Synthesis of phosphinic acid analogues of glycyl-glycine and crystal structure of n-glycyl-aminomethyl-(phenylphosphinic) acid

Article abstract of DOI:10.1081/SCC-120001512

Phosphinic acid analogues of Gly-Gly, NH₂CH₂CONHCH₂-P(R)O₂H (R=Me, Ph, t-Bu), were synthesised by the active ester method from free aminomethylphosphinic acids purified on cation exchange resins. The crystal and

Full text of DOI:10.1081/SCC-120001512

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SYNTHESIS OF PHOSPHINIC ACID ANALOGUES OF
GLYCYL–GLYCINE AND CRYSTAL STRUCTURE OF N-
GLYCYL-AMINOMETHYL-(PHENYLPHOSPHINIC) ACID
Michal Lukáš a , Pavel Vojtíšek a , Petr Hermann , Jan Rohovec a & Ivan Lukeš a
a Department of Inorganic Chemistry, Faculty of Sciences, Universita Karlova , Hlavova
2030, 128 40 Prague 2, Czech Republic
Published online: 21 Aug 2006.
To cite this article: Michal Lukáš , Pavel Vojtíšek , Petr Hermann , Jan Rohovec & Ivan Lukeš (2002) SYNTHESIS
OF PHOSPHINIC ACID ANALOGUES OF GLYCYL–GLYCINE AND CRYSTAL STRUCTURE OF N-GLYCYL-AMINOMETHYL-
(PHENYLPHOSPHINIC) ACID, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 32:1, 79-88, DOI: 10.1081/SCC-120001512
To link to this article: http://dx.doi.org/10.1081/SCC-120001512
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SYNTHETIC COMMUNICATIONS, 32(1), 79–88 (2002)
SYNTHESIS OF PHOSPHINIC ACID
ANALOGUES OF GLYCYL–GLYCINE
AND CRYSTAL STRUCTURE OF
N-GLYCYL-AMINOMETHYL-
(PHENYLPHOSPHINIC) ACID
Michal Lukas, Pavel Vojtısek, Petr Hermann,*
Jan Rohovec, and Ivan Lukes
Department of Inorganic Chemistry,
Faculty of Sciences, Universita Karlova,
Hlavova 2030, 128 40 Prague 2, Czech Republic
ABSTRACT
Phosphinic acid analogues of Gly-Gly, NH2CH2CONHCH2-
P(R)O2H (R¼Me, Ph, t-Bu), were synthesised by the active
ester method from free aminomethylphosphinic acids purified
on cation exchange resins. The crystal and molecular structure
was determined for Gly–Gly(PPh)ÁH2O (R¼Ph). The results
point to similar bond parameters as were found for Gly–Gly
and its phosphonic analogue Gly–Gly(P).
*Corresponding author. E-mail: petrh@prfdec.natur.cuni.cz
79
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

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LUKAS ET AL.
Phosphonic (ÀPO(OH)2) and phosphinic (ÀPO(R)OH, R¼H, alkyl,
aryl) acid analogues of amino acids and their oligopeptides are a well-known
class of enzyme inhibitors.1 Phosphinic acid derivatives strongly inhibit
enzymes such as matrix metalloproteinases and astacin,2 angiotensin I
converting enzyme,3 thrombin,4 endothelin converting enzyme5 and alter
functions of receptors, e.g. GABA receptors.6 Aminoalkylphosphinic
acid peptides have been proposed as compounds of interest for new drug
design, e.g. analgetics,7 antibiotics8 or agents against protozoa infections.9
Numerous complex oligopeptides containing aminoalkylphosphinic acids
has been synthesised; however, surprisingly no attention has been paid to
synthesis of the simplest dipeptides like analogues of Gly–Gly.
To continue our investigations on complexing properties of the metal
cations with dipeptides containing aminoalkylphosphonic acids10 and with
simple aminoalkylphosphinic acids,11 we envisaged to obtain a series of
simple phosphinodipeptides (Scheme 1). They contain phosphinic acid group
with a substituent exhibiting different electronic effects (methyl, phenyl and
t-butyl) to investigate a change in the complexing ability, similarly to our
previous studies.11 The results on the synthesis are presented in this paper.
Scheme 1.
SYNTHESIS
We used a route utilising easily available aminoalkylphosphinic acids
and N-hydroxysuccinimidyl esters of benzyloxycarbonyl-protected amino
acids patented12 some time ago. In the patents, dipeptides containing
alkyl/aryl chains were obtained in high yields and in pure state due to
precipitation of benzyloxycarbonyl-protected dipeptides. In contrast to the
patents, we used simplest amino acids (Scheme 2), glycine, aminomethyl-
(methylphosphinic) acid (Gly(PMe), aminomethyl(phenylphosphinic) acid
(Gly(PPh) and aminomethyl(tert-butylphosphinic) acids Gly(Pt-Bu). Two of
the acids were prepared by a known method11 from dichlorophosphines
RPCl2 (R¼Ph, t-Bu). As MePCl2 is an expensive and very air-sensitive
compound, Gly(PMe) was synthesised using a new route based on the

