Synthesis of bis(hydroxymethyl)phosphorylated compounds, analogs of α-aminophosphonic acids or alkylidenebisphosphonic acids

Article abstract of DOI:10.1016/S0040-4020(01)00929-2

The synthesis of two new series of functional phosphines oxides is described: analogs of glyphosate [α-aminomethylbis-(hydroxymethyl)phosphine oxide] and bisphosphonic acids [bis(hydroxymethyl)phosphoryl methylphosphonic acid] substituting the phosphonic group [-P(O)(OH)₂] by the bis(hydroxymethyl)phosphoryl group [-P(O)(CH₂OH)₂], have been synthesized in good yields, using the bis(benzyloxymethyl)chloromethyl phosphine oxide as a common precursor. The further purpose of this work is to evaluate the biological interest of the bis(hydroxymethyl)phosphoryl group in comparison to the phosphonic group present in a wide range of biological molecules.

Full text of DOI:10.1016/S0040-4020(01)00929-2

TETRAHEDRON
Pergamon
Tetrahedron 57 ,2001) 9149±9156
Synthesis of bisꢀhydroxymethyl)phosphorylated compounds,
analogs of a-aminophosphonic acids
or alkylidenebisphosphonic acids
Henri-Jean Cristau,p Christine Brahic and Jean-Luc Piratp
Â
Laboratoire de Chimie Organique ꢀUMR 5076), Ecole Nationale Superieure de Chimie de Montpellier, 8 Rue de l'Ecole Normale,
34296 Montpellier cedex 5, France
Received 5 April 2001; revised 4 September 2001; accepted 14 September 2001
AbstractÐThe synthesis of two new series of functional phosphines oxides is described: analogs of glyphosate [a-aminomethylbis-
,hydroxymethyl)phosphine oxide] and bisphosphonic acids [bis,hydroxymethyl)phosphoryl methylphosphonic acid] substituting the phos-
phonic group [±P,O),OH)2] by the bis,hydroxymethyl)phosphoryl group [±P,O),CH2OH)2], have been synthesized in good yields, using the
bis,benzyloxymethyl)chloromethyl phosphine oxide as a common precursor. The further purpose of this work is to evaluate the biological
interest of the bis,hydroxymethyl)phosphoryl group in comparison to the phosphonic group present in a wide range of biological molecules.
q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
Bisphosphonates are analogs of endogenous pyrophos-
phates and exhibit profound effects on bone metabolism.3
They can exert physico-chemical effects, binding to the
surface of calciumphosphate crystals and increasing their
formation and aggregation as well as their dissolution.
Many of themare very powerful inhibitors of bone resorp-
tion. They are used in human therapy, among others in
Paget's disease, tumor bone disease, and osteoporosis.4 A
drawback of the bisphosphonates, as a class of drugs, is their
poor bio-availability which is mostly attributed to their
highly ionic and polar structure.5 So they are not well
absorbed through the intestine, which means many of
The replacement of the phosphonic group [±P,O),OH)2],
present in a wide range of biological molecules, by the
bis,hydroxymethyl)phosphoryl group [±P,O),CH2OH)2]
should modify the physical and chemical properties of the
substrates. These modi®cations could improve, by the
change of lipophilicity, the bio-availability and the trans-
membranar transport of these compounds. The replacement
of the alkyl groups in phosphine oxide compounds by two
hydroxymethyl groups should also increase the complex-
ation properties. Therefore, the purpose was to synthesize
new analogs of a-aminophosphonic acids or alkylidene-
bisphosphonic acids to evaluate the biological interest of
the bis,hydroxymethyl)phosphoryl group in comparison to
the phosphonic group.
6
themcannot be given orally.
We have chosen to work on two monofunctionnalized
bisphosphonates: on one hand the tiludronatew, an arylthio-
methylenebisphosphonate which was discovered by Sano®7
and developed as anti-in¯ammatory and anti-rheumatismal
agent, and, on the other hand, the [2-,30-pyridyl)-ethyl-
idene]bisphosphonic acid 2-,30-PEBP) which has shown
very promising bone anti-resorptive properties.8
a-Aminophosphonic acids are of great interest as inhibitors
of biological processes;1 they are used in medicinal or
agricultural ®elds, as antibacterial agents, neuroactive com-
pounds, anticancer drugs or pesticides.
Among these, the glyphosate has achieved a prodigious
importance and is the world's largest sold herbicide.2
Keywords: Michaelis±Arbuzov reaction; Williamson reaction; a-amino-
phosphonic acid; bis,hydroxymethyl) phosphoryl group; bisphosphonic
acid.
p
Corresponding authors. Tel.: 133-4-67-14-43-12; fax: 133-4-67-14-43-
19; e-mail: cristau@cit.enscm.fr; pirat@cit.enscm.fr
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020,01)00929-2

9150
H.-J. Cristau et al. / Tetrahedron 57 ꢀ2001) 9149±9156
Scheme 1.
2. Results and discussion
used, to limit the formation of the monosubstituted deriva-
tive 5 ,Table 1).
The synthesis of glyphosate analogs, in which the phos-
phonic group [±P,O),OH)2] is substituted by the bis-
,hydroxymethyl)phosphoryl [±P,O),CH2OH)2] group, has
been performed using the tris,hydroxymethyl)phosphine
oxide 2 as precursor.
The ratio 2.2:1 of reagents affords less than 3% of the
monosubstituted compound 5 together, of course, with an
increased yield ,37%) of the trisubstituted product 6. Using
this excess of benzyl alcohol ,2.2 equiv.) bis,benzyloxy-
methyl) chloromethylphosphine oxide 4 is obtained in
60% yield in the crude mixture and in 35% yield after
puri®cation.
Tris,hydroxymethyl)phosphine oxide 2 is synthesized in
two steps9 ,60% overall yield) by reaction of tetrakis-
,hydroxymethyl)phosphonium chloride 1 with triethyl-
amine, to give the corresponding tris,hydroxymethyl)-
phosphine, followed by oxidation with hydrogen peroxide
,Scheme 1).
2.1. Synthesis of an analog of glyphosate
Starting frombis,benzyloxyemthyl) chloroemthylphos-
phine oxide 4, two different pathways were used in order
to build the ,O)P±C±N linkage ,Scheme 2).
