Synthesis of 2-phosphinoxidomethyl- and 2-phosphonomethyl glutaric acid derivatives

Article abstract of DOI:10.1002/hc.20142

Michael addition of the corresponding anions derived from diphenylphosphine oxide, dialkylphosphites, and a cyclic phosphite to α-methylene-glutaric esters (1) afforded the title compounds (2-6). Double debenzylation of 2-phosphono glutaric esters 4b and 5a by catalytic hydrogenation under the appropriate conditions gave the corresponding diacides 8 and 9, respectively.

Full text of DOI:10.1002/hc.20142

Heteroatom Chemistry
Volume 16, Number 7, 2005
Synthesis of 2-Phosphinoxidomethyl- and
2-Phosphonomethyl Glutaric Acid Derivatives
Ka´lma´n Harsa´nyi,1∗ Gyo¨rgy Doma´ny,1 Istva´n Greiner,1 Henrietta
Forintos,2 and Gyo¨rgy Keglevich2
1Gedeon Richter Ltd., 1475 Budapest, Hungary
2Department of Organic Chemical Technology, Budapest University of Technology and Economics,
1521 Budapest, Hungary
Received 6 April 2005; revised 26 April 2005
Y2P(O)CH2-substituents (where Y is phenyl, alkoxy,
ABSTRACT: Michael addition of the correspond-
or H) in position 2 that have potentially of NAAL-
ing anions derived from diphenylphosphine oxide,
ADase inhibition effect.
dialkylphosphites, and a cyclic phosphite to α-me-
α-Methylene-glutaric esters (1a and 1b) were
thylene-glutaric esters (1) afforded the title compounds
reacted with diphenylphosphine oxide and di-
(2–6). Double debenzylation of 2-phosphono glutaric
alkylphosphites in Michael addition. The >P(O)H
esters 4b and 5a by catalytic hydrogenation under
reagents were converted to the more reactive >P(O)−
the appropriate conditions gave the correspon-
anions by reaction with trimethylaluminum as de-
ꢀ
C
ding diacides 8 and 9, respectively.
2005 Wi-
scribed in earlier cases [4–6]. The reaction prod-
ucts were 2-diphenylphosphinoxidomethyl- and 2-
dialkylphosphonomethyl-glutaric esters 2, 3a–5a
3b, and 4b that were obtained in 48–65% yield af-
ter column chromatography (Scheme 1), and were
ley Periodicals, Inc. Heteroatom Chem 16:562–
565, 2005; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20142
1
characterized by 31P, 13C, and H NMR, as well as
INTRODUCTION
mass spectroscopy.
The method was then extended to the addition of
a cyclic phosphite, 1,3,2-dioxaphosphinane 2-oxide
at the end of the electron-poor double bond of 1a and
1b to afford 2-phosphonomethyl derivatives 6a and
6b, respectively (Scheme 1). Those were obtained in
∼46% yield and were characterized by 31P, 13C, and
1H NMR as well as mass spectroscopy.
The double debenzylation of bis(carboxylic es-
ter) 4b was attempted at 26◦C and 1 bar in methanol.
Surprisingly, monomethylester 7 was obtained from
the reaction mixture in a reasonable yield (65%)
(Scheme 2).
2-Phosphonomethyl-1,5-pentane diacid (2-PMPA) is
known to be an efficient drug in decreasing the risk of
stroke [1,2]. The beneficial result is based on the in-
hibition of the N-acetylated-α-linked acidic dipepti-
dase (NAALADase) enzyme. Jackson and coworkers
studied the effect of structural modifications, such
as the variation of the chain length, the modifica-
tion of the phosphonic moiety to a phosphinic func-
tion, and the replacement of the phosphorus atom
by other heteroatoms [3]. It was a challenge for us to
synthesize glutaric acids and esters with a variety of
Under the conditions of the reaction, the
2-substituted glutaric acid formed may undergo mo-
noesterification with the methanol used as solvent; a
direct alcoholysis by the action of methanol seems
to be less probable. Obviously, the acidic product
Dedicated to Professor Dr. Andra´s Lipta´k (University of
Debrecen) on the occasion of his 70th birthday.
∗Professor Harsa´nyi passed away while the paper was in press.
Correspondence to: Gyo¨rgy Keglevich; e-mail: keglevich@
mail.bme.hu.
c
ꢀ
2005 Wiley Periodicals, Inc.
562

