Synthesis of 5-amino-2-aminoalkyl-1,3-oxazol-4-ylphosphonic acid derivatives and their use in the preparation of phosphorylated peptidomimetics

Article abstract of DOI:10.1016/j.tet.2013.05.017

Starting from phthalimidoalkanoylamines 1 (amino-protected derivatives of glycine, β-alanine, γ-amino butyric, δ-amino valeric, and ε-amino caproic acids), a facile synthetic method has been developed to obtain diethyl 5-alkyl(dialkyl)amino-2-aminoalkyl-1,3-oxazol-4-ylphosphonates 7, which have been further used in the preparation of phosphorylated peptidomimetics 10 and 12.

Full text of DOI:10.1016/j.tet.2013.05.017

Accepted Manuscript
Synthesis of 5-amino-2-aminoalkyl-1,3-oxazol-4-ylphosphonic acid derivatives and
their use in the preparation of phosphorylated peptidomimetics
Kostyantyn M. Kondratyuk, Olena I. Lukashuk, Aleksandr V. Golovchenko, Igor V.
Komarov, Volodymyr S. Brovarets, Valery P. Kukhar
PII:
S0040-4020(13)00752-7
10.1016/j.tet.2013.05.017
TET 24355
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 March 2013
Revised Date: 23 April 2013
Accepted Date: 9 May 2013
Please cite this article as: Kondratyuk KM, Lukashuk OI, Golovchenko AV, Komarov IV, Brovarets
VS, Kukhar VP, Synthesis of 5-amino-2-aminoalkyl-1,3-oxazol-4-ylphosphonic acid derivatives and
their use in the preparation of phosphorylated peptidomimetics, Tetrahedron (2013), doi: 10.1016/
j.tet.2013.05.017.
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Synthesis of 5-amino-2-aminoalkyl-1,3-
oxazol-4-ylphosphonic acid derivatives and
their use in the preparation of
phosphorylated peptidomimetics
Kostyantyn M. Kondratyuka, Olena I. Lukashuka, Aleksandr V. Golovchenkoa, Igor V. Komarovb Volodymyr S.
,
Brovaretsa and Valery P. Kukhara
a Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, 1
Murmanska St., Kyiv 02660, Ukraine
b Research and Development Center for Chemistry and Biology, National Taras Shevchenko University, 62
Volodymyrska St., Kyiv 01033, Ukraine
a)
CO2Me
P(O)(OEt)2
N
P(O)(OEt)2
N
HN
O
P(O)(OEt)2
CCl3
Z-(S)-Gln
N
N
Et3N, dioxane, 100 deg C, 8h
H
PhtN
H2N
Z-(S)-Gln
N
N
HOBt, EDCI, THF, 0 deg C
CO2Me
CO2Me
b) N2H4H2Oexc, THF, H2O,
25 deg C, 16h
O
O
H
P(O)(OEt)2
N
AcOH, H2O, 75 deg C, 8h
Z-(S)-Gln-Gly
N
H
CO2Me
O

ACCEPTED MANUSCRIPT
1
Tetrahedron
journal homepage: www.elsevier.com
Synthesis of 5-amino-2-aminoalkyl-1,3-oxazol-4-ylphosphonic acid derivatives and
their use in the preparation of phosphorylated peptidomimetics
Kostyantyn M. Kondratyuka, Olena I. Lukashuka, Aleksandr V. Golovchenkoa, Igor V. Komarovb
,
Volodymyr S. Brovaretsa* and Valery P. Kukhara
a Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, 1 Murmanska St., Kyiv 02660, Ukraine
b Research and Development Center for Chemistry and Biology, National Taras Shevchenko University, 62 Volodymyrska St., Kyiv 01033, Ukraine
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Starting from phthalimidoalkanoylamines 1 (amino-protected derivatives of glycine, β-alanine,
γ-amino butyric, δ-amino valeric, and ε-amino caproic acids), a facile synthetic method has
been developed to obtain diethyl 5-alkyl(dialkyl)amino-2-aminoalkyl-1,3-oxazol-4-
ylphosphonates 7 which have been further used in the preparation of phosphorylated
peptidomimetics 10 and 12.
Available online
Keywords:
amino acid
aminophosphonic acid
oxazole
phosphono peptidomimetic
1. Introduction
phosphoryl residue in these compounds is inserted into the
peptide chain or terminates it. Phosphono peptides containing the
Currently aminophosphonic acids as structural analogues of
the corresponding amino carboxylic derivatives, where the
tetrahedral phosphonic acid functionality replaces the planar
carboxylic group, have found a wide range of practical
applications in the areas of biological, medicinal, and synthetic
chemistry.1 Phosphonic acids represent the “simplest” group of
phosphate isosteres. These molecules with C-P bond in place of
O-P bond are structurally similar to phosphate esters and
anhydrides, but are quite stable under typical chemical and
physiological conditions.2 Because of the tetrahedral
configuration at phosphorus, aminophosphonic acids mimic the
tetrahedral transition state of peptide hydrolysis and therefore can
act as inhibitors of peptidases or esterases. As a consequence, the
biological properties of aminophosphonic acids have been
studied extensively. However, limited cell permeability of highly
polar aminophosphonic acids and their derivatives leads to
intense search for new biologically active synthetic analogues of
aminophosphorus compounds.
phosphoryl group in the side chain of peptides have been less
studied due to their synthetic complexity.4 To synthesize
compounds with the phosphonoglycine residue, we have recently
applied regioselective acid-assisted opening of the 4-
phosphorylated oxazole ring.5a Though 4-phosphoryl-5-
aminooxazole derivatives are easily accessible and well studied,5
most of them bear only alkyl or aryl residues at position 2 of the
oxazole ring. Here we focus on the synthesis of diethyl 5-amino-
1,3-oxazol-4-ylphosphonates substituted at position
2 with
aminoalkyl chains of varying length. Such compounds, when
regioselectively ring-opened, may be particularly useful in the
synthesis of phosphorylated peptidomimetics.
2. Results and discussions
We have synthesized 5-amino-2-aminoalkyl-1,3-oxazol-4-
ylphosphonic acids by the reaction chain 1→→8 (see Schemes 1
and 2) starting from the condensation of ω,ω-
phthalimidoalkanamides 1a-e with chloral hydrate. Conversions
1→2→3 were studied previously6 with phthalimidopropionamide
From the biochemical point of view, phosphorylated peptides and
peptidomimetics are an area of special interest.1e,3 As a rule, the
(n=2)
and
phthalimidobutyramide
(n=3),
whereas
———
* Corresponding author. Tel.: +38-044-573-2561; fax: +38-044-573-2561; e-mail: brovarets@bpci.kiev.ua

ACCEPTED MANUSCRIPT
2
Tetrahedron
phthalimidoacetamide (n=1), phthalimidovaleramide (n=4), and
(R,S)-9 was prepared under similar conditions, followed by
HPLC analysis of (S)-9 and (R,S)-9 on a chiral column
(CHIRALPAK® IA). Phosphorylated peptidomimetics 10
resulting from the ring opening in (S)-9 under mild conditions (in
an AcOH-H2O mixture at 75°C)5а were analyzed likewise. It is
evident from HPLC data (see Experimental section) that no
racemisation occurs during the oxazole ring opening as well as in
peptide synthesis.
phthalimidohexanamide (n=5) have been reacted with chloral
hydrate for the first time. Compounds 2a-e were treated with
thionyl chloride to produce highly reactive tetrachloroethyl-
substituted amides which were then condensed with triethyl
phosphite by the Arbuzov reaction thus affording hitherto
unknown
trichloroethylphosphonates 4a-e.
diethyl
1-(phthalimidoalkanoylamino)-2,2,2-
On treatment with triethylamine, products 4a-e readily eliminate
HCl to give 2,2-dichloro-1-(phthalimidoalkanoylamino)-
ethenylphosphonates 5a-e (see Scheme 2). Heating of
trichloroethylphosphonates 4a-e or dichloroethenylphosphonates
5a-e with benzylamide or secondary amines in the presence of
excess triethylamine leads to oxazole condensation7 with the
substitution of all chlorine atoms. As a result, we have
synthesized a number of novel derivatives of diethyl 5-amino-2-
A phosphorylated peptidomimetic of more complex structure
was obtained by the above procedure from oxazole 7m. It was
reacted with Z-protected optically active (S)-glutamine to give
amide (S)-11 (see Scheme 5) which yielded, on ring opening,
peptidomimetic (S,R),(S,S)-12 containing the residues of four
amino acids ((S)-glutamine, glycine, phosphorylated glycine, and
isonipecotic acid). Compounds of this type may be involved in
biological studies on enzyme-dependent systems.
phthalimidoalkyl-1,3-oxazol-4-ylphosphonates
6а-n.
The structures of the compounds obtained (see Schemes 1-5)
were established by elemental analysis as well as by IR and
NMR (1H, 13C, 31P) spectroscopy and LC/MS method. The latter
is, however, uninformative for compounds 2a-e, 3a-e, (S)-11,
and (S,R),(S,S)-12, since they decompose under the conditions of
LC/MS analysis.
Phthalimidoalkyloxazoles 6a-n appear as crystals or viscous oils
stable on prolonged storage, sparingly soluble in hexane,
petroleum ether, and water, and highly soluble in alcohols,
tetrahydrofuran, and dichloromethane. When treated with
hydrazine hydrate in a THF-H2O mixture at room temperature,
these compounds are smoothly hydrazinolyzed to diethyl 5-
amino-2-aminoalkyl-1,3-oxazol-4-ylphosphonates 7а-n in high
yields.
3. Conclusions
We have developed a preparative method to obtain diethyl 5-
alkyl(dialkyl)amino-2-aminoalkyl-1,3-oxazol-4-ylphosphonates
7. It implies the successive treatment of phthalimido amides 1
with chloral hydrate, thionyl chloride, triethyl phosphite, amines,
and hydrazine hydrate. The resulting aminooxazoles have been
further used in the preparation of optically active phosphorylated
peptidomimetics 10 and 12 in which the introduced amino acid
residues are not racemized.
The primary aliphatic amino group of products 7а-n is readily
acylated with acyl chlorides to provide corresponding amides 8a-
e, as exemplified by the reaction of compounds 7f-j with 4-tert-
butylbenzoyl chloride (see Scheme 3).
Acylation of oxazole 7k with Z-(S)-Ala-OH under standard
conditions of peptide synthesis, i.e. in a THF solution in the
presence of 1-hydroxybenzotriazole (HOBt) and 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide (EDCI), also leads only to
amide (S)-9 (see Scheme 4). We used compound (S)-9 to
ascertain whether racemization at the chiral centre could occur
during the oxazole ring opening. To this end, racemic amide

ACCEPTED MANUSCRIPT
3
O
O
OH
O
Cl
Cl3CCH(OH)2
H2SO4
SOCl2
PhtN
PhtN
PhtN
dioxane
NH2
CCl3
2a-e (63-82%)
n
N
n
N
CCl3
n
H
H
1a-e
3a-e (99%)
P(OEt)3
dioxane
O
P(O)(OEt)2
PhtN
N
CCl3
n
H
4a-e (59-89%)
Scheme 1. n = 1 (a), 2 (b), 3 (c), 4 (d), 5 (e).
P(O)(OEt)2
N
HNR1R2, Et3N
dioxane
PhtN
1R2
NR
4a-e
Et3N, THF
n
O
6a-n (38-99%)
.
N2H4 H2O, THF-H2O
P(O)(OEt)2
N
O
P(O)(OEt)2
HNR1R2, Et3N
dioxane
PhtN
Cl
H2N
2
NR1
N
n
R
n
O
H
Cl
7a-n (66-99%)
5a-e (99%)
NR1R2
n
1
2
3
4
5
NHCH2Ph
N(CH2)5
6a, 7a
6f, 7f
6b,7b
6g, 7g
6l, 7l
6c, 7c
6h, 7h
6d, 7d
6i, 7i
6e, 7e
6j, 7j
N(CH2)4O
6k, 7k
6m, 7m
N(CH2)4CHCO2Me
6n, 7n
Scheme 2.
P(O)(OEt)2
N
N
4-Me3CC6H4COCl
Py, Et3N, CH2Cl2
Me CC H CONH
4-
7f-j
3
6
4
n
O
8a-e (88-95%)
Scheme 3. n = 1 (a), 2 (b), 3 (c), 4 (d), 5 (e).