Tris,chloromethyl)phosphine oxide 3 is then synthesized by
action of phosphorus pentachloride on compound 2,10 and
two chlorine atoms are substituted by benzyloxy groups
using a Williamson reaction between tris,chloromethyl)-
phosphine oxide 3 and two equivalents of benzyl alcoholate.
In the ®rst way ,i), compound 7 is synthesized by alkyl-
ation of benzyl N-benzylglycinate with bis,benzyloxy-
methyl) chloromethylphosphine oxide 4 ,Scheme 2).
Bis,benzyloxymethyl) chloromethylphosphine oxide 4 is
formed in 63% yield, but is obtained only in 23% yield
after puri®cation.
The benzyl groups are then cleaved by catalytic hydro-
genolysis ,ii) using 10% Pd/C and ammonium formate11
as the hydrogen donor to give ®nally compound 8 in 64%
yield.
This low yield can be explained by the formation of a
mixture ,20:63:17) of mono-, di- and trisubstituted deriva-
tives ,Table 1), which are hardly separated by column
chromatography or by distillation.
In the second way ,iii), compound 10 is obtained from
bis,benzyloxymethyl) chloromethylphosphine oxide 4
by a Gabriel reaction using potassiumphthalimide and
subsequent hydrazinolysis of 9.12
Therefore, to improve the separation by column chroma-
tography, by decreasing the number of compounds in the
crude mixture, an excess of benzyl alcohol ,2.2 equiv.) was
The alkylation of compound 10 by benzyl bromoacetate
using an excess of triethylamine in dimethylformamide
Table 1.
Formation yields ,%)
PhCH2OH/OvP,CH2Cl)3
2:1
2.2:1
20
3
63
60
17
37
p
represents shifts in toluene.

H.-J. Cristau et al. / Tetrahedron 57 ꢀ2001) 9149±9156
9151
Scheme 2.
affords the compound 12, and deprotection of the benzyl
groups is carried out by catalytic hydrogenation ,ii), in the
same way as for compound 7, to give the desired compound
8 in 80% yield.
The various compounds obtained have been characterized
1
by IR, 31P, H, 13C NMR spectra and mass spectroscopy.
The second way is interesting because we obtained, after
Scheme 3.

9152
H.-J. Cristau et al. / Tetrahedron 57 ꢀ2001) 9149±9156
Scheme 4.
deprotection of the benzyl groups by catalytic hydro-
genolysis of compound 10, the a-aminomethyl bis,hydroxy-
methyl)phosphine oxide 11, an analog of the a-amino-
methylphosphonic acid which can act as plant growth
regulator.13 But, the ®rst way is more satisfactory for two
reasons, ®rst the limited number of steps, and secondly the
better overall yield obtained in this case.
or tribenzyl phosphite to obtain, respectively, compounds
13 and 14 in good yields ,Scheme 3).
The use of tribenzyl phosphite in the Michaelis±Arbuzov
reaction requires an ef®cient removal of the benzyl chloride
generated during the reaction. This is achieved at high
temperature ,1608C) and reduced pressure ,4 Torr).15
In the next step various electrophiles react with the carb-
anion 17 obtained fromcompound 13, to give, after acidic
hydrolysis of the protecting groups the analogs 19 or 21 of
tiludronate or 2-,30-PEBP) ,Scheme 4)
2.2. Bisphosphonates
The purpose was to synthesize analogs of tiludronate and
2-,30-PEBP) in which only one phosphonic acid group is
replaced by a bis,hydroxymethyl)phosphine oxide group. In
a ®rst step, we chose to build the PCP link by Michaelis±
Arbuzov reaction, between a phosphite and a chloromethyl-
phosphine oxide.14
Till now, all the compounds tested, exhibit poor herbicide or
insecticide properties. Further, the potential therapeutic
properties are, at the present time, under investigations.
But, concerning their physico-chemical properties, a pre-
liminary work was done with the goal to evaluate the
electronic effects of the ±P,O),CH2OCH2Ph)2 group in
comparison to the ±P,O),OEt)2 group: a correlation
between the variation Dd of the 13C chemical shifts for
The synthesis is carried out without solvent by heating, at
1508C for 6±20 h, chloromethyl bis,benzyloxymethyl)-
phosphine oxide 4 with a small excess of triethyl phosphite

H.-J. Cristau et al. / Tetrahedron 57 ꢀ2001) 9149±9156
9153
4.1.1. Trisꢀhydroxymethyl)phosphine oxide 29 and tris-
ꢀchloromethyl)phosphine oxide 3.10 The titled compounds
were prepared according to the literature.
Table 2.
H±CH2±Z
4.1.2. Bisꢀbenzyloxymethyl) chloromethylphosphine
oxide 4 and trisꢀbenzyloxymethyl) phosphine oxide 6.
To a suspension of tris,chloromethyl)phosphine 3 ,3 g,
15.4 mmol), sodium hydride 95% ,0.87 g, 33.9 mmol) in
toluene ,60 ml), benzyl alcohol ,3.66 g, 33.9 mmol) was
added dropwise. The mixture was heated to 1108C for 3 h.
After cooling to roomtemperature, the residue was diluted
with water ,20 ml) and then treated with 1N HCl until
neutral pH.
Z
s2
pKa
±P,O),OEt)2
±P,O),CH2OCH2Ph)2
±C,O)OMe
0.64
0.66
0.74
0.82
31
30
25
20
±C,O)Me
the ±CH2Z methylenic carbon and the corresponding anion
±2CHZ ‰Dd ˆ danion 2 dneutralŠ; substituted by various Z
withdrawing groups ,Table 2), and the values of known
sZ Hammett constants,16 allowed to determine, for the
2
The aqueous layer was extracted with CH2Cl2. After extrac-
tion, the organic layer was dried ,MgSO4) and concentrated.
The residue was puri®ed by two successive ¯ash chroma-
tography ,CH2Cl2/MeOH, 100:0±95:5) to give 35% yield of
compound 4 ,1.82 g, 5.38 mmol) as a colorless oil and 20%
yield of compound 6 ,1.25 g, 3.0 mmol) as a white solid.