Synthesis of 2-Phosphinoxidomethyl- and 2-Phosphonomethyl Glutaric Acid Derivatives 563
SCHEME 1
formed by debenzylation may catalyze the esterifi-
cation. Presumably, the carboxyl group located far
from the phosphonomethyl group was converted to
an ester function due to its enhanced reactivity.
Using a less reactive alcohol, such as isopropanol
as the solvent of the catalytic debenzylation, the
expected phosphonomethyl-glutaric acid (8) was
obtained in a neat reaction and in 51% yield after
chromatography (Scheme 2).
Double debenzylation of phosphonic ester 5a by
catalytic hydrogenation at ambient temperature and
atmospheric pressure was successful in methanol
even after a shorter reaction time and led to phospho-
nic acid 9 that was characterized only by 31P NMR
and MS due to its very poor solubility (Scheme 3).
To summarize our results, Michael addition of
a variety >P(O)H species to the double bond of α-
methylene glutaric esters led to the corresponding
2->P(O)CH2-glutaric derivatives. Double debenzyla-
tion at the two carboxylic ester or phosphonic diester
moieties afforded the corresponding diacids. Biolog-
ical investigation of the above compounds will be
published under separate cover.
2-Diethylphosphono-glutaric acid 8 was char-
acterized by 31P and 13C NMR, as well as mass
spectroscopy.
EXPERIMENTAL
1
The 31P, 13C, and H NMR spectra were obtained on
a Bruker DRX-500 spectrometer operating at 202.4,
SCHEME 2
SCHEME 3

