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oxy}phenylpropanoyl)threonyl})-N6-[(benzyloxy)-
carbonyl]lysinate (10a). Yield 0.417 g (84.6%),
semicrystalline mass. 31P NMR spectrum (DMSO-d6):
δP 26.75 ppm. Mass spectrum, m/z: 986.1168 [M + H]+.
Benzyl-N2-(О-benzyl-N-{2-[(tert-butoxycarbonyl)-
amino]-3-(4-{[(cyclohexyloxy)(deuteromethyl)-
phosphoryl]oxy}phenylpropanoyl)threonyl})-N6-
[(benzyloxy)carbonyl]lysinate (10b). Yield 0.424 g
(85.8%), semicrystalline mass. 31P NMR spectrum
(DMSO-d6): δP 26.92 ppm. Mass spectrum, m/z:
989.1342 [M + H]+.
Yield 1.51 g (63%). 31P NMR spectrum (DMSO-d6): δP
27.02 ppm. Mass spectrum, m/z: 569. 6197 [M +Н]+.
General procedure for synthesis of compounds 8a,
8b. 1.59 g of compound 7a (or 1.51 g of compound 7b),
50 mLof ethanol, and 100 mg of 10% palladium on active
coal were charged into an apparatus for normal-pressure
hydrogenation. The apparatus was filled with hydrogen
and shaken during 8 h, bubbling hydrogen slowly. The
catalyst was filtered off, and the solvent was removed
under vacuum. The residue was triturated with 5 mL of
acetonitrile, filtered, and washed with 10 mL of diethyl
ether on a filter. O-[О-cyclohexylmethyl(deuteromethyl)-
phosphonyl]-L-tyrosine 8a, 8b with purify of 94% were
obtained.
General procedure for synthesis of compounds
11a, 11b. 10 mL of a 15% solution of anhydrous HCl
in dioxane was added to 0.424 g of the phosphorylated
tripeptide 10a, 10b. The mixture was stirred at room
temperature during 1 h, and the solvent was evaporated
under vacuum. 40 mL od ethyl acetate was added to the
residue, and the solvent was washed with 5% solution
of sodium hydrocarbonate (2×10 mL) and with 10 mL
of saturated solution od sodium chloride in water. After
drying over sodium sulfate and distilling off the solvent,
the residue (amorphous white mass) was subject to
hydrogenolysis without purification for the benzyl groups
deprotection.
Benzyl-N2-{N-[2-amino-3-(4-{[(cyclohexyloxy)-
(methyl)phosphoryl]oxy}phenyl)propanoyl]-О-
benzylthreonyl}-N6-[(benzyloxy)carbonyl]lysinate
(11a). 31P NMR spectrum (DMSO-d6): δP 26.65 ppm.
Mass spectrum, m/z: 886.0009 [M + H]+.
О-(О-Cyclohexylmethylphosphonyl)-L-tyrosine
(8a). Yield 0.625 g (65%), white crystals. 31P NMR
spectrum (D2O): δP 31.76 ppm. Mass spectrum, m/z:
342.3477 [M +Н]+.
О-(О-Cyclohexyldeuteromethylphosphonyl)-L-
tyrosine (8b). Yield 0.641 g (70%), white crystals. 31P
NMR spectrum (D2O): δP 31.92 ppm. Mass spectrum,
m/z: 345.3651 [M + Н]+.
The protected tripeptide Boc-Tyr-Thr(OBn)-Lys(Z)-
OBn 9 was prepared as described by us earlier [14].
The procedure for its phosphorylation with cyclo-
hexylmethyl(deuteromethyl)phosphonochloridate and
deprotection are given below.
General procedure for synthesis of compounds 10a,
10b. 0.017 g (0.0007 mol) of NaH washed with hexane
to remove mineral oil was added to a suspension of
0.412 g (0.0005 mol) of protected tripeptide 9 in
40 mL of anhydrous acetonitrile at stirring and cooling
to 5°C. The mixture was stirred during 30 min at room
temperature, 0.0006 mol of compound 6a, 6b in 10 mL
of anhydrous acetonitrile was added, and the mixture
was stirred during 2 h monitoring the reaction course
by TLC. The mixture was evaporated under vacuum
to half of the volume, poured into 40 mL of water, and
extracted with chloroform (3×30 mL). The extract was
washed with 20 mL of water, dried over MgSO4, and
concentrated under reduced pressure. The residue was
subject to chromatography on a 150×30 mm column
(SiO2, GeduranSi 60 40–63 μm, Merck) with methylene
chloride–ethyl acetate (3 : 1) as eluent. Products 10a, 10b
with 86% purity were isolated (31P NMR data).
Benzyl-N2-{N-[2-amino-3-(4-{[(cyclohexyloxy)-
(deuteromethyl)phosphoryl]oxy}phenyl)propanoyl]-
О-benzylthreonyl}-N6-[(benzyloxy)carbonyl]lysinate
(11b). 31P NMR spectrum (DMSO-d6): δP 26.83 ppm.
Mass spectrum, m/z: 889.1838 [M + H]+.
General procedure for synthesis of compounds 12a,
12b. The Bn-protected phosphorylated tripeptide 11a,
11b, 50 mL of ethanol, and 50 mg of freshly prepared
palladium hydroxide were charged into an apparatus
for normal-pressure hydrogenation. The apparatus was
filled with hydrogen and shaken during 36 h, bubbling
hydrogen slowly. After that, 50 mg of freshly prepared
palladium hydroxide was added and the hydrogenation
was performed further during 36 h. The reaction course
was monitored by TLC each 6 h. The catalyst was filtered
off, and the solvent was removed under vacuum. The
residue was triturated with 5 mL of acetonitrile, filtered,
and washed with 10 mL of diethyl ether on a filter. The
О-phosphorylated tripeptides 12a, 12b were obtained as
Benzyl-N2-(О-benzyl-N-{2-[(tert-butoxycarbonyl)-
amino]-3-(4-{[(cyclohexyloxy)(methyl)phosphoryl]-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 90 No. 4 2020