®rst time, the s2 Hammett constant for the ±P,O),OEt)2
and ±P,O),CH2OCH2Ph)2 groups.
We also evaluated the acidity of diethylmethylphosphonate
and methyl bis,benzyloxymethyl) phosphine oxide. The
pKa values higher than 30, are consistent with the literature
who recommend strong bases as R2NLi or RLi for the metal-
lation of these compounds.17 FromTable 2, we can establish
a classi®cation of the substituents to stabilize the carbanion:
1
Compound 4: 31P NMR ,81 MHz, CDCl3): d 40.66 ,s); H
NMR ,200 MHz, CDCl3): d 3.76 ,2H, d, 2JPHˆ6.2 Hz), 4.00
,4H, d, 2JPHˆ5.6 Hz), 4.63 ,4H, s), 7.30±7.34 ,10H, m); 13
C
1
NMR ,50 MHz, CDCl3): d 33.45 ,d, JPCˆ64.4 Hz, CH2),
1
3
63.11 ,d, JPCˆ83.7 Hz, CH2), 75.65 ,d, JPCˆ11.3 Hz,
CH2), 127.98 ,s, CH), 128.21 ,s, CH), 128.49 ,s, CH),
136.36 ,s, C); MS FAB1 ,NBA): [M1H]1: 339; IR
±CꢀO†Me . ±CꢀO†OMe . ±PꢀO†ꢀCH2OCH2Ph†
2
, ±PꢀO†ꢀOEt†
2
,NaCl): n 2890, 1500, 1455, 1435, 1210, 1190, 1095 cm21
.
Compound 6: Mp 608C; 31P NMR ,81 MHz, CDCl3): d 41.
1
2
3. Conclusion
22 ,s); H NMR ,200 MHz, CDCl3): d 3.97 ,6H, d, JPHˆ
5.4 Hz), 4.62 ,6H, s), 7.24±7.37 ,15H, m); 13C NMR
1
In order to evaluate the biological interest of the bis-
,hydroxymethyl)phosphoryl group in comparison to the
phosphonic group present in a wide range of biological
molecules, two kinds of derivatives have been synthesized
as analogs to glyphosatew and tiludronatew or 2-,30PEBP).
,50 MHz, CDCl3): d 62.95 ,d, JPCˆ79.9 Hz, CH2), 75.52
,d, 3JPCˆ10.4 Hz, CH2), 128 ,s, CH), 128.10 ,s, CH), 128.51
,s, CH), 136.88 ,s, C); MS FAB1 ,NBA): [M1H]1: 411; IR
,CCl4): n 2865, 1500, 1455, 1430, 1390, 1240, 1205, 1185,
1095, 1030 cm21
.
First, we elaborated a new chloromethylphosphorylated
building block 4 allowing the access to the various target
molecules. Then we have developed from this building
block, some synthetic ways leading to the analogs 8 and
11 of a-aminoalkylphosphonic acids, and analogs 19, 21
and 22 of the bisphosphonic acids in good yields.
4.1.3. Bisꢀbenzyloxymethyl) phtalimidomethylphosphine
oxide 9. A suspension of bis,benzyloxymethyl) chloro-
methylphosphine oxide 4 ,2.61 g, 7.7 mmol) and potassium
phtalimide ,1.71 g, 9.25 mmol) in DMF ,30 ml) was
re¯uxed for 3 h. Water ,50 ml) was added to the cooled
reaction mixture. The aqueous layer was extracted with
CH2Cl2. The organic layer was dried ,MgSO4), concen-
trated, and the residue puri®ed by column chromatography
with CH2Cl2/MeOH ,100:0±95:5) to give 58% yield of
compound 9 ,2 g, 4.45 mmol) as a colorless oil.
4. Experimental
4.1. General
1
31P NMR ,81 MHz, CDCl3): d 38.65 ,s); H NMR ,200
2
MHz, CDCl3): d 4.06 ,4H, d, JPHˆ5.9 Hz), 4.26 ,2H, d,
All solvents were distilled prior to use, and commercially
available reagents used without further puri®cation. All
2JPHˆ6.9 Hz), 4.60 ,4H, s), 7.22±7.32 ,10H, m), 7.59±7.75
1
,4H, 2m); 13C NMR ,50 MHz, CDCl3): d 33.03 ,d, JPCˆ
reactions were monitored by TLC ,Merck, SIL G/UV254
)
1
or 31P NMR. Merck silica gel ,20±40 mm) was used for
¯ash column chromatography and Merck silica gel ,63±
200 mm) for column chromatography. Melting points were
determined using a Wild Leitz 350 and are given uncor-
66.2 Hz, CH2), 65.15 ,d, JPCˆ79.9 Hz, CH2), 75.77 ,d,
3JPCˆ11.2 Hz, CH2), 123.42 ,s, CH), 127.89 ,s, CH),
127.97 ,s, CH), 128.43 ,s, CH), 131.82 ,s, C), 134.15 ,s,
CH), 136.69 ,s, C), 167.49 ,s, C); MS FAB1 ,NBA):
[M1H]1: 450; IR ,CCl4): n 1740, 1470, 1455, 1260,
1
rected. H, 13C, and 31P NMR spectra were recorded on a
1195, 1180, 1095 cm21
.
BRUKER AC-200 spectrometer. Chemical shifts are
expressed in ppmand coupling constants in Hz. IR spectra
were obtained with a Perkin±Elmer 377. Mass spectra were
measured with a Jeol JMS DX-300 spectrometer.
4.1.4. Bisꢀbenzyloxymethyl) aminomethyl phosphine
oxide hydrochloride 10, HCl. Hydrazine hydrate ,0.27 g,

9154
H.-J. Cristau et al. / Tetrahedron 57 ꢀ2001) 9149±9156
5.35 mmol) was added with stirring to a solution of
compound 9 ,2 g, 4.45 mmol) in absolute ethanol ,13 ml)
and the mixture re¯uxed for 1 h and 30 min. The reaction
mixture was ®ltered after cooling, and the ®ltrate concen-
trated before addition of 30 ml of water. The reaction
mixture was then extracted, dried ,MgSO4) and concen-
trated. The light-yellow oily residue was dissolved in
100 ml of dry ether to which a solution of ether hydrochloric
acid 5N was added. The white crystalline hydrochloride
formed was ®ltered off, washed with ether and dried to
give 73% yield of compound 10 ,1.18 g, 3.32 mmol).