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81
Scheme 2.
reaction of N-tritylmethanimine TrN¼CH2 with MeP(O)(H)(OEt) under
conditions for synthesis of aminoalkylphosphonic acid esters.13 The starting
ethyl methylphosphinate acid was synthesized14 from hypophosphorous
acid, hexamethyldisilazane and methyl iodide15 followed by esterification
of the methylphosphinic acid obtained with ethyl chloroformate.
The peptide bond formation proceeded with reasonable yields (NMR
check), however, separation of the dipeptides from the reaction mixtures was
difficult. The protected glycine dipeptides did not precipitate from
reaction mixtures as was described12 for derivatives containing other amino
acids with more hydrophobic side chains. Therefore, purification of crude
products was a crucial point of the syntheses. For aminomethyl(methyl-
phosphinic) dipeptide, the pure protected dipeptide was obtained by a extrac-
tion (removing nonpolar by-products and Z-Gly) and chromatography on the
sulfonic acid cation exchange resin to remove free aminomethyl(methyl-
phosphinic) acid which was trapped on the resin. Deprotection with HBr/
AcOH gave pure phosphinodipeptide in 80% yield.
Unfortunately, the same strategy could not be used for the other
two phosphinic acid dipeptides as the protected dipeptides are insoluble
in water at acid pH and their extraction properties are similar to those
of the starting materials and by-products. Therefore, the partly purified
crude reaction mixture was used in following deprotection steps. Removing
of benzyloxycarbonyl group with HBr/AcOH gave a mixture of glycine,
aminophosphinic acid and their dipeptide. The mixture was subse-
quently purified by a combination of chromatography on sulfonic and
carboxylic acid cation exchange resins. Aminomethylphosphinic acids
were removed from sulfonated resins by gradient elution with water and
dilute ammonia solutions (0.1–2%) with a mixture of glycine and the
dipeptide being eluted first. Water elution of carboxylic resin afforded
the pure phosphinic dipeptides and glycine was trapped on the resin. We
found that extractions (see Experimental) removed a major part of
impurities but reduced yields of the pure dipeptides. Thus, mixtures of
common amino acids, aminoalkylphosphinic acids, and even amino-
phosphonic aicds,14 and their dipeptides could be separated in a multigram
scale using chromatography on sulfonic and/or carboxylic acid ion-
exchange resins.