564 Harsa´nyi et al.
125.7, and 500 MHz, respectively. Chemical shifts are
downfield relative to 85% H3PO4 or TMS. The cou-
plings are given in Hz. Mass spectrometry was per-
formed on a ZAB-2SEQ instrument. The starting α-
methylene-glutaric esters 1a and 1b were prepared
by the dimerization of the corresponding acrylates
in the presence of hexamethylphosphorous triamide
as described earlier [1].
2-(Dimethylphosphonomethyl)-Glutaric Acid
Dibenzyl Ester (3b)
Yield: 53%; 31P NMR (CDCl3)δ 30.1; 13C NMR (CDCl3)
δ 27.9 (JPC = 142.2, C6), 28.1 (JPC = 13.6, C3), 30.8
(C4), 38.8 (C2), 51.3 (MeO), 51.6 (MeO), 67.1 (JPC
=
6.0, CH2OP), 172.4 (C5), 173.9 (JPC = 7.3, C1);1H
NMR (CDCl3) δ 3.53 (s, 3H, MeO), 3.65 (s, 3H, MeO);
FAB-MS, 435 (M + H)+; (M + H)f+ound = 435.1530,
C22H28O7P requires 435.1573.
1,3,2-Dioxaphosphinane 2-oxide was prepared
by a known procedure [7].
2-(Diethylphosphonomethyl)-Glutaric Acid
Dimethyl Ester (4a)
General Procedure for the Synthesis of
Phosphonomethyl- and
Phosphinoxidomethyl-Glutaric Acid Esters
(2, 3a–6a, 3b, 4b, 6b)
Yield: 65%; 31P NMR (CDCl3) δ 28.7; 13C NMR (CDCl3)
δ 16.0 (CH3CH2), 27.5 (JPC = 133.1, C6), 28.1 (C3),
30.9 (C4), 38.9 (C2), 51.3 (MeO), 51.6 (MeO), 61.5
(CH3CH2), 172.5 (C5), 174.1 (JPC = 6.3, C1); 1H NMR
A solution of 5.8 mmol of dialkylphosphite or di-
phenylphosphine oxide in 15 mL of dry dichlo-
romethane was treated with 2.9 mL (5.8 mmol) of
2 M trimethylaluminum in hexane at 0◦C. After a
20 min stirring, 5.8 mmol of α-methylene-glutaric es-
ter (1a or 1b) in 5 mL of dichloromethane was added
dropwise. The mixture was stirred at room tempera-
ture for 16 h then treated with 5.6 mL of hydrochloric
acid in 50 mL of water. The organic phase was sep-
arated, dried (Na2SO4), and evaporated. Purification
by column chromatography (silica gel, 3% methanol
in chloroform) afforded the title compounds.
3
4
(CDCl3)δ 1.28 (dt, JHH = 7.1, JPH = 3.6, 6H, CH
3
CH2), 3.64 (s, 3H, MeO), 3.68 (s, 3H, MeO), 4.02–4.10
(m, 4H, CH3CH ), FAB-MS, 311 (M + H)+; (M +
2
H)+found = 311.1236, C12H24O7P requires 311.1260.
2-(Diethylphosphonomethyl)-Glutaric Acid
Dibenzyl Ester (4b)
Yield: 48%; 31P NMR (CDCl3) δ 28.9; 13C NMR (CDCl3)
δ 16.1 (CH3CH2), 27.5 (JPC = 142.3, C6), 28.1 (JPC
=
12.2, C3), 31.0 (C4), 39.0 (C2), 61.5 (J = 7.2, CH3CH2),
61.5 (J = 8.0, CH3CH2), 66.0 (CH2Ph), 66.4 (CH2Ph),
1
171.9 (C5), 173.4 (JPC = 8.3, C1); H NMR (CDCl3)
2-(Diphenylphosphinoxidomethyl)-Glutaric Acid
Dimethyl Ester (2)
3
4
δ 1.28 (dt, JHH = 12.6,
JPH = 5.8, 6H, CH2CH ),
3
4.02–4.08 (m, 4H, CH CH3) 5.08 (s, 2H, CH Ph)
2
2
5.12 (s, 2H, CH Ph); FAB-MS, 463 (M + H)+; (M +
Yield: 59%; 31P NMR (CDCl3) δ 29.3; 13C NMR (CDCl3)
δ 28.5 (JPC = 9.7, C3), 30.8 (C4), 31.4 (JPC = 70.7,
C6), 37.9 (JPC = 2.1, C2), 51.1 (MeO), 51.4 (MeO),
2
H)+found = 463.1840, C24H32O7P requires 463.1886.
1
172.2 (C5), 173.9 (JPC = 6.2, C1); H NMR (CDCl3)
2-(Dibenzylphosphonomethyl)-Glutaric Acid
Dimethyl Ester (5a)
δ 3.42 (s, 3H, MeO), 3.61 (s, 3H, MeO); FAB-MS, 375
(M + H)+; (M + H)f+ound = 375.1351, C20H24O5P re-
quires 375.1361.
Yield: 53%; 31P NMR (CDCl3) δ 30.1; 13C NMR (CDCl3)
δ 27.9 (JPC = 142.2, C6), 28.1 (JPC = 13.6, C3), 30.8
(C4), 38.8 (C2), 51.3 (MeO), 51.6 (MeO), 67.1 (JPC
=
6.0, CH2OP), 172.4 (C5), 173.9 (JPC = 7.3, C1); 1H
NMR (CDCl3) δ 3.53 (s, 3H, MeO), 3.65 (s, 3H, MeO);
FAB-MS, 435 (M + H)+; (M + H)f+ound = 435.1530,
C22H28O7P requires 435.1573.
2-(Dimethylphosphonomethyl)-Glutaric Acid
Dimethyl Ester (3a)
Yield: 48%; 31P NMR (CDCl3) δ 31.4; 13C NMR (CDCl3)
δ 26.5 (JPC = 142.5, C6), 27.9 (JPC = 12.6, C3), 30.8
(C4), 38.7 (JPC = 3.6, C2), 51.3 (MeO), 51.6 (MeO),
52.0 (d, J = 6.9, MeO), 52.1 (d, J = 7.0, MeO), 172.4
2-(2ꢁ-Oxo-[1ꢁ,3ꢁ,2ꢁ]dioxaphosphinan-2ꢁ-
ylmethyl)-Glutaric Acid Dimethyl Ester (6a)
1
(C5), 173.9 (JPC = 8.4, C1); H NMR (CDCl3) δ 3,67
Yield: 50%; 31P NMR (CDCl3) δ 24.7; 13C NMR (CDCl3)
δ 25.9 (JPC = 7.5, C8), 26.0 (JPC = 137.6, C6), 27.8
(JPC = 13.0, C3), 30.7 (C4), 38.5 (JPC = 3.5, C2), 51.2
(s, 3H, MeO), 3.71 (s, 3H, MeO), 3.72 (d, J = 10.9 Hz,
3H, MeO), 3.73 (d, J = 10.9 Hz, 3H, MeO); FAB-MS,
283 (M + H)+; (M + H)f+ound = 283.0946, C10H20O7P re-
quires 283.0947.
(MeO), 51.6 (MeO), 66.1 (JPC = 8.8, C7), 66.1 (JPC
=