4.1.7. Benzyl N-bisꢀbenzyloxymethyl)phosphorylmethyl-
N-benzylglycinate 7. To a solution of compound 4 ,1.78 g,
5.3 mmol) in DMF ,10 ml), was added triethylamine ,5.6 g,
37 mmol) and benzyl N-benzylglycinate18 ,2.56 g,
10.6 mmol). The reaction mixture was heated for 7 days at
808C. After concentration of solvent and excess of triethyl-
amine, the residue was dissolved in ether and the triethyl-
ammonium chloride formed was ®ltered off. After removal
of solvent in vacuum, the residue was redissolved in
CH2Cl2, washed with 10% HCl and water to eliminate
benzyl N-benzylglycinate. The organic layer was washed
with NH4OH ,10%) and dried ,MgSO4). Removal of solvent
in vacuumyielded an oil, which was puri®ed by column
chromatography ,AcOEt/hexane, 50:50±70:30). Compound
7 ,1.18 g, 3.23 mmol) was obtained in 61% yield as a
colorless oil.
1
Mp: 155.58C; 31P NMR ,81 MHz, CDCl3): d 36.37 ,s); H
NMR ,200 MHz, CDCl3): d 3.54 ,2H, d, 2JPHˆ6.6 Hz), 4.14
,4H, d, 2JPHˆ6.3 Hz), 4.50 ,4H, s), 7.16±7.26 ,10H, m); 13
C
1
NMR ,50 MHz, CDCl3): d 32.37 ,d, JPCˆ64.5 Hz, CH2),
1
3
63.70 ,d, JPCˆ84.7 Hz, CH2), 75.43 ,d, JPCˆ12.7 Hz,
CH2), 127.91 ,s, CH), 127.97 ,s, CH), 128.33 ,s, CH),
138.68 ,s, C).
31P NMR ,81 MHz, CDCl3): d 44.73 ,s); 1H NMR
2
,200 MHz, CDCl3): d 3.33 ,2H, d, JPHˆ5.5 Hz), 3.64
2
,2H, s), 3.90±3.92 ,4H, m, ABX system, JHAHB
ˆ
2
2
4.1.5. Bisꢀbenzyloxymethyl) aminomethyl phosphine
oxide 10. To a suspension of compound 10, HCl ,1.5 g,
4.22 mmol) in dry ether ,20 ml) was added triethylamine
,0.51 g, 5.06 mmol). After stirring the triethylammonium
chloride formed was ®ltered off, and the ®ltrate was concen-
trated. An oil was obtained ,1.32 g, 4.13 mmol) correspond-
ing to compound 10 ,98% yield).
212.6 Hz, JPHAˆ4.9 Hz, JPHBˆ6.4 Hz), 3.92 ,2H, s),
2
4.52±4.54 ,4H, m, AB system, JHAHBˆ212.1 Hz), 5.13
,2H, s), 7.25±7.37 ,20H, m); 13C NMR ,50 MHz, CDCl3):
1
3
d 47.35 ,d, JPCˆ80.1 Hz, CH2), 55.19 ,d, JPCˆ4.3 Hz,
3
1
CH2), 60.37 ,d, JPCˆ7.5 Hz, CH2), 62.35 ,d, JPCˆ
3
80.4 Hz, CH2), 66.19 ,s, CH2), 75.40 ,d, JPCˆ11.0 Hz,
CH2), 127.57 ,s, CH), 127.97 ,s, CH), 128.07 ,s, CH),
128.34 ,s, CH), 128.36 ,s, CH), 128.45 ,s, CH), 128.50 ,s,
CH), 128.63 ,s, CH), 129.25 ,s, CH), 135.75 ,s, C), 136.95
,s, C), 137.98 ,s, C), 190.17 ,d, 4JPCˆ1.3 Hz, C); MS FAB1
,GT): [M1H]1: 558; IR ,NaCl): n 1739, 1497, 1454, 1430,
31P NMR ,81 MHz, CDCl3): d 42.78 ,s); 1H NMR
,200 MHz, CDCl3): d 2.62 ,2H, bs, NH2), 3.22 ,2H, d,
2
2JPHˆ5.2 Hz), 3.93 ,4H, d, JPHˆ5.9 Hz), 4.59 ,4H, s),
7.26±7.36 ,10H, m); 13C NMR ,50 MHz, CDCl3): d 36.71
1207, 1179, 1098 cm21
.
1
1
,d, JPCˆ68.4 Hz, CH2), 63.73 ,d, JPCˆ78.6 Hz, CH2),
3
75.53 ,d, JPCˆ11.1 Hz, CH2), 127.95 ,s, CH), 128.11 ,s,
4.1.8. Diethyl bisꢀbenzyloxymethyl)phosphorylmethyl-
phosphonate 13. A stirred mixture of bis,benzyloxy-
methyl)chloromethylphosphine oxide 4 ,2.3 g, 6.7 mmol)
and triethyl phosphite ,1.34 g, 8 mmol), under nitrogen
was heated at 1508C for 20 h. Excess triethyl phosphite
was removed by vacuum distillation. The residue was puri-
®ed by ¯ash chromatography ,AcOEt/MeOH, 100:0±93:7)
to give 69% of compound 13 ,2.04 g, 4.63 mmol) as a
colorless oil.
CH), 128.46 ,s, CH), 136.60 ,s, C); MS FAB1 ,NBA):
[M1H]1: 320; IR ,CCl4): n 3500, 1495, 1455, 1435,
1210, 1195, 1095 cm21
.