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LUKAS ET AL.
CRYSTAL STRUCTURE OF GLY–GLY(PPH)ÁH2O16
Molecular structure of N-glycyl-aminomethyl(phenylphosphinic) acid
is depicted in Figure and selected bond distances are presented in Table. The
peptide in the solid state is present in the zwitterionic form. Parameters of
the peptide moiety are the same as those for Gly–Gly17 as well as for
Gly–Gly(P).18 The presence of the phosphinic acid moiety does not alter
the bond arrangement.
An interesting feature of the structure is its crystal packing. The
structure consists of hydrophilic and hydrophobic layers. The hydrophilic
part is filled with water molecules linked by hydrogen bonds (2.77–2.86 A)
to the dipeptide molecules and themselves. A water molecule interacts with
two closest molecules of Gly–Gly(PPh) in the same elementary cell: with
phosphinic acid group of one molecule and carbonyl oxygen of the other.
Non-bonding interactions between benzene rings stabilise the hydro-
phobic layer. The layered arrangement in the structure differs from
three-dimensional structures of the other two dipeptides stabilised by
hydrogen bonds.
Table. Bond Lengths (A) and Angles (ꢀ) in Molecule of Gly–Gly(PPh
)
Bond Lengths Angles
P–O1 1.485(2)
C1–N1 1.455(3)
N1–C2 1.330(2)
C2–C3 1.514(3)
C2–O3 1.233(2)
C3–N2 1.470(3)
O1–P–O2 117.6(1)
O1–P–C1 108.7(1)
O1–P–C11 108.3(1)
O2–P–C1 107.6(1)
O2–P–C11 109.1(1)
C1–P–C11 104.7(1)
P–C1–N1 110.8(1)
C1–N1–C2 122.6(2)
N1–C2–C3 114.2(2)
N1–C2–O3 124.6(2)
C3–C2–O3 121.3(2)
N2–C3–C2 111.3(2)
P–O2 1.517(1)
P–C1 1.836(2)
P–C11 1.804(2)
Figure. Molecular structure of Gly–Gly(PPh) with atom numbering scheme.

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83
We synthesised three new phosphinic acid dipeptides which can be
used for investigation of the phosphorus peptides interaction with metal
cations. Unprotected amino acids and phosphinic acid dipeptides can be
separated on cation exchange resins probably due to small differences in
pKA’s of the compounds and the separation suggests general utilization. The
same conditions with the cation exchange resins were also successfully used
for purification of phosphorus acid derivatives of tetraazamacrocycles.14
Molecular structure of phenylphosphinic acid dipeptide reveals no differ-
ences in bonds and angles between phosphinic and phosphonic dipeptides
and common glycyl–glycine.
EXPERIMENTAL
Reactions with trivalent phosphorus compounds were done in a
standard Schlenk apparatus. Solvents were purified using established
procedures.19 N-(benzyloxycarbonyl)glycine,20 succinimidyl N-(benzyloxy-
carbonyl)glycinate,21 Gly(PPh),11 Gly(Pt-Bu),11 N-tritylmethanimine13a were
synthetized by the methods published. Other chemicals were obtained from
commercial sources. Cation exchange resins used were Dowex 50 W Â 4
(50–100 mesh, sulfonic acid resin) (Fluka) and Amberlite CG50/N1
(100–200 mesh, carboxylic acid resin) (Rohm & Haas) in the Hþ form.
NMR spectra were recorded on a Varian Unity Plus at 400 MHz (1H,
internal reference TMS (CDCl3) or t-BuOH (D2O)), 161.9 MHz ( 31P{1H},
external reference 85% H3PO4) and 100.6 MHz (13C, internal reference
t-BuOH (D2O)). TLC silica plates (‘‘Silufol’’, Kavalier, Czech Republic)
were developed in the following mixtures: i-PrOH:25% aq.
NH3:H2O ¼ 10:1:1 (A); BuOH:AcOH:H2O ¼ 4:2:3 (B); i-PrOH:25% aq.
NH3:H2O ¼ 15:3:3 (C), CHCl3:acetone ¼ 1:3 (D). Detection with ninhydrin
(0.3% in EtOH) or with Bromocresol Green (0.5% in EtOH with several
drops of aqueous Na2HPO4 solution to give a persistent blue colour).
Melting points were determined on a Kofler hot-plate apparatus and were
uncorrected. Elemental analyses were performed in the Institute of Macro-
molecular Chemistry of the Academy of Sciences of the Czech Republic.
X-ray structure analysis: CAD 4 (Enraf Nonius) at 293(1) K with
MoKa (ꢀ ¼ 0.71073 A); scan ! À 2#; lattice parameters determined from
25 reflections (#; 13–14ꢀ); Lorenzian-polarization correction were applied
using program JANA 98;24 no absorption correction were applied; the
structure solved by the combination of direct methods and Fourier
method; refined by full-matrix least-squares techniques (SHELXS86,25
SHELXK9726); the positions of hydrogen atoms found on the difference
maps and refined isotropically. Crystallographic data for the structure