ACCEPTED MANUSCRIPT
4
Tetrahedron
P(O)(OEt)2
N
O
N
H
Z-(S)-Ala-OBt
O
N
7k
O
N
O
THF, 0 deg C
H
O
(S)-9 (65%)
AcOH, H2O, 75oC
P(O)(OEt)2
O
O
H
N
N
O
O
N
N
H
H
O
O
(S,R),(S,S)-10 (99%)
P(O)(OEt)2
N
O
N
H
Z-(R,S)-Ala-OBt
O
N
7k
O
N
O
THF, 0 deg C
H
O
(R,S)-9 (62%)
AcOH, H2O, 75oC
P(O)(OEt)2
O
O
H
N
N
O
O
N
N
H
H
O
O
(R,R),(R,S),(S,R),(S,S)-10 (99%)
Scheme 4.
O
NH2
P(O)(OEt)2
N
O
N
Z-(S)-Gln-OBt
H
N
7m
CO2Me
O
O
N
H
THF, 0 deg C
O
O
(S)-11 (45%)
AcOH, H2O, 75oC
NH2
P(O)(OEt)2
O
O
H
N
N
O
N
N
H
O
H
CO2Me
O
(S,R),(S,S)-12 (99%)
Scheme 5.

ACCEPTED MANUSCRIPT
5
3279, 3036, 2985, 2943, 1778, 1730, 1537, 1416 cm-1; δH
4. Experimental section
4.1. General
(DMSO-d6) 9.24 (1Н, d, J 8.8 Hz, NH), 7.95-7.85 (5Н, m,
aromatic, ОН), 5.72 (1Н, m, CH), 4.38 (1Н, d, J 17.1 Hz,
CHaHb), 4.28 (1Н, d, J 17.1 Hz, CHaHb); δC (DMSO-d6) 167.9
(С=О), 167.0 (С=О), 135.2, 132.0, 123.7, 102.7 (CCl3), 81.3
(CH), 40.4 (CH2).
The NMR spectra were obtained on a Bruker Avance DRX-
500 instrument [1H (500 MHz), 31P (202 MHz), 13C (125 MHz)]
in a solution of DMSO-d6, CDCl3 relative to internal TMS or
external 85% phosphoric acid. The IR spectra were recorded on a
Vertex 70 spectrometer from KBr pellets, or dichloromethane
solution, or adaptor ATR. The melting points were determined on
a Fisher-Johns instrument. Elemental analysis was carried out in
the analytical laboratory of IBOPC NASU. The LC/MS spectra
were recorded on an Agilent 1100 Series high-performance liquid
chromatograph equipped with a diode matrix with an Agilent
LC\MSD SL mass selective detector allowing fast switching
between positive and negative ionization modes. The LC/MS
parameters were set as follows: column, Zorbax SBC18 1.8 ꢀm,
4.6х15 mm (PN 821975-932); solvents A, acetonitrile–water
mixture (95:5), 0.1% trifluoroacetic acid and B, 0.1% aqueous
trifluoroacetic acid; eluent flow rate, 3 ml/min; injection volume,
1 ꢀl; UV detection, 215, 254, 265 nm; atmospheric-pressure
chemical ionization (APCI) was used; scanning range, m/z 80–
1000. Optical purity was measured on the Agilent 1100 system
with diode array detector on a CHIRALPAK® IA column (5 µm,
4.6x250 mm); mobile phase, hexane:2-propanol. The reaction
progress was TLC-monitored on Silica gel 60 F254 (Merck).
4.3.2. 5-(1,3-Dioxo-2,3-dihydro-1H-isoindol-2-yl)-N-(2,2,2-
trichloro-1-hydroxyethyl)pentanamide (2d).
Yield 123.98 g, 63% as colorless crystals; mp 109-110°С dec;
[Found: С, 45.63; H, 3.97; Cl, 27.21; N, 7.01. C15H15Cl3N2O4
requires С, 45.77; H, 3.84; Cl, 27.02; N, 7.12%]; νmax (KBr)
3313, 1771, 1708, 1656 cm-1; δH (DMSO-d6) 8.65 (1Н, d, J 9.1
Hz, NH), 7.86 (4Н, m, aromatic), 7.61 (1Н, d, J 5.7 Hz, ОН),
5.73 (1Н, dd, J 9.1, 5.7 Hz, СН), 3.57 (2Н, m, CH2), 2.24 (2Н, m,
CH2), 1.59 (2Н, m, CH2), 1.52 (2Н, m, CH2); δC (DMSO-d6)
172.9 (С=О), 168.4 (С=О), 134.9, 132.1, 123.5, 103.0 (CCl3),
80.8 (CH), 37.7, 35.1, 28.1, 23.0.
4.3.3. 6-(1,3-Dioxo-2,3-dihydro-1H-isoindol-2-yl)-N-(2,2,2-
trichloro-1-hydroxyethyl)hexanamide (2e).
Yield 130.46 g, 64% as a colorless crystals; mp 105-107°С
dec; [Found: С, 47.03; H, 4.33; Cl, 26.24; N, 6.70.
C16H17Cl3N2O4 requires С, 47.14; H, 4.20; Cl, 26.09; N, 6.87%];
νmax (KBr) 3256, 1771, 1711, 1665 cm-1; δH (DMSO-d6) 8.64
(1Н, m, NH), 7.83 (4Н, m, aromatic), 7.68 (1Н, m, ОH), 5.72
(1Н, m, CH), 3.55 (2Н, m, CH2), 2.18 (2Н, m, CH2), 1.61 (2Н,
m, CH2), 1.46 (2Н, m, CH2), 1.25 (2Н, m, CH2); δC (DMSO-d6)
173.1 (С=О), 168.4 (С=О), 134.8, 132.0, 123.4, 103.0 (CCl3),
80.8 (CH), 37.7, 35.4, 28.1, 26.2, 25.1.
4.2. Phthalimido amides
Commercially unavailable compounds 1a-c,8 and 1d9 were
obtained by known methods.
4.2.1. 6-(1,3-Dioxo-2,3-dihydro-1H-isoindol-2-yl)hexanamide
(1e)
4.4. General procedure for the preparation of 3a-e.
Tetrachloroethylamides.
A
mixture of 6-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-
yl)hexanoic acid10 (156.77 g, 0.60 mol), thionyl chloride (55 mL,
0.75 mol), and dry benzene (400 mL) was refluxed for 2 h and
evaporated in vacuo; the residue was dissolved in dry
dichloromethane (800 mL). Through the solution stirred and
cooled at 20°C, a current of dry ammonia was passed to
saturation, followed by washing with water (3x100 mL), drying
over sodium sulfate, and evaporation to dryness in vacuo to give
the analytically pure product (151.48 g, 97%) as a colorless
crystals; mp 154-155°С; [Found: С, 64.49; H, 6.34; N, 11.24.
C13H14N2O3 requires С, 64.60; H, 6.20; N, 11.38%]; νmax (KBr)
3387, 3195, 2931, 2852, 1775, 1720, 1649 cm-1; δH (DMSO-d6)
7.85 (4H, m, aromatic), 7.21 (1H, br s, NH), 6.67 (1H, br s, NH),
3.56 (2H, m, CH2), 2.03 (2H, m, CH2), 1.59 (2H, m, CH2), 1.50
(2H, m,CH2), 1.25 (2H, m, CH2); δC (DMSO-d6) 175.0 (С=О),
168.4 (С=О), 134.9, 132.0, 123.4, 37.8, 35.4, 28.2, 26.4, 25.1;
LCMS: found m/z 261.2, MH+.
Compounds 3a, 3d, and 3e were obtained similarly to
previously described6 3b and 3c.
A mixture of one of compounds 2a-e (0.30 mol), thionyl
chloride (33 mL, 0.45 mol), and dry dioxane (150 mL) was
refluxed with stirring until no more gas was evolved and another
30 min. After evaporation under reduced pressure to dryness, the
resulting residue was heated to boiling with stirring in the
minimum amount of dry benzene and cooled. The crystalline
precipitate was filtered, washed on the filter with the minimum
amount of dry benzene, and dried in vacuo to give the
analytically pure product.
4.4.1. 2-(1,3-Dioxo-2,3-dihydro-1H-isoindol-2-yl)-N-(1,2,2,2-
tetrachloroethyl)acetamide (3a).
Yield 104.41 g, 99% as a colorless crystals; mp 152-153°С;
[Found: С, 38.88; H, 2.25; Cl, 38.51; N, 7.49. C12H8Cl4N2O3
requires С, 38.95; H, 2.18; Cl, 38.33; N, 7.57%]; νmax (KBr)
3278, 1730, 1692 cm-1; δH (CDCl3) 7.91 (2Н, m, aromatic), 7.78
(2Н, m, aromatic), 7.30 (1Н, br s, NH), 6.53 (1Н, d, J 10.5 Hz,
СНN), 4.51 (2Н, s, CH2); δC (CDCl3) 167.6 (С=О), 165.6 (С=О),
134.6, 131.8, 123.9, 99.2 (CCl3), 73.6 (CHCl), 40.8.
4.3. General procedure for the preparation of 2a-e.
Condensation of amides 1a-e with chloral hydrate.
Compounds 2b,c were obtained by known methods.6
A mixture of one of compounds 1a, 1d, or 1e (0.50 mol),
chloral hydrate (165.40 g, 1.00 mol), and conc. sulfuric acid (1
mL) was kept at a temperature of 95-100°C for 8h, cooled, and
ground in water (500 mL). The crystalline precipitate was
filtered, washed on the filter with water to pH 7, and
recrystallized from 2-propanol.
4.4.2. 5-(1,3-Dioxo-2,3-dihydro-1H-isoindol-2-yl)-N-(1,2,2,2-
tetrachloroethyl)pentanamide (3d).
Yield 122.39 g, 99% as a cream crystals; mp 96-97°С;
[Found: С, 43.59; H, 3.53; Cl, 34.58; N, 6.69. C15H14Cl4N2O3
requires С, 43.72; H, 3.42; Cl, 34.41; N, 6.80%]; νmax (ATR)
3305, 1770, 1701 cm-1; δH (CDCl3) 7.84 (2H, m, aromatic), 7.73
(2H, m, aromatic), 6.89 (1H, d, J 10.4 Hz, NH), 6.55 (1H, d, J
10.4 Hz, CH), 3.74 (2H, m, CH2), 2.44 (2H, m, CH2), 1.67 (4H,
m, 2CH2); δC (CDCl3) 171.8 (С=О), 168.6 (C=O), 134.1, 132.0,
123.3, 99.5 (CCl3), 73.8 (CHCl), 36.8, 35.4, 27.7, 22.3.
4.3.1. 2-(1,3-Dioxo-2,3-dihydro-1H-isoindol-2-yl)-N-(2,2,2-
trichloro-1-hydroxyethyl)acetamide (2a).
Yield 144.14 g, 82% as a colorless crystals; mp >180°С dec;
[Found: С, 40.91; H, 2.67; Cl, 30.41; N, 7.89. C12H19Cl3N2O4
requires С, 41.00; H, 2.58; Cl, 30.25; N, 11.38%]; νmax (KBr)