4.1.6. Benzyl N-bisꢀbenzyloxymethyl)phosphorylmethyl-
glycinate 12. To a stirred mixture of compound 10 ,1.3 g,
4 mmol) and triethylamine ,2 g, 20 mmol) in absolute
ethanol ,2 ml), was added benzyl bromoacetate ,0.93 g,
4 mmol) and re¯uxed for 18 h.18 After concentration of
the excess of triethylamine, the residue mixture was dis-
solved in ether and the triethylammonium chloride formed
was ®ltered off. After ®ltration, the organic layer was washed
with aq. NH4OH ,10%) and dried ,MgSO4). Removal of
solvent in vacuumyielded an oil, which was puri®ed by
column chromatography ,AcOEt/MeOH, 100:0±95:5).
2
31P NMR ,81 MHz, CDCl3): d 21.21 ,d, JPPˆ12.8 Hz),
2
1
39.06 ,d, JPPˆ12.7 Hz); H NMR ,200 MHz, CDCl3): d
3
2
1.27 ,6H, t, JHHˆ7.1 Hz), 2.41 ,2H, dd, JP1Hˆ20.4 Hz,
2JP2Hˆ13.9 Hz), 4.00±4.03 ,4H, m, system ABX, JHAHB
ˆ
2
2
2
212.9 Hz, JP2HAˆ5.2 Hz, JP2HBˆ6.6 Hz), 4.15 ,4H, m,
3
3
A2M3X system, JMHAˆ7.1 Hz, JP1HAˆ8.2 Hz), 4.62±4.63
2
,4H, m, AB system. JHAHBˆ212.1 Hz), 7.26±7.32 ,10H,
Compound 12 ,0.83 g, 1.78 mmol) was obtained in 45%
yield as a yellow oil. 31P NMR ,81 MHz, CDCl3): d 43.21
,s); 1H NMR ,200 MHz, CDCl3): d 2.01 ,1H, bs, NH), 3.19
m); 13C NMR ,50 MHz, CDCl3): d 16.20 ,d, 3JP1Cˆ6.4 Hz,
1
1
CH3), 21.30 ,dd, JP1Cˆ135.5 Hz, JP2Cˆ53.39 Hz, CH2),
2
1
62.61 ,d, JP1Cˆ6.4 Hz, CH2), 64.13 ,dd, JP2Cˆ85.5 Hz,
2
2
3
,2H, d, JPHˆ7.7 Hz), 3.51 ,2H, s), 3.93 ,4H, d, JPHˆ
3JP1Cˆ3.5 Hz, CH2), 75.45 ,d, JP2Cˆ11.7 Hz, CH2),
5.9 Hz), 4.60 ,4H, s), 5.15 ,2H, s), 7.26±7.35 ,15H, m);
128.02 ,s, CH), 128.10 ,s, CH), 128.47 ,s, CH), 136.80 ,s,
C); MS FAB1 ,matrice NBA): [M1H]1: 441; IR ,NaCl) n
13C NMR ,50 MHz, CDCl3): d 43.66 ,d, JPCˆ75.8 Hz,
1
3
1
CH2), 51.80 ,d, JPCˆ12.3 Hz, CH2), 63.60 ,d, JPCˆ
1720, 1495, 1455, 1250, 1190, 1095, 1050, 1025 cm21
.
3
80.2 Hz, CH2), 66.50 ,s, CH2), 75.43 ,d, JPCˆ10.9 Hz,
CH2), 127.93 ,s, CH), 128.04 ,s, CH), 128.28 ,s, CH),
128.34 ,s, CH), 128.43 ,s, CH), 128.53 ,s, CH), 135.43 ,s,
4.1.9. Dibenzyl bisꢀbenzyloxymethyl)phosphorylmethyl-
phosphonate 14. A stirred mixture of bis,benzyloxy-
methyl)chloromethylphosphine oxide 4 ,0.78 g, 2.3 mmol)
and tribenzyl phosphite19 ,2.08 g, 5.9 mmol) was heated for
6 h at 1608C/4 mmHg. The crude mixture was puri®ed by
C), 136.73 ,s, C), 171.52 ,d, JPCˆ0.55 Hz, C); MS FAB1
4
,NBA): [M1H]1: 468; IR ,NaCl): n 3450, 1740, 1500,
1455, 1435, 1215, 1175, 1145, 1095 cm21
.

H.-J. Cristau et al. / Tetrahedron 57 ꢀ2001) 9149±9156
9155
2
¯ash chromatography ,CH2Cl2/MeOH, 100:0±98:2) to
give 60% of compound 14 ,0.78 g, 1.38 mmol) as a color-
less oil.
31P NMR ,81 MHz, CDCl3): d 24.45 ,d, JPPˆ1.9 Hz);
2
1
44.07 ,d, JPPˆ1.9 Hz); H NMR ,200 MHz, CDCl3): d
3
1.07 and 1.30 ,6H, 2d, JHHˆ7.1 and 7.1 Hz), 2.77 ,1H,
2
2
3
m, AMNXY system, JP1Hˆ22.2 Hz, JP2Hˆ13.5, JHH
ˆ
2
31P NMR ,81 MHz, CDCl3): d 22.56 ,d, JPPˆ12.8 Hz);
8.3, 5.2 Hz), 3.20±3.69 ,2H, m), 3.76±4.35 ,4H, m),
2
1
2
38.24 ,d, JPPˆ12.7 Hz); H NMR ,200 MHz, CDCl3): d
4.17±4.27 ,2H, m, ABXY system, JHAHBˆ213.2 Hz,
2
2
2
4
2.53 ,2H, dd, JP1Hˆ20.7 Hz, JP2Hˆ13.8 Hz), 3.96±3.98
2JP2HAˆ7.6 Hz, JP2HBˆ6.3 Hz, JP1HAˆ2.6 Hz), 3.65±4.08
,2H, m, ABXY system, 2JHAHBˆ212.7 Hz, 2JP2HAˆ6.6 Hz,
2
2
,4H, m, ABX system, JHAHBˆ212.9 Hz, JP2HAˆ5.4 Hz,
2
2JP2HBˆ6.6 Hz), 4.55±4.56 ,4H, m, AB system, JHAHB
ˆ
2JP2HBˆ6.4 Hz, JP1HAˆ2.0 Hz), 4.42±4.45 ,2H, m, AB
4
2