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LUKAS ET AL.
reported in this paper have been deposited with the Cambridge Crystallo-
graphic Data Centre as supplementary publication numbers CCDC-138778.
Copies of the data can be obtained free of charge on application to CCDC;
e-mail: deposit@ccdc.cam.ac.uk.
Aminomethyl(methylphosphinic) Acid Gly(PMe
)
Ethyl methylphosphinate (4.20 g, 0.039 mol) was dissolved in 4 mL of
dry toluene, the solution was heated to 100ꢀC and a hot solution of
TrN¼CH2 (10.60 g, 0.039 mol) in 20 mL of dry toluene was quickly
added. The mixture was kept at 100ꢀC for 4 h, cooled and left in a refrig-
erator overnight. The crystalline product TrNHCH2P(O)(Me)(OEt)22 was
filtered off and hydrolysed in a refluxing mixture of 20 mL of EtOH and
20 mL of conc. HCl for 12 h. Solvents were removed using vacuum evapo-
rator and the semi-solid was dissolved/suspended in 20 mL of water.
Insoluble Tr-Cl and other non-polar impurities were extracted with 3 Â 20 mL
of chloroform. The aqueous solution was purified on Dowex 50 (Hþ-form,
2 Â 15 cm) by elution with water (200 mL) followed by 5% aq. ammonia.
The fractions containing the product were evaporated and three times
co-distilled with water to remove excess of ammonia. The residue was
dissolved in 10 mL of water and acetone was added to cloudiness and the
mixture left overnight. The product was filtered off, washed with acetone
and dried in air. 3.30 g (77%). M.p. 290–295ꢀC (dec.), Rf ¼ 0.7 (A). 1H NMR
2
2
(KOD/D2O): 1.20 (d, 3H, JPH 13.1 Hz, PCH3); 2.63 (d, 2H; JPH 9.6 Hz,
NCH2P). 31P NMR (KOD/D2O): 42.5.
N-Glycyl-aminomethyl(methylphosphinic) Acid Gly–Gly(PMe
)
Aminomethyl(methylphosphinic) acid (1.00 g, 9.17 mmol) and
NaHCO3 (1.54 g, 18.34 mmol) was dissolved in a mixture of 50 mL of
EtOH and 25 mL of water and filtered through a small plug of cotton
wool. The filtrate was cooled to 0–5ꢀC in an ice-water bath. Succinimidyl
N-(benzyloxycarbonyl) glycinate (2.81g, 9.17 mmol) was dissolved in 35 mL
of hot EtOH and dropped over 15 min to the phosphinic acid solution. The
resulting solution was stirred in an ice-water bath for 2 h and at room tem-
perature for 20 h. Solvents were evaporated in vacuum, the residue was dis-
solved in 80 mL of water and the solution was extracted with 3 Â 1 5 mL of
EtOAc. The water phase was acidified with 10 mL of 2 M HCl and again
extracted with the same amount of EtOAc. The water phase was evaporated
to the dryness and redissolved in 10 mL of water containing some ammonia.