ACCEPTED MANUSCRIPT
6
Tetrahedron
4.4.2.
6-(1,3-Dioxo-2,3-dihydro-1H-isoindol-2-yl)-N-
Yield 63.70 g, 62% as a colorless crystals; mp 132-133°С;
(1,2,2,2-tetrachloroethyl)hexanamide (3e).
[Found: С, 44.34; H, 4.82; Cl, 20.84; N, 5.26; P, 6.25.
C19H24Cl3N2O6P requires С, 44.42; H, 4.71; Cl, 20.70; N, 5.45; P,
6.03%]; νmax (KBr) 3248, 1769, 1715, 1677, 1236, 1032 cm-1; δH
(DMSO-d6) 9.07 (1Н, d, J 10.1 Hz, NН), 7.85 (4Н, m, aromatic),
5.24 (1Н, dd, J 19.5, 10.1 Hz, СНР), 4.16-3.99 (4Н, m, 2ОСН2),
3.58 (2H, m, CH2), 2.36 (2H, m, CH2), 1.68-1.49 (4H, m, 2CH2),
1.23 (6H, m, 2ОСН2СН3); δC (DMSO-d6) 172.6 (С=О), 168.4
(С=О), 134.8, 132.2, 123.5, 97.7 (d, J 14.9 Hz, CCl3), 63.6
(ОСН2СН3), 61.3 (d, J 159.0 Hz, CP), 37.7, 32.9, 24.8, 16.6
(ОСН2СН3); δP (DMSO-d6) 15.0; LCMS: found m/z 515.0 MH+.
C19H24Cl3N2O6P requires 513.7.
Yield 126.55 g, 99% as a yellowish crystals; mp 159-160°С;
[Found: С, 45.02; H, 3.87; Cl, 33.46; N, 6.39. C16H16Cl4N2O3
requires С, 45.10; H, 3.78; Cl, 33.28; N, 6.57%]; νmax (KBr)
3257, 1771, 1712, 1666, 1529 cm-1; δC (CDCl3) 7.80 (2Н, m,
aromatic), 7.68 (2Н, m, aromatic), 6.53 (2Н, m, CHNH), 3.65
(2Н, m, CH2), 2.31 (2Н, m, CH2), 1.78-1.62 (4Н, m, 2CH2), 1.37
(2Н, m, CH2); δC (CDCl3) 171.7 (С=О), 134.0, 168.4 (С=О),
132.1, 123.2, 99.5 (CCl3), 73.7 (CHCl), 37.6, 36.2, 28.2, 26.2,
24.5.
4.5. General procedure for the preparation of 4a-e.
Arbuzov rearrangement.
4.5.5. Diethyl [2,2,2-trichloro-1-[6-(1,3-dioxo-2,3-dihydro-
1H-isoindol-2-yl)hexanamido]ethyl]phosphonate (4e).
A mixture of one of compounds 3a-e (0.20 mol), triethyl
phosphite (42 mL, 0.24 mol), and dry dioxane (200 mL) was
refluxed for 3 h under argon and evaporated to dryness in vacuo;
the residue was recrystallized from dioxane (3a, 3b) or 2-
propanol (3c-e).
Yield 62.27 g, 59% as a colorless crystals; mp 152-153°С;
[Found: С, 46.46; H, 5.33; Cl, 20.34; N, 5.18; P, 6.03.
C20H26Cl3N2O6P requires С, 46.55; H, 5.21; Cl, 20.15; N, 5.31; P,
5.87%]; νmax (KBr) 3248, 1773, 1685, 1241, 1030 cm-1; δH
(DMSO-d6) 9.05 (1Н, d, J 10.4 Hz, NН), 7.85 (4Н, m, aromatic),
5.24 (1Н, dd, J 19.3, 10.4 Hz, СНР), 4.16-4.02 (4Н, m, 2ОСН2),
3.56 (2H, m, CH2), 2.32 (2H, m, CH2), 1.58 (4H, m, 2CH2), 1.32-
1.19 (8H, m, CH2, 2ОСН2СН3); δC (DMSO-d6) 173.2 (С=О),
168.4 (С=О), 134.9, 132.1, 123.5, 97.8 (d, J 14.5 Hz, CCl3), 63.6
(ОСН2СН3), 61.3 (d, J 159.0 Hz, CP), 37.8, 34.9, 28.2, 26.3,
25.2, 16.7 (ОСН2СН3); δP (DMSO-d6) 15.0; LCMS: found m/z
527.0 M+. C20H26Cl3N2O6P requires 527.8.
4.5.1. Diethyl [2,2,2-trichloro-1-[2-(1,3-dioxo-2,3-dihydro-
1H-isoindol-2-yl)acetamido]ethyl]phosphonate (4a).
Yield 83.95 g, 89% as a colorless crystals; mp 195-196°С;
[Found: С, 40.63; H, 3.96; Cl, 22.71; N, 5.78; P, 6.73.
C16H18Cl3N2O6P requires С, 40.74; H, 3.85; Cl, 22.55; N, 5.94; P,
6.57%]; νmax (KBr) 3213, 1777, 1724, 1261, 1026 cm-1; δH
(DMSO-d6) 9.68 (1Н, d, J 10.2 Hz, NН), 7.92 (2Н, m, aromatic),
7.89 (2Н, m, aromatic), 5.19 (1Н, dd, J 19.2, 10.2 Hz, СНР),
4.44 (2Н, s, CH2), 4.22-4.10 (4Н, m, 2ОСН2), 1.38-1.24 (6H, m,
2ОСН2СН3); δC (DMSO-d6) 167.8 (С=О), 167.6 (С=О), 135.2,
132.0, 123.8, 97.3 (d, J 14.0 Hz, CCl3), 64.0 (ОСН2СН3), 61.8 (d,
J 159.0 Hz, CP), 16.7 (ОСН2СН3); δP (DMSO-d6) 14.2; LCMS:
found m/z 471.0 M+. C16H18Cl3N2O6P requires 471.7.
4.6. General procedure for the preparation of 5a-e.
Dichloroenamides.
A mixture of one of compounds 4a-e (0.01 mol), Et3N (4.2
mL, 0.03 mol), and dry THF (50 mL) was stirred at 20-25°C for
18 h. The precipitate was filtered and washed on the filter with
dry THF, and the combined filtrates were evaporated to dryness
in vacuo to give the analytically pure product.
4.5.2. Diethyl [2,2,2-trichloro-1-[3-(1,3-dioxo-2,3-dihydro-
1H-isoindol-2-yl)propanamido]ethyl]phosphonate (4b).
4.6.1. Diethyl [2,2-dichloro-1-[2-(1,3-dioxo-2,3-dihydro-1H-
isoindol-2-yl)acetamido]ethenyl]phosphonate (5a).
Yield 68.96 g, 71% as a colorless crystals; mp 166-167°С;
[Found: С, 41.95; H, 4.26; Cl, 22.02; N, 5.63; P, 6.49.
C17H20Cl3N2O6P requires С, 42.04; H, 4.15; Cl, 21.90; N, 5.77; P,
6.38%]; νmax (KBr) 3234, 1774, 1719, 1676, 1263, 1130 cm-1; δH
(DMSO-d6) 9.32 (1Н, d, J 10.3 Hz, NН), 7.85 (4Н, m, aromatic),
5.23 (1Н, dd, J 19.3, 10.3 Hz, СНР), 4.14-4.00 (4Н, m, 2ОСН2),
3.83 (2H, m, CH2), 2.79 (2H, m, CH2), 1.21 (6H, m, 2ОСН2СН3);
δC (DMSO-d6) 170.8 (С=О), 168.0 (С=О), 134.9, 132.1, 123.4,
97.6 (d, J 14.5 Hz, CCl3), 63.7 (ОСН2СН3), 61.3 (d, J 159.0 Hz,
CP), 34.4, 33.3, 16.6 (ОСН2СН3); δP (DMSO-d6) 14.7; LCMS:
found m/z 487.0 MH+. C17H20Cl3N2O6P requires 485.7.
Yield 4.31 g, 99% as a colorless crystals; mp 159-160°С;
[Found: С, 44.08; H, 4.05; Cl, 16.44; N, 6.27; P, 7.25.
C16H17Cl2N2O6P requires С, 44.16; H, 3.94; Cl, 16.29; N, 6.44; P,
7.12%]; νmax (KBr) 3198, 1775, 1724, 1261, 1023, 984 cm-1; δH
(CDCl3) 8.32 (1Н, br s, NН), 7.88 (2Н, m, aromatic), 7.75 (2H,
m, aromatic), 4.52 (2H, s, CH2), 4.16 (4Н, m, 2ОСН2), 1.36 (6H,
m, 2ОСН2СН3); δC (CDCl3) 167.6 (С=О), 164.8 (С=О), 136.5 (d,
J 33.7 Hz, CCl2), 134.0, 132.2, 124.8 (d, J 217.8 Hz, CP), 123.5,
63.8 (ОСН2СН3), 40.5, 16.1 (ОСН2СН3); δP (CDCl3) 8.7; LCMS:
found m/z 435.0 M+. C16H17Cl2N2O6P requires 435.2.
4.5.3. Diethyl [2,2,2-trichloro-1-[4-(1,3-dioxo-2,3-dihydro-
1H-isoindol-2-yl)butanamido]ethyl]phosphonate (4c).
4.6.2. Diethyl [2,2-dichloro-1-[3-(1,3-dioxo-2,3-dihydro-1H-
isoindol-2-yl)propanamido]ethenyl]phosphonate (5b).
Yield 65.96 g, 66% as a colorless crystals; mp 133-134°С;
[Found: С, 43.18; H, 4.54; Cl, 21.33; N, 5.51; P, 6.38.
C18H22Cl3N2O6P requires С, 43.26; H, 4.44; Cl, 21.25; N, 5.61; P,
6.20%]; νmax (KBr) 3240, 1769, 1710, 1680, 1246, 1019 cm-1; δH
(DMSO-d6) 9.13 (1Н, d, J 10.2 Hz, NН), 7.85 (m, 4Н, aromatic),
5.24 (1Н, dd, J 19.31, 10.2 Hz, СНР), 4.18-4.01 (4Н, m,
2ОСН2), 3.62 (2H, m, CH2), 2.38 (2H, m, CH2), 1.87 (2H, m,
CH2), 1.24 (6H, m, 2ОСН2СН3); δC (DMSO-d6) 172.6 (С=О),
168.4 (С=О), 134.8, 132.2, 123.5, 97.7 (d, J 14.9 Hz, CCl3), 63.6
(ОСН2СН3), 61.3 (d, J 159.0 Hz, CP), 37.7, 32.9, 24.8, 16.6
(ОСН2СН3); δP (DMSO-d6) 14.9; LCMS: found m/z 501.0 MH+.
C18H22Cl3N2O6P requires 499.7.
Yield 4.44 g, 99% as a colorless crystals; mp 148-149°С;
[Found: С, 45.37; H, 4.39; Cl, 15.91; N, 6.05; P, 6.98.
C17H19Cl2N2O6P requires С, 45.45; H, 4.26; Cl, 15.78; N, 6.24; P,
6.89%]; νmax (KBr) 3234, 1773, 1721, 1683, 1246, 1037, 1001
cm-1; δH (CDCl3) 8.20 (1Н, br s, NН), 7.74 (2Н, m, aromatic),
7.64 (2H, m, aromatic), 4.08 (4Н, m, 2ОСН2), 3.97 (2H, m,
CH2), 2.74 (2H, m, CH2), 1.26 (6H, t, J 7.0 Hz, 2ОСН2СН3); δC
(CDCl3) 168.0 (С=О), 135.5 (d, J 27.3 Hz, CCl2), 134.0, 132.1,
125.0 (d, J 208.5 Hz, CP), 123.2, 63.5 (ОСН2СН3), 34.1 (2СН2),
16.1 (ОСН2СН3); δP (CDCl3) 9.1; LCMS: found m/z 449.0 M+.
C17H19Cl2N2O6P requires 449.2.
4.6.3. Diethyl [2,2-dichloro-1-[4-(1,3-dioxo-2,3-dihydro-1H-
isoindol-2-yl)butanamido]ethenyl]phosphonate (5c).
4.5.4. Diethyl [2,2,2-trichloro-1-[5-(1,3-dioxo-2,3-dihydro-
1H-isoindol-2-yl)pentanamido]ethyl]phosphonate (4d).

