-substituted β-amidophosphonates

Article abstract of DOI:10.1016/S0040-4039(00)02145-6

A simple and general asymmetric synthesis of β-amidophosphonates is described. The method involves the highly selective addition (up to 95% d.e.) of diethyl phosphite to various chiral α,β-unsaturated carboxylic amides derived from chiral aminoalcohols.

Full text of DOI:10.1016/S0040-4039(00)02145-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1025–1028
Diastereoselective synthesis of a-substituted b-amidophosphonates
Ge´raldine Castelot-Deliencourt, Xavier Pannecoucke and Jean-Charles Quirion*
IRCOF, LHO, UPRESA-CNRS 6014, INSA et Universite´ de Rouen, 1 rue Tesnie`re, F-76821 Mont Saint-Aignan, France
Received 8 October 2000; accepted 21 November 2000
Abstract—A simple and general asymmetric synthesis of b-amidophosphonates is described. The method involves the highly
selective addition (up to 95% d.e.) of diethyl phosphite to various chiral a,b-unsaturated carboxylic amides derived from chiral
aminoalcohols. © 2001 Elsevier Science Ltd. All rights reserved.
Phosphonic acids and their derivatives have been pre-
pared and studied as isosteric analogs of carboxylic
acids. Phosphorylated aminoacids1 (Fig. 1) are of par-
ticular interest and have found widespread use as
enzyme inhibitors,2 antiviral drugs,3 antibiotics4 and
neurodrugs.5 Phaclofen, a g-aminophosphonic acid,
was described as the first selective GABAB antagonist.6
They are also known to exhibit strong herbicidal activ-
ity.7 Furthermore, aminophosphonic acids are found as
constituents of natural products.8 Generally, biological
activity is strongly dependent upon the chirality a or b
to the phosphorus atom.
formation of carbon phosphorus bonds is the Pudovik
reaction11 involving the addition of compounds con-
taining a labile PꢀH bond with unsaturated activated
systems to afford racemic12 or optically active13 prod-
ucts. Particularly attractive was the possibility of devel-
oping an asymmetric version of the method described
by Barycki12 involving conjugate addition of diethyl
phosphite anions to a,b-unsaturated amides.
Diastereoselective conjugate additions of organometal-
lic reagents to chiral a,b-unsaturated oxazolines,14 oxa-
zolidinones,15 or amides16 is a valuable method for the
asymmetric synthesis of optically active b-substituted or
a,b-disubstituted carbonyl compounds.
Numerous synthetic methods for a- and b-aminophos-
phonates have been developed during the past two
decades,9 whereas fewer methods have been devoted to
g-aminophosphonate preparations. Although their syn-
thesis has been already reported,10 these methods lack
versatility and their application to optically active com-
pounds and polysubstituted derivatives appears to be
difficult. One of the most versatile pathways for the
We report in this article the stereocontrolled synthesis
of a-substituted b-amidophosphonates utilizing
a
method that capitalizes on the highly diastereofacial
addition of the diethyl phosphite anion to an a,b-unsat-
urated amide derived from a chiral aminoalcohol.
Figure 1. Examples of biologically active g-aminophosphonic acids.
Keywords: asymmetric synthesis; phosphonic acids and derivatives; Michael addition.
* Corresponding author. Tel.: (33)2.35.52.29.20; fax: (33)2.35.52.29.59; e-mail: quirion@ircof.insa-rouen.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02145-6

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G. Castelot-Deliencourt et al. / Tetrahedron Letters 42 (2001) 1025–1028
the d.e. unchanged (entry 3). On the other hand, the
addition of TMEDA to LDA afforded the expected
Table 1. Diastereoselective 1,4-addition of diethyl phos-
phite to crotonyl amides 1a,b
Michael adduct with
a reduced yield (entry 3).
OX
OX
Ph
Attempted activation with a Lewis acid completely
inhibited the reaction. Finally, the best results were
obtained by using NaH (2 equiv.) (entry 5). Neither the
replacement of THF by Et2O nor the use of TMSCl to
displace the equilibrium of the reaction toward the
formation of the b-amidophosphonate increased the
chemical yields or the diastereoselectivity. The reaction
could be performed at higher temperatures (−20°C, 0°C
or rt) or with a large excess of diethyl phosphite anion
without any change in diastereoselectivity but with
slightly lower yields.