Synthesis of 2-Phosphinoxidomethyl- and 2-Phosphonomethyl Glutaric Acid Derivatives 565
1
9.4, C7), 172.3 (C5), 173.8 (JPC = 8.3, C1); H NMR
ester 7. Yield 65%; 31P NMR (CDCl3) δ 29.9; FAB-
MS, (M + H)+found = 297.1080, C11H22O7P requires
297.1103.
Catalytic hydrogenation of dibenzyl phospho-
nate 5a under similar conditions (in methanol, af-
ter a reaction time of 5 h) gave 9 in 95% yield; 31P
NMR (CDCl3) δ 27.1; FAB-MS, 255 (M + H)+; (M +
H)+found = 255.0620 C8H16O7P requires 255.0634.
(CDCl3) δ 3.67 (s, 3H, MeO), 3.71 (s, 3H, MeO);
FAB-MS, 295 (M + H)+; (M + H)f+ound = 295.0945,
C11H20O7P requires 295.0947.
2-(2ꢁ-Oxo-[1ꢁ,3ꢁ,2ꢁ]dioxaphosphinan-2ꢁ-
ylmethyl)-Glutaric Acid Dibenzyl Ester (6b)
Yield: 43%; 31P NMR (CDCl3) δ 25.2; 13C NMR (CDCl3)
δ 26.0 (JPC = 7.4, C3), 26.3 (JPC = 138.7, C6), 28.1
(JPC = 13.3, C8), 31.0 (C4), 38.8 (JPC = 3.4, C2), 65.9
(JPC = 6.2, C7), 66.0 (CH2Ph), 66.5 (CH2Ph), 171.8
(C5), 173.3 (JPC = 8.1, C1); FAB-MS, 447 (M + H)+; (M
+ H)+found = 447.1561, C23H28O7P requires 447.1573.
AKNOWLEDGMENTS
Gy.K is grateful to Dr Zsuzsa Ja´szay and Professor
Dr. Imre Petneha´zy (Department of Organic Chem-
ical Technology, Budapest University of Technology
and Economics) for carrying out the debenzylations.
Debenzylation of 2-(Diethylphosphonomethyl)-
Glutaric Acid Dibenzyl Ester 4b;
2-(Diethylphosphonomethyl)-Glutaric Acid (8)
REFERENCES
To the mixture of 2.3 g (5.0 mmol) of 4b in 20 mL
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on carbon (Selcat) and the suspension was then hy-
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til two equivalents of hydrogen were absorbed. The
mixture was filtered and the solvent evaporated. Pu-
rification of the crude product so obtained by column
chromatography (silica gel, 20% methanol in chloro-
form) afforded 0.72 g (51%) of the diacid derivative 8;
31P NMR (CDCl3) δ 29.6; 13C NMR (CDCl3) δ 16.5
(JPC = 6.0, CH3CH2), 27.6 (JPC = 147.4, C6), 28.2
(JPC = 16.6, C3), 31.4 (C4), 39.2 (JPC = 2.8, C2), 62.6
(JPC = 6.8, CH3CH2), 177.1 (C5), 177.8 (JPC = 8.6, C1);
FAB-MS, 283 (M + H)+; (M + H)f+ound = 283.0939,
C10H20O7P requires 283.0947.
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Catalytic hydrogenation carried out under the
same conditions, but in methanol led to monomethyl