ACCEPTED MANUSCRIPT
7
Yield 4.58 g, 99% as a colorless crystals; mp 69-70°С;
[Found: С, 46.59; H, 4.68; Cl, 15.50; N, 5.88; P, 6.82.
C18H21Cl2N2O6P requires С, 46.67; H, 4.57; Cl, 15.31; N, 6.05; P,
6.69%]; νmax (KBr) 3208, 1775, 1722, 1665, 1242, 1011, 964 cm-
1; δH (CDCl3) 7.94 (1Н, br, NН), 7.79 (2Н, m, aromatic), 7.68
(2Н, m, aromatic), 4.13 (4Н, m, 2ОСН2), 3.76 (2H, t, J 7.0 Hz,
CH2), 2.32 (2H, t, J 7.5 Hz, CH2), 2.01 (2H, m, CH2), 1.30 (6H, t,
J 7.0 Hz, 2ОСН2СН3); δC (CDCl3) 170.1 (С=О), 168.6 (С=О),
135.3 (d, J 29.6 Hz, CCl2), 134.1, 132.0, 125.2 (d, J 213.6 Hz,
CP), 123.3, 63.5 (ОСН2СН3), 37.1, 33.5, 25.0, 16.2 (ОСН2СН3);
δP (CDCl3) 9.3; LCMS: found m/z 463.0 M+. C18H21Cl2N2O6P
requires 463.3.
Yield 3.755 g, 40% (by method A), 4.037 g, 43% (by
method B) as a yellowish crystals; mp 174-175°С; [Found: С,
58.76; H, 5.24; N, 8.76; P, 6.77. C23H24N3O6P requires С, 58.85;
H, 5.15; N, 8.95; P, 6.60%]; νmax (KBr) 3302, 1722, 1639, 1600,
1224, 1031, 972 cm-1; δH (CDCl3) 7.89 (2Н, m, aromatic), 7.77
(2Н, m, aromatic), 7.26-7.15 (5Н, m, С6Н5), 6.39 (1Н, t, J 6.2
Hz, CH2NН), 4.85 (2Н, s, CH2), 4.39 (2Н, d, J 6.2 Hz, CH2NН),
4.11-3.95 (4Н, m, 2ОСН2), 1.28 (6H, t, J 7.0 Hz, 2ОСН2СН3); δC
(CDCl3) 167.1 (С=О), 163.9 (d, J 39.4 Hz, О-С=С-Р), 148.1 (d, J
21.9 Hz, О-С=N), 137.9, 134.3, 132.0, 128.6, 127.5, 127.4,
123.6, 95.9 (d, J 255.3 Hz, CP), 62.3 (ОСН2СН3), 47.4, 34.5,16.2
(ОСН2СН3); δP (CDCl3) 13.9; LCMS: found m/z 470.0 MH+.
C23H24N3O6P requires 469.4.
4.6.4. Diethyl [2,2-dichloro-1-[5-(1,3-dioxo-2,3-dihydro-1H-
isoindol-2-yl)pentanamido]ethenyl]phosphonate (5d).
4.7.2. Diethyl [5-(benzylamino)-2-[2-(1,3-dioxo-2,3-dihydro-
1H-isoindol-2-yl)ethyl]-1,3-oxazol-4-yl]phosphonate (6b).
Yield 4.73 g, 99% as a colorless crystals; mp 108-109°С;
[Found: С, 47.72; H, 4.96; Cl, 14.99; N, 5.69; P, 6.65.
C19H23Cl2N2O6P requires С, 47.81; H, 4.86; Cl, 14.86; N, 5.87; P,
6.49%]; νmax (KBr) 3206, 1769, 1705, 1675, 1574, 1243, 1008,
972 cm-1; δH (CDCl3) 7.81 (2Н, m, aromatic), 7.70 (2Н, m,
aromatic), 7.64 (1Н, br, NН), 4.16 (4Н, m, 2ОСН2), 3.70 (2H, m,
CH2), 2.37 (2H, m, CH2), 1.73 (4H, m, 2CH2), 1.34 (6H, m,
2ОСН2СН3); δC NMR (CDCl3) 170.6 (С=О), 168.3 (С=О), 135.4
(d, J 28.7 Hz, CCl2), 133.9, 132.1, 125.1 (d, J 210.4 Hz, CP),
123.2, 63.5 (ОСН2СН3), 37.3, 35.4, 27.9, 22.6, 16.2 (ОСН2СН3);
δP (CDCl3) 9.3; LCMS: found m/z 477.0 M+. C19H23Cl2N2O6P
requires 477.3.
Yield 3.674 g, 38% (by method A), 3.964 g, 41% (by method
B) as a colorless crystals; mp 133-134°С; [Found: С, 59.52; H,
5.54; N, 8.53; P, 6.55. C24H26N3O6P requires С, 59.62; H, 5.42;
N, 8.69; P, 6.41%]; νmax (KBr) 3393, 1713, 1641, 1597, 1222,
1024, 957 cm-1; δH (CDCl3) 7.81 (2Н, m, aromatic), 7.70 (2Н, m,
aromatic), 7.34-7.23 (5Н, m, С6Н5), 6.28 (1Н, t, J 6.5 Hz,
CH2NН), 4.38 (2Н, d, J 6.5 Hz, CH2NН), 4.07-3.90 (6Н, m,
2ОСН2, CH2), 3.02 (2H, t, J 6.7 Hz, CH2), 1.25 (6H, t, J 7.0 Hz,
2ОСН2СН3); δC (CDCl3) 167.7 (С=О), 164.0 (d, J 39.4 Hz, О-
С=С-Р), 151.3 (d, J 21.9 Hz, О-С=N), 138.1, 134.0, 132.0,
128.6, 127.5, 127.3, 123.3, 95.4 (d, J 254.8 Hz, CP), 62.1
(ОСН2СН3), 47.3, 35.4, 27.1, 16.2 (ОСН2СН3); δP (CDCl3) 14.4;
LCMS: found m/z 484.0 MH+. C24H26N3O6P requires 483.5.
4.6.5. Diethyl [2,2-dichloro-1-[6-(1,3-dioxo-2,3-dihydro-1H-
isoindol-2-yl)hexanamido]ethenyl]phosphonate (5e).
4.7.3. Diethyl [5-(benzylamino)-2-[3-(1,3-dioxo-2,3-dihydro-
1H-isoindol-2-yl)propyl]-1,3-oxazol-4-yl]phosphonate (6c).
Yield 4.86 g, 99% as a colorless crystals; mp 119-120°С;
[Found: С, 48.80; H, 5.24; Cl, 14.56; N, 5.52; P, 6.45.
C20H25Cl2N2O6P requires С, 48.89; H, 5.13; Cl, 14.43; N, 5.70; P,
6.30%]; νmax (KBr) 3170, 1770, 1708, 1678, 1245, 1016, 973 cm-
1; δH (CDCl3) 7.84 (2Н, m, aromatic), 7.71 (2Н, m, aromatic),
7.27 (1Н, br, NН), 4.17 (4Н, m, 2ОСН2), 3.69 (2H, t, J 7.0 Hz,
CH2), 2.32 (2H, t, J 7.5 Hz, CH2), 1.72 (4H, m, 2CH2), 1.41 (2H,
m, CH2), 1.35 (6H, t, J 7.0 Hz, 2ОСН2СН3); δC (CDCl3) 170.4
(С=О), 168.3 (С=О), 134.5 (d, J 29.4 Hz, CCl2), 133.8, 132.1,
124.8 (d, J 209.4 Hz, CP), 123.1, 63.5 (ОСН2СН3), 37.7, 36.1,
28.6, 26.3, 24.8, 16.2 (ОСН2СН3); δP (CDCl3) 9.4; LCMS: found
m/z 491.0 M+. C20H25Cl2N2O6P requires 491.3.
Yield 4.577 g, 46% (by method A), 4.875 g, 49% (by method
B) as a colorless crystals; mp 104-105°С; [Found: С, 60.25; H,
5.79; N, 8.29; P, 6.39. C25H28N3O6P requires С, 60.36; H, 5.67;
N, 8.45; P, 6.23%]; νmax (KBr) 3331, 1773, 1720, 1650, 1599,
1222, 1250, 964 cm-1; δH (CDCl3) 7.84 (2Н, m, aromatic), 7.71
(2Н, m, aromatic), 7.34-7.22 (5Н, m, С6Н5), 6.28 (1Н, t, J 6.5
Hz, NH), 4.44 (2H, d, J 6.5Hz, CH2NН), 4.04 (4Н, m, 2ОСН2),
3.75 (2Н, t, J 7.0 Hz, CH2), 2.69 (2Н, t, J 7.7 Hz, CH2), 2.10 (2Н,
m, CH2), 1.30 (6H, t, J 7.0 Hz, 2ОСН2СН3); δC (CDCl3) 168.2
(С=О), 163.5 (d, J 39.4 Hz, О-С=С-Р), 153.8 (d, J 22.4 Hz, О-
С=N), 138.3, 134.0, 128.6, 127.5, 127.4, 127.3, 123.2, 95.5 (d, J
254.8 Hz, CP), 62.1 (ОСН2СН3), 47.4, 37.2, 25.8, 25.4, 16.2
(ОСН2СН3); δP (CDCl3) 14.5; LCMS: found m/z 498.2 MH+.
C25H28N3O6P requires 497.5.
4.7. General procedure for the preparation of 6a-n.
Oxazole cyclization.
Method A. A mixture of one of compounds 4a-e (20 mmol),
the corresponding amine (21 mmol), and Et3N (16.7 mL, 120
mmol) in dry dioxane (100 mL) was refluxed for 24 h and
cooled. The precipitate was filtered and washed on the filter with
dry dioxane; the combined filtrates were evaporated in vacuo to
dryness. Compounds 6f-n were thus obtained in the analytically
pure state without further purification. To purify compounds 6a-
e, the residue after evaporation was recrystallized from the
minimum amount of 2-propanol. If necessary, the reaction
products can be purified by extraction with boiling petroleum
ether (bp 80-110°C), followed by evaporation of the combined
extracts in vacuo.
4.7.4. Diethyl [5-(benzylamino)-2-[4-(1,3-dioxo-2,3-dihydro-
1H-isoindol-2-yl)butyl]-1,3-oxazol-4-yl]phosphonate (6d).
Yield 4.706 g, 46% (by method A), 5.013 g, 49% (by method
B) as a yellow crystals; mp 99-100°С; [Found: С, 60.96; H, 6.02;
N, 8.02; P, 6.21. C26H30N3O6P requires С, 61.05; H, 5.91; N,
8.21; P, 6.06%]; νmax (KBr) 3303, 1770, 1720, 1707, 1636, 1238,
1016, 968 cm-1; δH (CDCl3) 7.85 (2Н, m, aromatic), 7.73 (2Н, m,
aromatic), 7.34-7.23 (5Н, m, С6Н5), 6.29 (1Н, t, J 6.5 Hz, NH),
4.44 (2H, d, J 6.5 Hz, CH2NН), 4.05 (4Н, m, 2ОСН2), 3.70 (2Н,
m, CH2), 2.68 (2Н, m, CH2), 1.73 (4Н, m, 2CH2), 1.31 (6H, t, J
7.0 Hz, 2ОСН2СН3); δC (CDCl3) 168.2 (С=О), 163.6 (d, J 38.9
Hz, О-С=С-Р), 154.5 (d, J 21.4 Hz, О-С=N), 138.4, 133.9,
132.1, 128.6, 127.3, 123.2, 95.4 (d, J 255.8 Hz, CP), 62.2
(ОСН2СН3), 47.4, 37.4, 27.9, 27.2, 24.1, 16.2 (ОСН2СН3); δP
(CDCl3) 14.5; LCMS: found m/z 512.4 MH+. C26H30N3O6P
requires 511.5.
Method B. The above procedure was performed starting from
compounds 5a-e and using less Et3N (13.9 mL, 100 mmol).
Compounds 6a-n produced by methods A and B provided
identical characterization data.
4.7.1. Diethyl [5-(benzylamino)-2-[(1,3-dioxo-2,3-dihydro-
1H-isoindol-2-yl)methyl]-1,3-oxazol-4-yl]phosphonate (6a).
4.7.5. Diethyl [5-(benzylamino)-2-[5-(1,3-dioxo-2,3-dihydro-
1H-isoindol-2-yl)pentyl]-1,3-oxazol-4-yl]phosphonate (6e).