HPO(OEt)2 2 eq.
Base
N
N
O
Ph
(EtO)2P
O
O
1a
1b
: X = H
: X = CH2Ph
2a
2b
Entry
Amide
Basea
Product (yield % D.e.b
%)
1
2
3
4
1a
1a
1a
1a
n- or s-BuLi
LDA
LDA, TMEDA 2a (32)
LDA,
BF3/OEt2
NaH
2a (30)
2a (55)
70
70
66
0
In order to assess the importance of a free hydroxyl
group (which could be involved in a chelation process
as previously suggested16), benzyl O-protected croton-
amide 1b was synthesized in the usual manner starting
from (R)-O-benzylaminobutanol. When 1b was treated
with (EtO)2P(O)H and NaH to give the Michael
adduct, a significantly lower diastereoselectivity was
observed (entry 6).
2a (0)
5
6
1a
1b
2a (50)
2b (45)
92
30
NaH
a 2 equiv. of base and 2 equiv. of diethyl phosphite were used.
b Measured on the crude product by 31P NMR or by HPLC.
We then turned our attention to the influence of the
chiral auxiliary (Table 2). A series of aminoalcohols
were used to prepare crotonyl amides 1c–e which were
employed in a Michael addition type reaction with the
diethyl phosphite anion. The same diastereoselectivities
as with aminobutanol were observed with valinol and
phenylglycinol derivatives (entries 1 and 2), showing the
relative unimportance of the nature of the group a to
the nitrogen atom. But introduction of a substituent a
to the oxygen atom of the aminoalcohol dramatically
decreased the diastereoselectivity (entry 3). The same
results were observed when a-methylbenzylamine or
(S)-4-benzyl-2-oxazolidinone were used as chiral auxil-
iaries (entries 4 and 5), confirming our hypothesis that
the presence of a free hydroxy group is necessary to get
high diastereoselection. Oxazolines (1h,i) were prepared
in 78 and 54% yields, respectively, from the correspond-
Crotonamide (1a) was first selected to study the
diastereoselectivity of such an addition (Table 1). Com-
pound 1a was easily prepared in 74% yield by conden-
sation of trans-crotonyl chloride with (R)-N-benzyl-
aminobutanol in a biphasic system (CH2Cl2, aq.
NaOH). The Michael adduct (2a) was obtained in
moderate yield by treating diethyl phosphite (2 equiv.)
with a base (2 equiv.), followed by reaction of the
resulting anion with 1a in THF at −78°C. Use of
alkyllithiums as bases (entry 1) led to a similar
diastereoselectivity (d.e.: 70%); the low yields were due
to mono- and disubstitution of the phosphonate ethoxy
group of the resulting adduct by the corresponding
butyl anions. Using LDA improved the yields but left
Table 2. Diastereoselective 1,4-addition of diethyl phosphite to crotonyl amides 1c–i18
Ph
O
Ph
Ph
R2
N
O
R1
N
N
Me
N
O
OH
R2
O
R1
O
O
1c : R1=iPr; R2=H
1d : R1=Ph; R2=H
1e : R1=Me; R2=Ph
Ph
1h : R1=Ph; R2=H
1i : R1=Me; R2=Ph
1g
1f
Entry
Amide
Basea
Product (yield %)
% D.e.b
1
2
3
4
5
6
7
1c
1d
1e
1f
1g
1h
1i
NaH
NaH
NaH
NaH
NaH
LDA
LDA
2c (53)
2d (50)
2e (55)
2f (27)
2g (45)
2h (55)
2i (60)
92
92
24
45
40
80
80
a 2 equiv. of base and 2 equiv. of diethyl phosphite were used.
b Measured on the crude product by 31P NMR or by HPLC.

G. Castelot-Deliencourt et al. / Tetrahedron Letters 42 (2001) 1025–1028
1027
Acknowledgements
ing secondary amides by treatment with MsCl and Et3N.
When used with our described conditions, these products
led to Michael adducts in very low yields. Using LDA
instead of NaH allowed us to obtain satisfactory yields
(55–60%), but only moderate d.e. (80%).