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85
The solution was transferred onto the top of a cation exchange resin (Hþ-
form, Dowex 50, 2 Â 15 cm) column, eluted with water (500 mL) and the
fractions containing protected dipeptide23 were evaporated. Excess of HCl
was removed by co-distillation with water (2 Â 10 mL) and the residue was
dried by co-distillation with anhydrous EtOH (3 Â 10 mL). 35 mL of HBr/
AcOH (35%) was added to the oily residue at 0ꢀC. The mixture was stirred for
1.5 h at the temperature then evaporated to dryness. The resulting hydro-
bromide of the product was converted to the free acid on a Dowex 50
(Hþ-form, 2 Â 15 cm) column by elution with water (200 mL) followed by
8% aq. ammonia. Peptide fractions were evaporated to give an oily residue,
which was dissolved with heating in 30 mL of MeOH and 3 mL of water and
evaporated. The residue was redissolved with heating in 30 mL of MeOH and
0.5 mL of water. Anhydrous EtOH was carefully added up to persistent
cloudiness which was redissolved with one drop of MeOH. After standing
overnight at room temperature, the product was filtered off, washed with
anhydrous MeOH and left to dry in air. Yield 1.20 g (80%).
Elemental analysis (calc): C 29.03% (28.92%), H 6.40% (6.67%), N
16.63% (16.86%). M.p. 233–235ꢀC (dec.), Rf ¼ 0.7 (B). H NMR (D2O):
1
2
1.14 (d, 3H, JPH 13.6 Hz, PCH3); 3.31(d, 2H, JPH 10.0 Hz, NCH2P);
2
5
3.74 (d, 2H, JPH 1.2 Hz, CH2C(O)NHCH2P). 31P NMR (D2O): 15.84.
1
1
13C NMR (D2O): 17.35 (d, JPC 93.4 Hz, PCH3); 43.40 (d, JPC 99.6 Hz,
3
NCH2P); 43.51(s, CH C(O)N); 169.49 (d, JPC 4.3 Hz, C(O)NHCH2P).
2
N-Glycyl-aminomethyl(phenylphosphinic) Acid Gly–Gly(PPh) and
N-Glycyl-aminomethyl(tert-butylphosphinic) Acid Gly–Gly(Pt-Bu
)
AMP(PPh
)
or AMP(Pt-Bu
)
(6.6 mmol) and NaHCO3 (1.10 g,
13.2 mmol) were dissolved in a mixture of 30 mL of water and 15 mL of
EtOH and the solution was cooled in an ice-water bath. Z-Gly-OSuc (2.02 g,
6.6 mmol) dissolved in 20 mL of hot EtOH was dropped into the solution
during 15 min. The mixture was stirred in the bath for 2 h and at room
temperature for 20 h. The cloudy solution was filtered and the filtrate was
evaporated to dryness. The residue was dissolved in water (50 mL) and the
solution was alkalinized with 5 M NaOH to pH ꢁ12. The alkaline solution
was extracted with 4 Â 15 mL of EtOAc. The water phase was acidified to
Ph ꢁ1with conc. HCl, diluted to 100 mL with water and extracted again
with 4 Â 15 mL of EtOAc. The organic phase was evaporated to dryness
and dissolved in EtOH. Residual water was removed by co-distillation
with anhydrous EtOH (3 Â 15 mL) and peptide was deprotected with
10 mL of HBr/AcOH (35%, room temperature, 1.5 h). The mixture was
evaporated to dryness, co-distilled with anhydrous EtOH (3 Â 15 mL) and