ACCEPTED MANUSCRIPT
8
Tetrahedron
Yield 4.414 g, 42% (by method A), 4.625 g, 44% (by
6.51. C24H32N3O6P requires С, 58.89; H, 6.59; N, 8.58; P,
6.33%]; νmax (СН2Сl2) 1771, 1708, 1617, 1572, 1257, 1020, 958
cm-1; δH (CDCl3) 7.83 (2Н, m, aromatic), 7.71 (2Н, m, aromatic),
4.10 (4Н, m, 2ОСН2), 3.70 (2H, m, CH2), 3.45 (4H, m, 2CH2),
2.65 (2H, m, CH2), 1.74 (4H, m, 2CH2), 1.62 (6H, m, 3CH2),
1.32 (6H, t, J 7.0 Hz, 2ОСН2СН3); δC (CDCl3) 168.3 (С=О),
161.9 (d, J 36.9 Hz, О-С=С-Р), 153.9 (d, J 21.9 Hz, О-С=N),
133.9, 132.1, 123.2, 99.8 (d, J 256.8 Hz, CP), 62.1 (ОСН2СН3),
49.5, 37.5, 28.0, 27.3, 25.4, 24.3, 24.0, 16.3 (ОСН2СН3); δP
(CDCl3) 14.5; LCMS: found m/z 490.4 MH+. C24H32N3O6P
requires 489.5.
method B) as a yellow crystals; mp 96-97°С; [Found: С, 61.60;
H, 6.23; N, 7.84; P, 6.03. C27H32N3O6P requires С, 61.71; H,
6.14; N, 8.00; P, 5.89%]; νmax (KBr) 3293, 1773, 1715, 1644,
1594, 1228, 1024, 961 cm-1; δH (CDCl3) 7.83 (2Н, m, aromatic),
7.71 (2Н, m, aromatic), 7.35-7.23 (5Н, m, С6Н5), 6.29 (1Н, t, J
6.5 Hz, NH), 4.44 (2H, d, J 6.5 Hz, CH2NН), 4.12-3.97 (4Н, m,
2ОСН2), 3.66 (2Н, t, J 7.3 Hz, CH2), 2.62 (2Н, t, J 7.5 Hz, CH2),
1.71 (4Н, m, 2CH2), 1.36 (2Н, m, CH2), 1.30 (6H, t, J 7.0 Hz,
2ОСН2СН3); δC (CDCl3) 168.4 (С=О), 163.6 (d, J 38.9 Hz, О-
С=С-Р), 154.9 (d, J 21.9 Hz, О-С=N), 138.4, 133.9, 132.1,
128.6, 127.5, 127.3, 123.2, 95.3 (d, J 255.8 Hz, CP), 62.2
(ОСН2СН3), 47.5, 37.5, 28.2, 27.7, 26.4, 26.2, 16.2 (ОСН2СН3);
δP (CDCl3) 14.7; LCMS: found m/z 526.2 MH+. C27H32N3O6P
requires 525.5.
4.7.10. Diethyl [2-[5-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-
yl)pentyl]-5-(piperidin-1-yl)-1,3-oxazol-4-yl]phosphonate (6j).
Yield 8.560 g, 85% (by method A), 9.064 g, 90% (by method
B) as a brown viscous oil; [Found: С, 59.54; H, 6.92; N, 8.17; P,
6.31. C25H34N3O6P requires С, 59.63; H, 6.81; N, 8.35; P,
6.15%]. νmax (СН2Сl2) 1772, 1709, 1617, 1571, 1256, 1021, 953
cm-1; δH (CDCl3) 7.82 (2Н, m, aromatic), 7.70 (2Н, m, aromatic),
4.10 (4Н, m, 2ОСН2), 3.66 (2H, t, J 7.3 Hz, CH2), 3.45 (4H, m,
2CH2), 2.59 (2H, t, J 7.5 Hz, CH2), 1.77-1.55 (10H, m, 5CH2),
1.40 (2H, m, CH2), 1.31 (6H, m, 2ОСН2СН3); δC (CDCl3) 168.4
(С=О), 161.8 (d, J 36.9 Hz, О-С=С-Р), 154.3 (d, J 21.9 Hz, О-
С=N), 133.9, 132.1, 123.2, 99.7 (d, J 257.3 Hz, CP), 62.1
(ОСН2СН3), 49.6, 37.8, 28.2, 27.7, 26.5, 26.3, 25.4, 24.0,16.3
(ОСН2СН3); δP (CDCl3) 14.5; LCMS: found m/z 504.2 MH+.
C25H34N3O6P requires 503.5.
4.7.6. Diethyl [2-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-
yl)methyl]-5-(piperidin-1-yl)-1,3-oxazol-4-yl]phosphonate (6f).
Yield 8.769 g, 98% (by method A), 8.859 g, 99% (by method
B) as a yellowish crystals mp 57-60°С; [Found: С, 56.28; H,
5.97; N, 9.22; P, 7.10. C21H26N3O6P requires С, 56.37; H, 5.86;
N, 9.39; P, 6.92%]; νmax (СН2Сl2) 1777, 1724, 1620, 1284, 1025,
961 cm-1; δH (CDCl3) 7.89 (2Н, m, aromatic), 7.76 (2Н, m,
aromatic), 4.84 (2H, s, CH2), 4.08 (4Н, m, 2ОСН2), 3.46 (4H, m,
2CH2), 1.61 (6H, m, 3CH2), 1.29 (6H, m, 2ОСН2СН3); δC
(CDCl3) 167.2 (С=О), 162.2 (d, J 36.9 Hz, О-С=С-Р), 147.4 (d, J
21.9 Hz, О-С=N), 134.2, 132.0, 123.6, 100.1 (d, J 255.8 Hz, CP),
62.3 (ОСН2СН3), 49.4, 34.5, 25.3, 23.9, 16.2 (ОСН2СН3); δP
(CDCl3) 13.7; LCMS: found m/z 448.2 MH+. C21H26N3O6P
requires 447.4.
4.7.11. Diethyl [2-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-
yl)methyl]-5-(morpholin-4-yl)-1,3-oxazol-4-yl]phosphonate (6k).
Yield 8.808 g, 98% (by method A), 8.898 g, 99% (by method
B) as a yellow viscous oil; [Found: С, 53.37; H, 5.48; N, 9.18; P,
6.98. C20H24N3O7P requires С, 53.45; H, 5.38; N, 9.35; P,
6.89%]. νmax (СН2Сl2) 1777, 1724, 1618, 1280, 1026, 969 cm-1;
δH (CDCl3) 7.85 (2Н, m, aromatic), 7.73 (2Н, m, aromatic), 4.81
(2H, s, 2CH2), 4.05 (4Н, m, 2ОСН2), 3.72 (4H, m, 2CH2), 3.49
(4H, m, 2CH2), 1.25 (6H, t, J 7.0 Hz, 2ОСН2СН3); δC (CDCl3)
167.2 (С=О), 161.6 (d, J 36.9 Hz, О-С=С-Р), 148.2 (d, J 21.9
Hz, О-С=N), 134.3, 131.9, 123.6, 101.6 (d, J 252.3 Hz, CP),
66.2, 62.5 (ОСН2СН3), 48.3, 34.5, 16.2 (ОСН2СН3); δP (CDCl3)
12.5; LCMS: found m/z 450.2 MH+. C20H24N3O7P requires 449.4.
4.7.7. Diethyl [2-[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-
yl)ethyl]-5-(piperidin-1-yl)-1,3-oxazol-4-yl]phosphonate (6g).
Yield 9.044 g, 98% (by method A), 9.137 g, 99% (by method
B) as a yellowish crystals mp 76-77°С; [Found: С, 57.15; H,
6.23; N, 8.95; P, 6.84. C22H28N3O6P requires С, 57.26; H, 6.12;
N, 9.11; P, 6.71%]; νmax (СН2Сl2) 1774, 1717, 1620, 1240, 1027,
967 cm-1; δH (CDCl3) 7.81 (2Н, m, aromatic), 7.70 (2Н, m,
aromatic), 4.08-3.93 (6Н, m, 2ОСН2, CH2), 3.41 (4H, m, 2CH2),
3.00 (2H, t, J 6.6 Hz, CH2), 1.58 (6H, m, 3CH2), 1.24 (6H, t, J
7.0 Hz, 2ОСН2СН3); δC (CDCl3) 167.7 (С=О), 162.3 (d, J 36.9
Hz, О-С=С-Р), 150.9 (d, J 22.4 Hz, О-С=N), 134.0, 132.1,
123.3, 100.1 (d, J 255.8 Hz, CP), 62.1 (ОСН2СН3), 49.6, 35.4,
27.1, 25.4, 24.0,16.2 (ОСН2СН3); δP (CDCl3) 14.0; LCMS: found
m/z 462.2 MH+. C22H28N3O6P requires 461.5.
4.7.12. Diethyl [2-[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-
yl)ethyl]-5-(morpholin-4-yl)-1,3-oxazol-4-yl]phosphonate (6l).
Yield 9.083 g, 98% (by method A), 9.176 g, 99% (by method
B) as a yellow viscous oil; [Found: С, 54.35; H, 5.76; N, 8.92; P,
6.74. C21H26N3O7P requires С, 54.43; H, 5.65; N, 9.07; P,
6.68%]; νmax (СН2Сl2) 1774, 1717, 1618, 1284, 1026, 969 cm-1;
δH (CDCl3) 7.79 (2Н, m, aromatic), 7.69 (2Н, m, aromatic), 4.09-
3.90 (6Н, m, 2ОСН2, CH2), 3.71 (4H, m, 2CH2), 3.46 (4H, m,
2CH2), 3.00 (2H, t, J 6.6 Hz, CH2), 1.22 (6H, t, J 7.0 Hz,
2ОСН2СН3); δC (CDCl3) 167.7 (С=О), 161.8 (d, J 36.9 Hz, О-
С=С-Р), 151.7 (d, J 21.9 Hz, О-С=N), 134.1, 132.0, 123.3, 101.7
(d, J 253.3 Hz, CP), 66.3, 62.3 (ОСН2СН3), 48.5, 35.3, 27.0, 16.2
(ОСН2СН3); δP (CDCl3) 12.8; LCMS: found m/z 464.2 MH+.
C21H26N3O7P requires 463.4.
4.7.8. Diethyl [2-[3-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-
yl)propyl]-5-(piperidin-1-yl)-1,3-oxazol-4-yl]phosphonate (6h).
Yield 8.654 g, 91% (by method A), 9.034 g, 95% (by method
B) as a brown viscous oil; [Found: С, 58.02; H, 6.47; N, 8.69; P,
6.67. C23H30N3O6P requires С, 58.10; H, 6.36; N, 8.84; P,
6.51%]; νmax (СН2Сl2) 1772, 1709, 1618, 1572, 1257, 1019, 956
cm-1; δH (CDCl3) 7.80 (2Н, m, aromatic), 7.69 (2Н, m, aromatic),
4.08 (4Н, m, 2ОСН2), 3.73 (2H, t, J 7.0 Hz, CH2), 3.43 (4H, m,
2CH2), 2.65 (2H, t, J 7.5 Hz, CH2), 2.07 (2H, m, CH2), 1.60 (6H,
m, 3CH2), 1.29 (6H, t, J 7.0 Hz, 2ОСН2СН3); δC (CDCl3) 168.2
(С=О), 161.9 (d, J 36.9 Hz, О-С=С-Р), 153.1 (d, J 21.9 Hz, О-
С=N), 134.0, 132.0, 123.2, 99.7 (d, J 255.8 Hz, CP), 62.1
(ОСН2СН3), 49.5, 37.3, 25.8, 25.4, 25.3, 24.0, 16.3 (ОСН2СН3);
δP (CDCl3) 14.3; LCMS: found m/z 476.2 MH+. C23H30N3O6P
requires 475.5.
4.7.13. Methyl 1-[4-(diethoxyphosphoryl)-2-[(1,3-dioxo-2,3-
dihydro-1H-isoindol-2-yl)methyl]-1,3-oxazol-5-yl]piperidine-4-
carboxylate (6m).
Yield 9.806 g, 97% (by method A), 10.008 g, 99% (by method
B) as a yellow viscous oil; [Found: С, 54.57; H, 5.67; N, 8.13; P,
6.23. C23H28N3O8P requires С, 54.65; H, 5.58; N, 8.31; P,
6.13%]; νmax (KBr) 1774, 1731, 1620, 1257, 1019, 970 cm-1; δH
(CDCl3) 7.88 (2Н, m, aromatic), 7.75 (2Н, m, aromatic), 4.83
(2Н, m, СН2), 4.08 (4Н, m, 2ОСН2), 3.94 (2Н, m, СН2), 3.67
4.7.9. Diethyl [2-[4-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-
yl)butyl]-5-(piperidin-1-yl)-1,3-oxazol-4-yl]phosphonate (6i).
Yield 9.105 g, 93% (by method A), 9.301 g, 95% (by method
B) as a brown viscous oil; [Found: С, 58.78; H, 6.70; N, 8.39; P,