211.9 Hz), 5.07 ,4H, m, ABX system, JHAHBˆ212.0 Hz,
system, 2JHAHBˆ211.5 Hz), 4.61±4.74 ,2H, m, AB system,
3JP1HAˆ7.9 Hz, JP1HBˆ8.3 Hz), 7.22±7.33 ,20H, m); 13C
2JHAHBˆ211.7 Hz), 7.13±7.54 ,12H, m), 8.45 ,2H, m); 13
C
3
1
NMR ,50 MHz, CDCl3): d 23.58 ,dd, JP1Cˆ133.9 Hz,
NMR ,50 MHz, CDCl3): d 15.97 and 16.27 ,2d, 3JP1Cˆ6.5,
6.2 Hz, CH3), 26.94 ,dd, 2JP1Cˆ5.2 Hz, 2JP2Cˆ2.7 Hz, CH2),
36.97 ,dd, 1JP1Cˆ131.5 Hz, 1JP2Cˆ49.5 Hz, CH), 62.15 and
1JP2Cˆ53.5 Hz, CH2), 65.04 ,dd, JP2Cˆ85.0 Hz, JP1C
ˆ
1
3
2
4.1 Hz, CH2), 67.85 ,d, JP1Cˆ6.1 Hz, CH2), 75.28 ,d,
3JP2Cˆ11.5 Hz, CH2), 127.86±128.50 ,CH), 135.85 ,dd,
63.03 ,2d, JP1Cˆ6.6, 6.4 Hz, CH2), 63.27 and 66.13 ,dd,
2
3JP1Cˆ6.4 Hz, JP2Cˆ0.5 Hz, C), 136.77 ,s, C); MS FAB1
1JP2Cˆ83.8 Hz, JP1Cˆ5.9 Hz, d, JP2Cˆ82.2 Hz, CH2),
5
3
1
,NBA): [M1H]1: 565; IR ,NaCl): n 1495, 1457, 1259,
75.57 and 75.64 ,2d, JP2Cˆ12.3, 10.67 Hz, CH2), 123.17
3
1183, 1085, 1000, 876, 825 cm21
.
,s, CH), 127.99 ,s, CH), 128.05 and 128.14 ,2s, CH), 128.22
,s, CH), 128.42 and 128.50 ,2s, CH), 134.65 ,dd, 3JPCˆ5.58,
7.07 Hz, C), 136.52 ,s, CH), 137.09 ,s, C), 148. 05 and
150.40 ,2s, CH); FAB1 ,NBA): [M1H]1: 532; IR
,NaCl): n 1496, 1450, 1248, 1185, 1092, 1040, 1020, 970,
4.1.10. Diethyl bisꢀbenzyloxymethyl)phosphoryl-4-chloro-
phenylthiomethylphosphonate 18. To a solution of com-
pound 13 ,0.3 g, 0.68 mmol) in DMF ,6 ml) was added
under nitrogen, at 08C, sodiumhydride ,0.03 g, 1.36
mmol) in small portions. After 40 min, bis,4-chlorophenyl)-
disul®de20 ,0.22 g, 0.75 mmol) was added in one portion.
The mixture was stirred for 3 h at room temperature.
825, 740, 710 cm21
.
4.2. General procedure for deprotection
4.2.1. Hydrogenolysis
After acidi®cation with HCl ,1N) and ®ltration, the reaction
mixture was concentrated and then puri®ed by ¯ash
chromatography ,AcOEt/hexane, 50:50±90:10). Compound
18 ,0.26 g, 0.45 mmol) was obtained in 65% yield as a
colorless oil.
4.2.1.1. Hydrogenolysis of benzyl N-bisꢀbenzyloxy-
methyl)phosphorylmethyl-N-benzyl glycinate 7. To a
solution of compound 7 ,0.2 g, 0.36 mmol) in dry methanol
,10 ml) was added under nitrogen, Pd/C 10% ,0.04 mg) and
ammonium formate ,0.11 g, 1.81 mmol). The mixture is
re¯uxed during 4 h. After cooling, the reaction mixture
was ®ltered on celite, and the ®ltrate concentrated to give
an oil. After precipitation in a mixture of water/acetone,
compound 8 ,0.05 g, 0.23 mmol) was obtained as a white
powder ,yield 64%).
2
31P NMR ,81 MHz, CDCl3): d 18.77 ,d, JPPˆ6.6 Hz),
2
1
43.44 ,d, JPPˆ6.6 Hz); H NMR ,200 MHz, CDCl3): d
3
1.22 and 1.26 ,6H, 2t, JHHˆ7.2 and 7.2 Hz), 3.59 ,1H,
2
2
dd, JP1Hˆ19.7 Hz, JP2Hˆ12.3 Hz), 4.10±4.37 ,8H, m),
2
4.36. 4.47 ,2H, m, AB system, JHAHBˆ211.4 Hz), 4.59±
4.71 ,2H, m, AB system, 2JHAHBˆ211.7 Hz), 7.06±7.46 ,m,
3
CH); 13C NMR ,50 MHz, CDCl3): d 16.67 ,d, JP1C
ˆ
Mp: 133±1358C: 31P NMR ,81 MHz, D2O): d 44.47 ,s); 1H
1
1
2
5.7 Hz, CH3), 39.39 ,dd, JP1Cˆ138.9 Hz, JP2Cˆ42.3 Hz,
NMR ,200 MHz, D2O): d 3.76 ,2H, d, JPHˆ7.6 Hz), 3.80
1
3
,2H, s), 4.31 ,4H, d, JPHˆ2.7 Hz); 13C NMR ,50 MHz,
2
CH), 62.55 and 65.35 ,dd, JP2Cˆ89.8 Hz, JP1Cˆ5.0 Hz,
1
2
1
3
d, JP2Cˆ82.2 Hz, CH2), 64.26 and 64.44 ,2d, JP1Cˆ6.3
D2O): d 41.92 ,d, JPCˆ59.6 Hz, CH2), 53.77 ,d, JPCˆ
3
1
and 6.8 Hz, CH2), 75.88 and 76.03 ,2d, JP2Cˆ12.6 and
5.5 Hz, CH2), 58.38 ,d, JPCˆ78.5 Hz, CH2), 173.45 ,s,
C); FAB1 ,NBA): [M1H]1: 198.