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LUKAS ET AL.
dissolved in 10 mL of water. The resulting hydrobromide of the product was
purified by chromatography on a Dowex 50 (Hþ-form, 2 Â 15 cm) column
by elution with water (200 mL) followed by 0.1% aq. ammonia. Peptide
fractions were evaporated to dryness. A residual amount of glycine was
removed using a carboxylic acid exchange resin (Amberlite CG50/N1)
column by elution with water. The pure peptide fractions were evaporated,
redissolved in a minimum amount of water and decolorized with charcoal.
The peptide was obtained after addition of THF to cloudiness, standing of
the solution for several days, filtration and drying at room temperature.
Gly–Gly(PPh)ÁH2O, Yield 65%. Elemental analysis (calc.): C 43.91%
(44.21%), H 6.14% (6.31%), N 11.37% (11.38%). M.p. 259–261ꢀC (dec.),
1
Rf ¼ 0.75 (A); 0.4 (B). H NMR (D2O): 3.47; 3.56 (s, 2H, CH2C(O)N);
7.3–7.7 (m, 5H, Ph). 31P NMR (D2O): 26.96. 13C NMR (D2O): 43.91
1
(s, CH2C(O)N; 43.92 (d, JPC 104.1 Hz, NCH2P); 131.06 (d, JPC 12.3 Hz,
2
3
C2–P); 134.10 (d, JPC 9.5 Hz, C3–P); 134.63 (d, JPC 2.6 Hz, C4–P); 169.28
4
3
(d, JPC 4.2 Hz, C(O)NHCH2P).
Single crystals of Gly–Gly(PPh)ÁH2O suitable for X-ray studies were
grown from water solution by slow evaporation (3 weeks).
Gly–Gly(Pt-Bu): Yield 55%. Elemental analysis (calc.): C 38.21%
(40.38%); H 8.13% (8.23%); N 12.03% (13.46%). M.p. 280–285ꢀC (dec.),
1
3
Rf ¼ 0.5 (B). H (D2O): 0.95 (d, 9H, JPH 14.7 Hz, PC4H9); 3.40 (d, 2H,
2JPH 7.7 Hz, NCH2P); 3.70 (s, 2H, CH2C(O)N). 31P (D2O): 45.10. 13C
1
(D2O): 26.02 (s, PC(CH3)3); 33.80 (d, JPC 95.5 Hz; P-C(CH3)3); 37.80
1
3
(d, JPC 88.5 Hz; CH2P); 42.59 (s, CH2C(O)N); 168.5 (d, JPC 4.6 Hz;
C(O)NHCH2P).
ACKNOWLEDGMENT
The work was supported by the Grant Agency of the Czech Republic
(No. 203/97/0256) and by a grant of the Universita Karlova (GAUK 243/
1999/B, to P.V.). We also thank the Grant Agency of the Czech Republic
(No. 203/99/0067, to J. Fabry) for support of access to CCDC.
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N.T.; Meldal, M. Chem. Eur. J. 1999, 5, 2877 and references therein.

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(no. 29); monoclinic; a ¼ 11.6921(8) A, b ¼ 13.532(1) A, c ¼ 7.3996(8) A,
V ¼ 1170.8(2) A3; Z ¼ 4;
Æ|ÁFO| ¼ 0.025;
#
range: 2# ꢂ 28ꢀ; R ¼ Æ||FO| À |FC||/
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20. Bergmann, M.; Zervas, L. Chem. Ber. 1932, 65, 1 1 93.
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Soc. 1964, 86, 1839.
3
22. Tr-NHCH2P(Me)(O)(OEt): 1H NMR (CDCl3): 1.28 (t, 3H, JHH
2
6.8 Hz, OCH2CH3); 1.65 (d, 3H, JPH 14.0 Hz, PCH3); 1.9 (bs, 1H,
NH); 2.4–2.6 (m, 2H, NCH2P); 7.1–7.3 (m, 15H, Ph); 31P NMR
(CDCl3): 51.2.
23. Z-NHCH2C(O)NHCH2P(O)(Me)OH: m.p. 140–144ꢀC (dec.) (hot
2
water); 1H NMR (LiOD/D2O): 1.32 (d, 3H, JPH 14.0 Hz, PCH3);
2
5
3.49 (d, 2H, JPH 8.0 Hz, NCH2P); 3.79 (d, 2H, JPH 0.8 Hz,
CH2C(O)NHCH2P); 4.79 (s, 2H, CH2Ph); 7.31–7.36 (m, 5H, Ph); 31P
NMR (CDCl3): 44.9.
24. Petrıcek, V.; Dusek, M. JANA 98. Crystallographic Computing System.
Institute of Physics, Academy of Sciences of the Czech Republic:
Prague, 1998.
25. Sheldrick, G.M. Acta Crystallogr., Sect. A.: Fundam. Crystallogr.
1990, 46, 467.
26. Sheldrick, G.M. SHELXL97. Programfor Crystal Structure
Refinement from Diffraction Data. University of Goettingen:
Goettingen, 1997.
Received in the Netherlands February 15, 2000

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