ACCEPTED MANUSCRIPT
9
(3Н, s, ОСН3), 3.11 (2H, m, CH2), 2.47 (1Н, m, СН), 1.94 (2Н,
39.4, 32.1, 16.2 (ОСН2СН3); δP (CDCl3) 14.5; LCMS: found
m/z 354.2 MH+. C16H24N3O4P requires 353.4.
m, СН2), 1.78 (2Н, m, СН2), 1.28 (6Н, m, 2ОСН2СН3); δC
(CDCl3) 174.6 (С=О), 167.2 (С=О), 161.7 (d, J 36.9 Hz, О-С=С-
Р), 147.9 (d, J 21.9 Hz, О-С=N), 134.3, 132.0, 123.6, 101.2 (d, J
258.8 Hz, CP), 62.4 (ОСН2СН3), 51.8, 47.9, 40.4, 34.5, 27.5,
16.2 (ОСН2СН3); δP (CDCl3) 13.0; LCMS: found m/z 506.2
MH+. C23H28N3O8P requires 505.5.
4.8.3.
Diethyl
[2-(3-aminopropyl)-5-(benzylamino)-1,3-
oxazol-4-yl]phosphonate (7c).
Yield 2.461 g, 67% as a yellow viscous oil; [Found: С, 55.49;
H, 7.24; N, 11.29; P, 8.51. C17H26N3O4P requires С, 55.58; H,
7.13; N, 11.44; P, 8.43%]. νmax (ATR) 2931, 1633, 1589, 1216,
1019, 961 cm-1; δH (CDCl3) 7.35-7.23 (5Н, m, С6Н5), 6.31 (1Н, t,
J 6.3 Hz, NH), 4.44 (2H, d, J 6.3 Hz, CH2), 4.13-3.96 (4Н, m,
2ОСН2), 2.68 (4Н, m, 2СН2), 1.80 (2H, m, CH2), 1.56 (2Н, br,
NH2), 1.30 (6Н, t, J 7.0 Hz, 2ОСН2СН3); δC (CDCl3) 163.5 (d, J
39.4 Hz, О-С=С-Р), 154.8 (d, J 21.9 Hz, О-С=N), 138.3, 128.6,
127.4, 127.2, 95.4 (d, J 256.3 Hz, CP), 62.1 (ОСН2СН3), 47.5,
41.3, 30.7, 25.3,16.2 (ОСН2СН3); δP (CDCl3) 14.5; LCMS: found
m/z 368.2 MH+. C17H26N3O4P requires 367.4.
4.7.14. Methyl 1-[4-(diethoxyphosphoryl)-2-[2-(1,3-dioxo-2,3-
dihydro-1H-isoindol-2-yl)ethyl]-1,3-oxazol-5-yl]piperidine-4-
carboxylate (6n).
Yield 10.182 g, 98% (by method A), 10.286 g, 99% (by
method B) as a yellow viscous oil; [Found: С, 55.40; H, 5.94; N,
7.91; P, 6.08. C24H30N3O8P requires С, 55.49; H, 5.82; N, 8.09; P,
5.96%]; νmax (СН2Сl2) 1774, 1717, 1620, 1234, 1028, 968 cm-1;
δH (CDCl3) 7.82 (2Н, m, aromatic), 7.72 (2Н, m, aromatic), 4.03-
3.92 (6Н, m, 2ОСН2, СН2), 3.91 (2Н, m, СН2), 3.70 (3Н, s,
ОСН3), 3.08 (2H, m, CH2), 3.03 (2H, t, J 6.7 Hz, CH2), 2.48 (1Н,
m, СН), 1.94 (2Н, m, СН2), 1.78 (2Н, m, СН2), 1.26 (6Н, m,
2ОСН2СН3); δC (CDCl3) 174.7 (С=О), 167.7 (С=О), 161.9 (d, J
36.9Hz, О-С=С-Р), 151.4 (d, J 21.9 Hz, О-С=N), 134.0, 132.0,
123.3, 101.3 (d, J 254.8 Hz, CP), 62.2 (ОСН2СН3), 51.8, 48.1,
40.5, 35.4, 27.6, 27.1, 16.2 (ОСН2СН3); δP (CDCl3) 13.3; LCMS:
found m/z 520.2 MH+. C24H30N3O8P requires 519.5.
4.8.4. Diethyl [2-(4-aminobutyl)-5-(benzylamino)-1,3-oxazol-
4-yl]phosphonate (7d).
Yield 2.517 g, 66% as a yellow viscous oil; [Found: С, 56.59;
H, 7.51; N, 10.89; P, 8.26. C18H28N3O4P requires С, 56.68; H,
7.40; N, 11.02; P, 8.12%]; νmax (ATR) 2931, 1630, 1589, 1220,
1020, 959 cm-1; δH (CDCl3) 7.35-7.23 (5Н, m, С6Н5), 6.33 (1Н, t,
J 6.3 Hz, NH), 4.45 (2H, d, J 6.3 Hz, CH2), 4.13-3.97 (4Н, m,
2ОСН2), 2.67 (2Н, m, СН2), 2.63 (2H, m, CH2), 1.70 (2H, m,
CH2), 1.56 (2Н, br, NH2), 1.45 (2H, m, CH2), 1.30 (6Н, t, J 7.0
Hz, 2ОСН2СН3); δC (CDCl3) 163.5 (d, J 39.4 Hz, О-С=С-Р),
154.8 (d, J 21.9 Hz, О-С=N), 138.3, 128.6, 127.4, 127.2, 95.4 (d,
J 256.3 Hz, CP), 62.1 (ОСН2СН3), 47.4, 41.7, 33.0, 27.7, 24.2,
16.2 (ОСН2СН3); δP (CDCl3) 14.7; LCMS: found m/z 382.2
MH+. C18H28N3O4P requires 381.4.
4.8. General procedure for the preparation of 7a-n.
Removal of the phthalimido protecting group by
hydrazinolysis.
A mixture of one of compounds 7a-n (10 mmol), hydrazine
hydrate (2.5 mL, 50 mmol), THF (60 mL), and water (20 mL)
was stirred at 20-25°C for 48 h with TLC monitoring. After
addition of EtOAc (100 mL) to the reaction mixture, it was
washed with saturated aqueous K2CO3 (5x10 ml) and dried over
K2CO3; the resulting precipitate was filtered and washed on the
filter with EtOAc. The combined filtrates were evaporated to
dryness in vacuo at a temperature above 35°C and the residue
was dissolved in absolute CH2Cl2 (50 mL). The solution was
filtered through activated carbon and evaporated in vacuo to
dryness to give the analytically pure product.
4.8.5. Diethyl [2-(5-aminopentyl)-5-(benzylamino)-1,3-oxazol-
4-yl]phosphonate (7e).
Yield 2.610 g, 66% as a yellow viscous oil; [Found: С, 57.63;
H, 7.76; N, 10.47; P, 7.99. C19H30N3O4P requires С, 57.71; H,
7.65; N, 10.63; P, 7.83%]; νmax (ATR) 2930, 1632, 1589, 1223,
1021, 960 cm-1; δH (CDCl3) 7.30-7.18 (5Н, m, С6Н5), 6.26 (1Н,
br, NH), 4.40 (2H, m, CH2), 4.09-3.91 (4Н, m, 2ОСН2), 3.33
(2Н, br, NH2), 2.64 (2H, m, CH2), 2.57 (2H, m, CH2), 1.64 (2Н,
m, 2СН2), 1.45 (2H, m, CH2), 1.26 (8Н, m, 2ОСН2СН3, CH2); δC
(CDCl3) 163.5 (d, J 39.4 Hz, О-С=С-Р), 155.1 (d, J 22.4 Hz, О-
С=N), 138.4, 128.6, 127.5, 127.3, 95.4 (d, J 256.3 Hz, CP), 62.1
(ОСН2СН3), 47.5, 42.40, 33.3, 27.8, 26.7, 26.3, 16.2
(ОСН2СН3); δP (CDCl3) 14.8; LCMS: found m/z 396.2 MH+.
C19H30N3O4P requires 395.4.
4.8.1. Diethyl [2-(aminomethyl)-5-(benzylamino)-1,3-oxazol-
4-yl]phosphonate (7a).
Yield 2.749 g, 81% as a yellow viscous oil; [Found: С, 52.99;
H, 6.60; N, 12.20; P, 9.22. C15H22N3O4P requires С, 53.09; H,
6.53; N, 12.38; P, 9.13%]; νmax (KBr) 2982, 1647, 1591, 1209,
1025, 964 cm-1; δH (CDCl3) 7.37-7.24 (5Н, m, С6Н5), 6.35 (1Н, t,
J 6.5 Hz, NH), 4.47 (2H, d, J 6.5 Hz, CH2), 4.15-3.99 (4Н, m,
2ОСН2), 3.80 (2Н, s, СН2), 1.65 (2Н, br, NH2), 1.32 (6Н, t, J 7.0
Hz, 2ОСН2СН3); δC (CDCl3) 163.7 (d, J 39.4 Hz, О-С=С-Р),
155.3 (d, J 20.9 Hz, О-С=N), 138.2, 128.7, 127.6, 127.3, 95.5 (d,
J 256.8 Hz, CP), 62.2 (ОСН2СН3), 47.4, 39.3, 16.2 (ОСН2СН3);
δP (CDCl3) 14.5; LCMS: found m/z 338.2 M-H-. C15H22N3O4P
requires 339.3.
4.8.6. Diethyl [2-(aminomethyl)-5-(piperidin-1-yl)-1,3-oxazol-
4-yl]phosphonate (7f).
Yield 3.141 g, 99% as a yellow viscous oil; [Found: С, 49.12;
H, 7.71; N, 13.05; P, 9.87. C13H24N3O4P requires С, 49.21; H,
7.62; N, 13.24; P, 9.76%]; νmax (ATR) 2926, 1615, 1572, 1222,
1017, 951 cm-1; δH (CDCl3) 4.10 (4Н, m, 2ОСН2), 3.76 (2Н, s,
СН2), 3.46 (4Н, m, 2СН2), 2.07 (2H, br, NH2), 1.62 (6H, m,
3CH2), 1.31 (6Н, m, 2ОСН2СН3); δC (CDCl3) 161.8 (d, J 36.9
Hz, О-С=С-Р), 154.7 (d, J 20.9 Hz, О-С=N), 100.0 (d, J 256.8
Hz, CP), 62.1 (ОСН2СН3), 49.5, 39.2, 25.4, 23.9, 16.3
(ОСН2СН3); δP (CDCl3) 13.6; LCMS: found m/z 318.2 MH+.
C13H24N3O4P requires 317.3.
4.8.2. Diethyl [2-(2-aminoethyl)-5-(benzylamino)-1,3-oxazol-
4-yl]phosphonate (7b).
Yield 2.473 g, 70% as a yellow viscous oil; [Found: С, 54.29;
H, 6.93; N, 11.78; P, 8.87. C16H24N3O4P requires С, 54.38; H,
6.85; N, 11.89; P, 8.77%]; νmax (ATR) 2926, 1632, 1218, 1019,
959 cm-1; δH (CDCl3) 7.35-7.20 (5Н, m, С6Н5), 6.33 (1Н, t, J 6.5
Hz, NH), 4.43 (2H, d, J 6.5 Hz, CH2), 4.04 (4Н, m, 2ОСН2), 3.00
(2H, t, J 6.5 Hz, CH2), 2.73 (2H, t, J 6.5 Hz, CH2), 1.66 (2Н, br,
NH2), 1.28 (6Н, t, J 7.0 Hz, 2ОСН2СН3); δC (CDCl3) 163.6 (d, J
39.4 Hz, О-С=С-Р), 153.5 (d, J 21.9 Hz, О-С=N), 138.3, 128.6,
127.5, 127.2, 95.7 (d, J 256.8 Hz, CP), 62.1 (ОСН2СН3), 47.5,
4.8.7. Diethyl [2-(2-aminoethyl)-5-(piperidin-1-yl)-1,3-oxazol-
4-yl]phosphonate (7g).
Yield 3.280 g, 99% as a yellow viscous oil; [Found: С, 50.64;
H, 8.00; N, 12.56; P, 9.43. C14H26N3O4P requires С, 50.75; H,
7.91; N, 12.68; P, 9.35%]; νmax (ATR) 2926, 1618, 1572, 1256,