We gratefully acknowledge the RINCOF and Re´gion
Haute Normandie for financial support (G.C.-D.).
To evaluate the scope of the reaction, we then studied
the influence of the double bond substituent on the
diastereoselectivity. Unsaturated amides derived from
(R)-N-benzylphenylglycinol were prepared by condensa-
tion with the corresponding acyl chlorides. The results of
Michael addition are given in Table 3. Chemical yields
were independent of the substituents (52–55%) unlike
diastereoselectivity, which was highly dependent on elec-
tronic nature of the substituent R (entry 3). Indeed, we
observed that when R is an alkyl group, the diastereose-
lectivity is always higher than 90%, but when we changed
R to a phenyl, the diastereoselectivity dropped to 45%.
References
1. Frank, A. W. Crit. Rev. Biochem. 1984, 16, 51.
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9. (a) Edmundson, R. S. Dictionary of Organophosphorus
Compounds; Chapman and Hall: London, 1988; (b)
Maury, C.; Gharbaoui, T.; Royer, J.; Husson, H. P. J.
Org. Chem. 1996, 61, 3687; (c) Hanessian, S.; Cantin, L.
D.; Roy, S.; Andreotti, D.; Gomtsyan, A. Tetrahedron
Lett. 1997, 38, 1103; (d) Nobuto, M.; Hirayama, M.;
Fukatsu, S. Tetrahedron Lett. 1984, 25, 1147; (e) Blazis,
V. J.; Koeller, K. J.; Spilling, C. D. J. Org. Chem. 1995,
60, 931; (f) Dhawan, B.; Redmore, D. Phosphorus Sulfur
1987, 32, 119.
10. (a) Froestl, W.; Mickel, S. J.; von Sprecher, G.; Diel, P.
J.; Hall, R. G.; Maier, L.; Strub, D.; Melillo, V.; Bau-
mann, P. A.; Bernasconi, R.; Gentsch, C.; Hauser, K.;
Jaekel, J.; Kerlsson, G.; Klebs, K.; Maitre, L.;
Marescaux, C.; Pozza, M. F.; Schmutz, M.; Steinmann,
M. W.; van Riezen, H.; Vassout, A.; Mondadori, C.;
Olpe, H.-R.; Waldmeier, P. C.; Bittiger, H. J. Med.
Chem. 1995, 38, 3313; (b) Dellaria, Jr., J. F.; Maki, R. G.
Tetrahedron Lett. 1986, 27, 2337; (c) Winsel, H.; Gaz-
izova, V.; Kulinkovich, O.; Pavlov, V.; de Mejeire, A.
Synlett 1999, 1999.
NMR studies did not allow the determination of the
configuration of the newly-created asymmetric center.
This problem was solved by an X-ray analysis of deriva-
tive 3.17 The relative configuration is opposite to the one
observed by Mukaiyama and Brown16 indicating a differ-
ent mechanism for the conjugate addition. Currently, we
favor a chelated process in which the nitrogen substituent
induces steric hindrance in the vicinity of the double
bond.
H
N
OH
(EtO)2P
O
Ph
O
3
In conclusion, an asymmetric synthesis of substituted
amidophosphonates has been developed. Our strategy
allows the preparation of a large variety of functionalized
derivatives. Particularly attractive is the possibility of
gaining access to new g-aminophosphonic acids in enan-
tiomerically pure form. Such an application and new
experiments to clarify the mechanism are in progress and
will be reported in due course.
Table 3. Diastereoselective 1,4-addition of diethyl phos-
phite to amides 1j–l: influence of the b substituent
OH
OH
Ph
O
Ph
HPO(OEt)2 (2 eq.)
R
N
R
N
11. Pudovik, A. N.; Kanavolova, I. V. Synthesis 1979, 81.
12. Barycki, J.; Mastalerz, P.; Soroka, M. Tetrahedron Lett.
1970, 3147.
NaH (2 eq.)
Ph
(EtO)2P
O
Ph
O
2j
2k
2l
13. Gro¨ger, H.; Wilken, J.; Martens, J. Z. Naturforsch., Teil
B 1996, 51, 1305.