10.9 Hz, CH2), 128.04 ,s, CH), 128.13 ,s, CH), 128.44 ,s,
CH), 129.32 ,s, CH), 132.68 ,s, CH), 132.94 ,dd, 3JPCˆ2.01,
3.02 Hz, C), 134.23 ,s, C), 136.57 and 137.03 ,2s, C); MS
FAB1 ,NBA): [M1H]1: 584; IR ,NaCl): n 1495f, 1480,
4.2.1.2. Hydrogenolysis of benzyl N-bisꢀbenzyloxy-
methyl)phosphorylmethylglycinate 12. To a solution of
compound 12 ,0.2 g, 0.43 mmol) in dry methanol ,10 ml)
was added, under nitrogen, Pd/C 10% ,0.04 mg) and
ammonium formate ,0.135 g, 2.14 mmol). The mixture
was re¯uxed during 4 h, then, after cooling, ®ltered on
celite and the ®ltrate concentrated to give compound 8 as
a yellow oil. After precipitation in a mixture of water/
acetone, compound 8 was obtained as a white powder
,68 mg, 0.35 mmol) ,yield 80%).
1455, 1250, 1190, 1095, 1050, 1020, 970 cm21
.
4.1.11. Diethyl bisꢀbenzyloxymethyl)phosphoryl-2-ꢀ3-
pyridyl)ethylphosphonate 20. To a solution of compound
13 ,0.6 g, 1.36 mmol) in dimethylformamide ,6 ml) was
added under nitrogen, at 08C, sodiumhydride ,0.07 g,
2.70 mmol) in small portions. After 40 min, 3-picolyl-
chloride ,0.2 g, 1.49 mmol) was added in one portion. The
mixture was heated at 508C for 6 h. After cooling to room
temperature, the mixture was treated with HCl ,1N). After
®ltration, the residue was washed successively with NaOH
5% and water, dried ,MgSO4) and concentrated. The residue
was puri®ed by chromatography on alumina ,AcOEt/
MeOH, 100:0±97:3). Compound 20 ,0.5 g, 0.94 mmol)
was obtained in 69% yield as a yellow oil.
4.2.1.3. Hydrogenolysis of diethyl bisꢀbenzyloxy-
methyl)phosphorylmethylphosphonate 13. To a solution
of compound 13 ,0.28 g, 0.64 mmol) in absolute ethanol
,1 ml) was added Pd/C 10% ,0.03 mg), After consumption
of the required volume of hydrogen in 2 h, the mixture was
®ltered on celite and the ®ltrate concentrated to give

9156
H.-J. Cristau et al. / Tetrahedron 57 ꢀ2001) 9149±9156
compound 15 ,54.6 mg, 0.21 mmol) as a yellow oil ,yield
33%).
,1 ml, 12 mmol) is re¯uxed at 1008C for 18 h. The excess
HCl and water is removed by vacuum distillation. After
addition of 5 ml of ethanol, the mixture is concentrated by
vacuum in order to remove HCl. After a chromatographic
separation on reverse phase ,H2O/MeOH, 50:50±60:40 we
obtained, after basi®cation with NaOH ,1N) ,pHˆ11±12),
86% yield of compound 21 ,0.082 g, 0.24 mmol) as a
yellow oil.
31P NMR ,81 MHz, D2O): d 22.43 ,d, 2JPPˆ13.3 Hz), 44.17
2
1
,d, JPPˆ13.3 Hz); H NMR ,200 MHz, CD3OD): d 1.32
3
2
2
,6H, t, JHHˆ7.0 Hz), 2.67 ,2H, dd, JP1Hˆ20.7 Hz, JP2H
ˆ
2
13.4 Hz), 4.06±4.09 ,4H, m, ABX system, JHAHB
ˆ
2
2
214.1 Hz, JP2HAˆ3.1 Hz, JP2HBˆ4.2 Hz), 4.18 ,4H, m,
A2M3X system, JMHAˆ7.2 Hz, JP1HAˆ7.4 Hz); 13C NMR
3
3
3
2
,50 MHz, CDCl3): d 16.24 ,d, JP1Cˆ6.4 Hz, CH3), 22.18
31P NMR ,81 MHz, D2O): d 12.73 ,bs); 52.62 ,d, JPPˆ
1
1
1
1
5.1 Hz); H NMR ,200 MHz, D2O): d 2.65 ,1H, m), 3.23
,dd, JP1Cˆ134.4 Hz, JP2Cˆ48.3 Hz), 57.85 ,dd, JP2C
ˆ
3
2
78.6 Hz, JP1Cˆ3.5 Hz, CH2), 63.07 ,d, JP1Cˆ6.5 Hz,
,2H, m), 3.87 and 4.23 ,4H, 2m), 7.44 ,1H, m), 7.91 ,1H,
m), 8.45 ,1H, m); 13C NMR ,50 MHz, D2O): d 31.16 ,m,
CH2); MS FAB1 ,NBA): [M1H]1: 261; IR ,NaCl): n
3200±3500, 1240, 1165, 1095, 1050, 1025, 975F cm21
.
CH2); 42.01 ,dd, JP1Cˆ109.1 Hz, JP2Cˆ45.5 Hz, CH),
1
1
1
1
58.76 and 60.78 ,d, JP2Cˆ71.6 Hz, dd, JP2Cˆ72.1 Hz,
3JP1Cˆ2.5 Hz, CH2), 135.70 ,m, C), 140.69 ,s, CH),
149.29 and 151.83 ,2s, CH).
4.2.1.4. Hydrogenolysis of dibenzyl bisꢀbenzyloxy-
methyl)phosphorylmethylphosphonate 14. To a solution
of compound 14 ,0.2 g, 0.45 mmol) in absolute ethanol
,1 ml) was added Pd/C 10% ,0.02 mg). After consumption
of the required volume of hydrogen, the mixture was ®ltered
on celite and the ®ltrate concentrated to give compound 16
,90 mg, 0.44 mmol) as a yellow oil ,yield 98%).
References
1. Kafarski, P.; Lejczak, B. Phosphorus, Sulfur Silicon 1991, 63,
193±215.