ACCEPTED MANUSCRIPT
10
Tetrahedron
1019, 954 cm-1; δH (CDCl3) 4.09 (4Н, m, 2ОСН2), 3.43 (4Н,
Yield 3.167 g, 95% as a yellow viscous oil; [Found: С, 46.73;
H, 7.35; N, 12.43; P, 9.41. C13H24N3O5P requires С, 46.84; H,
7.26; N, 12.61; P, 9.29%]; νmax (ATR) 2972, 1615, 1570, 1233,
1017, 948 cm-1; δH (CDCl3) 4.11 (4Н, m, 2ОСН2), 3.76 (4Н, m,
2СН2), 3.51 (4Н, m, 2СН2), 3.29 (2Н, br, NН2), 3.08 (2H, m,
CH2), 2.79 (2H, m, CH2), 1.32 (6Н, m, 2ОСН2СН3); δC (CDCl3)
161.3 (d, J 36.9 Hz, О-С=С-Р), 153.4 (d, J 21.9 Hz, О-С=N),
101.0 (d, J 255.8 Hz, CP), 66.3, 62.3 (ОСН2СН3), 48.5, 39.1,
31.3, 16.3 (ОСН2СН3); δP (CDCl3) 13.3; LCMS: found m/z 334.0
MH+. C13H24N3O5P requires 333.3.
m, 2СН2), 3.01 (2H, m, CH2), 2.71 (2H, m, CH2), 1.60 (8H, m,
3CH2, NH2), 1.30 (6Н, m, 2ОСН2СН3); δC (CDCl3) 161.8 (d, J
36.0 Hz, О-С=С-Р), 152.8 (d, J 21.9 Hz, О-С=N), 100.0 (d, J
256.8 Hz, CP), 62.1 (ОСН2СН3), 49.5, 39.5, 32.0, 25.4, 23.9,
16.2 (ОСН2СН3); δP (CDCl3) 13.6; LCMS: found m/z 332.2
MH+. C14H26N3O4P requires 331.4.
4.8.8. Diethyl [2-(3-aminopropyl)-5-(piperidin-1-yl)-1,3-
oxazol-4-yl]phosphonate (7h).
Yield 3.212 g, 93% as a yellow viscous oil; [Found: С, 52.02;
H, 8.25; N, 12.01; P, 9.11. C15H28N3O4P requires С, 52.16; H,
8.17; N, 12.17; P, 8.97%]; νmax (ATR) 2977, 1620, 1572, 1256,
1019, 956 cm-1; δH (CDCl3) 4.08 (4Н, m, 2ОСН2), 3.43 (4Н, m,
2СН2), 2.71 (2H, m, CH2), 2.63 (2H, m, CH2), 1.79 (2H, m,
CH2), 1.60 (8H, m, 3CH2, NH2), 1.30 (6Н, m, 2ОСН2СН3); δC
(CDCl3) 161.8 (d, J 36.9 Hz, О-С=С-Р), 154.1 (d, J 21.9 Hz, О-
С=N), 99.8 (d, J 256.8 Hz, CP), 62.1 (ОСН2СН3), 49.5, 41.4,
30.8, 25.4, 25.2, 24.0, 16.3 (ОСН2СН3); δP (CDCl3) 14.5; LCMS:
found m/z 346.2 MH+. C15H28N3O4P requires 345.4.
4.8.13. Methyl 1-[2-(aminomethyl)-4-(diethoxyphosphoryl)-
1,3-oxazol-5-yl]piperidine-4-carboxylate (7m).
Yield 2.590 g, 69% as a yellow viscous oil; [Found: С, 47.93;
H, 7.10; N, 11.03; P, 8.38. C15H26N3O6P requires С, 48.00; H,
6.98; N, 11.19; P, 8.25%]; νmax (ATR) 2953, 1731, 1635, 1255,
1018, 958 cm-1; δH (CDCl3) 4.14 (4Н, m, 2ОСН2), 4.01 (2Н, m,
СН2), 3.96 (2Н, br, NН2), 3.81 (2Н, s, СН2), 3.70 (3Н, s, ОСН3),
3.14 (2H, m, CH2), 2.52 (1Н, m, СН), 1.99 (2Н, m, СН2), 1.82
(2Н, m, СН2), 1.35 (6Н, m, 2ОСН2СН3); δC (CDCl3) 174.6
(С=О), 161.4 (d, J 36.9 Hz, О-С=С-Р), 155.3 (d, J 20.9 Hz, О-
С=N), 101.0 (d, J 255.8 Hz, CP), 62.2 (ОСН2СН3), 51.8, 40.2,
39.3, 27.6, 16.3 (ОСН2СН3); δP (CDCl3) 13.7; LCMS: found m/z
376.2 MH+. C15H26N3O6P requires 375.4.
4.8.9.
Diethyl
[2-(4-aminobutyl)-5-(piperidin-1-yl)-1,3-
oxazol-4-yl]phosphonate (7i).
Yield 3.306 g, 92% as a yellow viscous oil; [Found: С, 53.39;
H, 8.50; N, 11.52; P, 8.76. C16H30N3O4P requires С, 53.47; H,
8.41; N, 11.69; P, 8.62%]; νmax (ATR) 2934, 1619, 1573, 1258,
1018, 963 cm-1; δH (CDCl3) 4.11 (4Н, m, 2ОСН2), 3.46 (4Н, m,
2СН2), 2.71 (2H, m, CH2), 2.62 (2H, m, CH2), 1.73 (2H, m,
CH2), 1.64 (8H, m, 3CH2, NH2), 1.50 (2Н, m, СН2), 1.33 (6Н, m,
2ОСН2СН3); δC (CDCl3) 161.8 (d, J 36.9 Hz, О-С=С-Р), 154.4
(d, J 21.9 Hz, О-С=N), 99.8 (d, J 256.8 Hz, CP), 62.1
(ОСН2СН3), 49.6, 41.7, 33.1, 27.7, 25.4, 24.3, 24.0, 16.3
(ОСН2СН3); δP (CDCl3) 14.6; LCMS: found m/z 360.2 MH+.
C16H30N3O4P requires 359.4.
4.8.14. Methyl 1-[2-(2-aminoethyl)-4-(diethoxyphosphoryl)-
1,3-oxazol-5-yl]piperidine-4-carboxylate (7n).
Yield 2.609 g, 67% as a yellow viscous oil; [Found: С, 49.26;
H, 7.36; N, 10.62; P, 8.12. C16H28N3O6P requires С, 49.35; H,
7.25; N, 10.79; P, 7.95%]; νmax (ATR) 2949, 1732, 1619, 1568,
1290, 1018, 958 cm-1; δH (CDCl3) 4.11 (4Н, m, 2ОСН2), 3.95
(2Н, m, СН2), 3.68 (3Н, s, ОСН3), 3.11 (2Н, m, СН2), 3.04 (2H,
t, J 7.5 Hz, CH2), 2.74 (2H, t, J 7.5 Hz, CH2), 2.49 (1Н, m, СН),
1.97 (2Н, m, СН2), 1.80 (2Н, m, СН2), 1.53 (2Н, br, NН2), 1.32
(6Н, m, 2ОСН2СН3); δC (CDCl3) 174.7 (С=О), 161.5 (d, J 36.9
Hz, О-С=С-Р), 153.3 (d, J 21.9 Hz, О-С=N), 101.1 (d, J=256.3
Hz, CP), 62.2 (ОСН2СН3), 51.8, 48.1, 40.5, 39.4, 32.0, 27.6, 16.3
(ОСН2СН3); δP (CDCl3) 13.8; LCMS: found m/z 390.2 MH+.
C16H28N3O6P requires 389.4.
4.8.10. Diethyl [2-(5-aminopentyl)-5-(piperidin-1-yl)-1,3-
oxazol-4-yl]phosphonate (7j).
Yield 3.585 g, 96% as a yellow viscous oil; [Found: С, 54.60;
H, 8.72; N, 11.08; P, 8.38. C17H32N3O4P requires С, 54.68; H,
8.64; N, 11.25; P, 8.29%]; νmax (ATR) 2933, 1619, 1571, 1256,
1019, 955 cm-1; δH (CDCl3) 4.32 (2Н, br, NH2), 4.08 (4Н, m,
2ОСН2), 3.42 (4Н, m, 2СН2), 2.71 (2H, m, CH2), 2.55 (2H, m,
CH2), 1.61 (8H, m, 4CH2), 1.49 (2Н, m, СН2), 1.30 (8Н, m,
2ОСН2СН3, СН2); δC (CDCl3) 161.7 (d, J 36.9 Hz, О-С=С-Р),
154.5 (d, J 21.9 Hz, О-С=N), 99.7 (d, J 256.8 Hz, CP), 62.1
(ОСН2СН3), 49.5, 41.4, 32.1, 27.7, 26.6, 26.4, 25.4, 24.0, 16.3
(ОСН2СН3); δP (CDCl3) 14.7; LCMS: found m/z 374.2 MH+.
C17H32N3O4P requires 373.4.
4.9. General procedure for the preparation of 8a-e.
To a mixture of one of compounds 7f-j (1.0 mmol), pyridine
(1 mL), and dry CH2Cl2 (20 mL), a solution of 4-tert-
butylbenzoylchloride (216 mg, 1.1 mmol) in dry CH2Cl2 (2 mL)
was added dropwise at 0°C. After stirring at 20-25°C for 1 h and
addition of Et3N (1 mL), the reaction mixture was left overnight
and then washed successively with water, saturated aqueous
NaHCO3, 5% aqueous citric acid, and brine. Further drying over
anhydrous Na2SO4 followed by evaporation of the solvent in
vacuo provided the analytically pure product.
4.8.11. Diethyl [2-(aminomethyl)-5-(morpholin-4-yl)-1,3-
oxazol-4-yl]phosphonate (7k).
4.9.1. Diethyl (2-[[(4-tert-butylphenyl)formamido]methyl]-5-
(piperidin-1-yl)-1,3-oxazol-4-yl)phosphonate (8a).
Yield 3.033 g, 95% as a yellow viscous oil; [Found: С, 45.03;
H, 7.02; N, 13.00; P, 9.85. C12H22N3O5P requires С, 45.14; H,
6.94; N, 13.16; P, 9.70%]; νmax (ATR) 2975, 1610, 1571, 1263,
1016, 955 cm-1; δH (CDCl3) 4.12 (4Н, m, 2ОСН2), 3.79 (2Н, s,
СН2), 3.77 (2H, m, CH2), 3.54 (2H, m, CH2), 1.71 (2Н, br s,
NН2), 1.33 (6Н, m, 2ОСН2СН3); δC (CDCl3) 161.4 (d, J 36.9 Hz,
О-С=С-Р), 155.5 (d, J 20.9 Hz, О-С=N), 101.5 (d, J 255.8 Hz,
CP), 66.3, 62.3 (ОСН2СН3), 48.5, 39.2, 16.3 (ОСН2СН3); δP
(CDCl3) 13.2; LCMS: found m/z 320.0 MH+. C12H22N3O5P
requires 319.3.
Yield 420 mg, 88% as a yellow viscous oil; [Found: С, 60.23;
H, 7.69; N, 8.61; P, 6.61. C24H36N3O5P requires С, 60.36; H,
7.60; N, 8.80; P, 6.49%]; νmax (ATR) 3288, 1615, 1574, 1265,
1020, 961 cm-1; δH (CDCl3) 7.71 (2H, d, J 8.3 Hz, aromatic), 7.41
(2H, d, J 8.3 Hz, aromatic), 6.78 (1Н, br, NH), 4.60 (2Н, d, J 5.2
Hz, NНCH2), 4.10 (4Н, m, 2ОСН2), 3.46 (4Н, m, 2СН2), 1.60
(6Н, m, 3СН2), 1.30 (15Н, m, 2ОСН2СН3, С(СН3)3); δC (CDCl3)
167.2 (С=О), 161.6 (d, J 36.9 Hz, О-С=С-Р), 155.3, 150.4 (d, J
21.9 Hz, О-С=N), 130.9, 127.0, 125.5, 100.0 (d, J 256.8 Hz, CP),
62.2 (ОСН2СН3), 49.4, 36.8, 34.9 (С(СН3)3), 31.1 (С(СН3)3),
25.3, 23.9, 16.2 (ОСН2СН3); δP (CDCl3) 14.1; LCMS: found m/z
478.4 MH+. C24H36N3O5P requires 477.5.
4.8.12. Diethyl [2-(2-aminoethyl)-5-(morpholin-4-yl)-1,3-
oxazol-4-yl]phosphonate (7l).