1j : R=Et
1k : R=iPr
1l : R=Ph
14. (a) Meyers, A. I.; Whitten, C. E. J. Am. Chem. Soc. 1975,
97, 6266; (b) Meyers, A. I.; Whitten, C. E.; Smith, R. K.
J. Org. Chem. 1979, 44, 2250; (c) Meyers, A. I.; Shipman,
M. J. Org. Chem. 1991, 56, 7098; (d) Bernardi, A.;
Cardani, S.; Pilati, T.; Poli, G.; Scolastico, C.; Villa, R. J.
Org. Chem. 1988, 53, 1600.
Entry
Amide
Product (yield %)
% D.e.a
1
2
3
1j
1k
1l
2j (52)
2k (55)
2l (55)
>95
90
45
15. Andersson, P. G.; Schnik, H. E.; Osterlund, K. J. Org.
Chem. 1998, 63, 8067.
a Measured on the crude product by 31P NMR or by HPLC.

1028
G. Castelot-Deliencourt et al. / Tetrahedron Letters 42 (2001) 1025–1028
16. (a) Touet, J.; Baudouin, S.; Brown, E. Tetrahedron:
Asymmetry 1992, 3, 587; (b) Mukaiyama, T.; Iwasawa,
N. Chem. Lett. 1981, 913.
ture was purified by column chromatography on silica gel
(EtOAc/MeOH: 95/5) to provide 2d (0.8 g) with 50%
yield.
17. After simple transformation, the major isomer of com-
pound 2d was shown to possess an R configuration by
simple comparison of its 31P NMR spectra with the
known absolute configuration compound 3 derivative.
Full details concerning the synthesis of this product and
X-ray crystallographic data will be furnished in the forth-
coming full paper.
Description of the major diastereoisomer (presence of
rotamers): 31P NMR (CDCl3): l 34.52 and 35.75; 1H
NMR (CDCl3): l 1.09 (dd, J=6.9 and 17.9 Hz, 3H,
P-CH-CH3
(m, 1H, P-CH-CH2
P-CH-CH2, P-CH
O)2, CH2-OH), 4.41 and 4.6 (2d, J=17.7 Hz, N-CH2
C6H5), 5.65 and 5.62 (2d, J=4.4 Hz, 1H, N-CH
6.94–7.28 (m, 10H, H
J=5.2 Hz, P-CH-CH3), 16.8 and 16.9 (2d, J=5.7 Hz,
(CH3-CH2-O)2), 28.7 (d, J=142.6 Hz, P-CH-CH2), 35.9
(P-CH-CH2), 49.5 (N-CH2-C6H5), 61.9 (N-CH), 62.0–
62.4 (m, (CH3-CH2-O)2), 63.3 (C
(m, C ar.), 137.6 and 137.8 (C
J=12.5 Hz, C
6
), 1.16–1.24 (m, 6H, (CH3
6
-CH2-O)2), 2.14–2.22
), 2.59–2.68 (m, 2H,
6
), 2.22 (s, 1H, OH
-CH2), 3.93–4.09 (m, 6H, (CH3-CH2
6
6
6
6
-
-
6
6
18. Typical procedure for the 1,4-addition step
6
),
Synthesis of 2d: Diethyl phosphite (1.16 mL, 9 mmol) was
added to a suspension of NaH (0.206 g, 8.6 mmol) in
anhydrous THF (20 mL) under an inert atmosphere at
room temperature. After stirring for 1 h, the mixture was
cooled to −20°C, and a solution of amide 1d (1 g, 4.29
mmol) diluted in THF (10 mL) was added. After stirring
for 5 h at −20°C, water (10 mL) was added and the
compound was extracted with dichloromethane (3×20
mL). The combined organic layers were dried over mag-
nesium sulfate, filtered and concentrated. The crude mix-
6
ar.); 13C NMR (CDCl3): l 14.9 (d,
6
6
6
6
6
6
6
6
H2-OH), 126.4–129.3
6 ar. quat.), 173.8 (d,
6
6
=O).; MS(IC) m/z 434 (M+1)+, 403 (2.5),
326 (2.5), 314 (10), 209 (1); HRMS (MH)+ 434.2096
found 434.2098.
.
.