31P NMR ,81 MHz, D2O): d 17.01 ,d, 2JPPˆ12.9 Hz), 47.18
2. Franz, J. E. Ger. Offen. 2 152 826, 1972; Chem. Abstr. 1972,
77, 165079k.
2
1
,d, JPPˆ12.6 Hz); H NMR ,200 MHz, D2O): d 2.57 ,2H,
2
2
2
3. Sietsema, W. K.; Ebetino, F. H. Exp. Opin. Invest. Drugs
1994, 3, 1255±1276.
dd, JP1Hˆ19.8 Hz, JP2Hˆ14.6 Hz), 4.18 ,4H, d, JP2H
ˆ
ˆ
1
2.7 Hz); 13C NMR ,50 MHz, D2O): d 25.70 ,dd, JP1C
1
1
4. Fleisch, H. Medicina 1997, 57, 65±75.
5. Sietsema, W. K.; Ebetino, F. H. Exp. Opin. Invest. Drugs
1994, 3, 1255±1276.
129.20 Hz, JP2Cˆ53.0 Hz, CH2), 59.25 ,dd, JP2Cˆ81.0
Hz, 3JP1Cˆ3.4 Hz, CH2); MS FAB1 ,NBA): [M1 H]1: 205.
6. Rawls, R. L. Chem. Engng. 1998, 38±40.
Á
7. Breliere, J. C.; Edmonds-Alt, X.; Garcia, G. EP 100 718,
1983; Chem. Abstr. 1984, 100, 192078j.
4.2.2. Hydrolysis.
4.2.2.1. Hydrolysis of diethyl bisꢀbenzyloxymethyl)-
phosphorylmethylphosphonate 13. A stirred mixture of
compound 13 ,0.2 g, 0.45 mmol) in HCl 4N ,1.5 ml,
18 mmol) is re¯uxed at 1008C for 12 h. The excess HCl
and water were removed by vacuum distillation. After addi-
tion of the same quantity of ethanol, the mixture is concen-
trated by vacuumin order to remove the traces of HCl. This
last step is repeated ®ve times. We obtained compound 16
,84 mg, 0.41 mmol) as a yellow oil ,yield 91%).
8. Ebetino, F. H.; Degenhardt, C. R.; Jamieson, L. A.; Burdsall,
D. C. Heterocycles 1990, 2, 855±862.
9. ,a) Petrov, K. A.; Parshina, V. A.; Luzanova, B. J. Gen. Chem.
SSSR 1962, 32, 542±545. ,b) Ellis, J. W.; Harrison, K. N.;
Hoye, P. A. T.; Orpen, A. G.; Pringle, P. G.; Smith, M. B.
Inorg. Chem. 1992, 31, 3026±3033.
10. Maier, L. Helv. Chim. Acta 1969, 52, 858±871.
11. Ram, S.; Ehrenkaufer, R. E. Synthesis 1988, 2, 91±95.
12. ,a) Trostyanskaya, E. B.; Venkova, E. S.; Mikhailin, Y. A. J. Gen.
Chem. SSSR 1967, 37, 1572±1574. ,b) Varbanov, S.; Tsvetkov,
E. N.; Borisov, G. Phosphorus Sulfur 1984, 19, 305±309.
13. Cameron, D. G.; Hudson, H. R.; Pianka, M. Phosphorus,
Sulfur Silicon 1993, 83, 21±38.
4.2.2.2. Hydrolysis of diethyl bisꢀbenzyloxymethyl)-
phosphoryl-4-chlorophenylthiomethyl phosphonate 18.
A stirred mixture of compound 18 ,0.3 g, 0.51 mmol) in
HCl 4N ,2 ml, 24 mmol) is re¯uxed at 1008C for 18 h.
Excess HCl and water are removed by vacuum
distillation, After addition of 5 ml of ethanol, the mixture
is concentrated by vacuumin order to remove HCl. This
last step is repeated ®ve times. Compound 19 ,0.168 g,
0.48 mmol) is obtained as a colorless oil ,yield 94%).
14. Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev. 1981, 81,
415±430.
15. Saady, M.; Lebeau, L.; Mioskowski, C. Helv. Chim. Acta
1995, 78, 670±678.
16. ,a) Carey, F. A.; Sundberg, R. J. Advanced Organic
Chemistry; 3rd ed.; Plenum: New York, 1990; pp 196±209.
,b) Exner, O. In Correlation Analysis in Chemistry; Chapman,
N. B., Shorter, J., Eds.; Plenum: New York, 1978; Chapter 10.
17. Teulade, M. P.; Savignac, P. J. Organomet. Chem. 1986, 312,
283±295.
31P NMR ,81 MHz, D2O): d 11.72 ,d, 2JPPˆ10.6 Hz); 53.71
2
1
,d, JPPˆ10.6 Hz); H NMR ,200 MHz, D2O): d 3.12 ,1H,
2
2
dd, JP1Hˆ17.5 Hz, JP2Hˆ10.7 Hz), 3.98±4.12 ,4H, m),
7.26±7.32 ,4H, m; 13C NMR ,50 MHz, D2O): d 45.12 ,dd,
1
1JP1Cˆ112.3 Hz, JP21Cˆ40.7 Hz, CH), 59.78 and 60.89 ,d,
3
1JP2Cˆ78.4 Hz, dd, JP2Cˆ73.1 Hz, JP1Cˆ2.9 Hz), 130.29
18. Bossler, H. G.; Seebach, D. Helv. Chim. Acta 1994, 77, 1124±
1165.
3
,s, CH), 132.88 ,s, CH), 133.04 ,dd, JPCˆ1.6, 2.6 Hz, C),
136.01 ,s, C); MS FAB1 ,NBA): [M1H]1: 347.
19. Campbell, M. M.; Carruthers, N. I.; Mickel, J. S. Tetrahedron
1982, 38, 2513±2524.
20. Wang, Z. Y.; Bonanno, G.; Hay, A. S. J. Org. Chem. 1992, 57,
2751±2753.
4.2.2.3. Hydrolysis of diethyl bisꢀbenzyloxymethyl)-
phosphoryl-2-ꢀ3-pyridyl)ethylphosphonate 20. A stirred
mixture of compound 20 ,0.15 g, 0.28 mmol) in HCl 4N