ACCEPTED MANUSCRIPT
11
4.9.2. Diethyl (2-[2-[(4-tert-butylphenyl)formamido]ethyl]-5-
To a solution of the appropriate protected amino acid [Z-
(piperidin-1-yl)-1,3-oxazol-4-yl)phosphonate (8b).
(S)-alanine, or Z-(R,S)-alanine, or Z-(S)-glutamine] (5 mmol) and
HOBt (675 mg, 5 mmol) in dry THF (20 mL), EDCI (846 mg, 5
mmol) was added at -20°C and the mixture was stirred at this
temperature for 12 h. After addition of the appropriate
aminomethyloxazole (7k or 7m) (5 mmol), stirring continued for
another 12h at 0°C, followed by addition of EtOAc (50 mL) and
successive washing with 20 ml of brine, 10% AcOH, brine, and
saturated aqueous K2CO3. Further drying over MgSO4 and
evaporation of the solvent in vacuo provided the analytically pure
product.
Yield 452 mg, 92% as a yellow viscous oil; [Found: С, 61.00;
H, 7.88; N, 8.37; P, 6.48. C25H38N3O5P: С, 61.08; H, 7.79; N,
8.55; P, 6.30%]; νmax (ATR) 3309, 1616, 1573, 1259, 1021, 963
cm-1; δH (CDCl3) 7.70 (2Н, d, J 8.3 Hz, aromatic), 7.36 (3Н, m,
NH, aromatic), 4.05 (4Н, m, 2ОСН2), 3.77 (2Н, m, СН2), 3.41
(4Н, m, 2СН2), 2.88 (2Н, m, СН2), 1.56 (6Н, m, 3СН2), 1.27
(15Н, m, 2ОСН2СН3, С(СН3)3); δC (CDCl3) 167.2 (С=О), 161.8
(d, J 36.5 Hz, О-С=С-Р), 154.8, 152.6 (d, J 21.7 Hz, О-С=N),
131.6, 126.8, 125.3, 100.0 (d, J=256.8 Hz, CP), 62.1
(ОСН2СН3), 49.5, 36.5, 34.8 (С(СН3)3), 31.1 (С(СН3)3), 27.7,
25.3, 23.9, 16.2 (ОСН2СН3); δP (CDCl3) 14.3; LCMS: found m/z
492.2 MH+. C25H38N3O5P requires 491.6.
4.10.1.
Benzyl
N-[(1S)-1-([[4-(diethoxyphosphoryl)-5-
(morpholin-4-yl)-1,3-oxazol-2-yl]methyl]carbamoyl)ethyl]carba-
4.9.3. Diethyl (2-[3-[(4-tert-butylphenyl)formamido]propyl]-
mate [(S)-9].
5-(piperidin-1-yl)-1,3-oxazol-4-yl)phosphonate (8c).
Obtained from Z-(S)-Ala and oxazole 7k. Yield 1.704 g, 65%
as a yellow viscous oil; [Found: С, 52.60; H, 6.44; N, 10.55; P,
6.06. C23H332N0 4O8P requires С, 52.67; H, 6.34; N, 10.68; P,
5.91%]; [a]D -6.7 (c 1.5, EtOH); νmax (ATR) 3282, 1718, 1675,
1617, 1574, 1528, 1230, 1018, 962 cm-1; δH (CDCl3) 7.30 (6H,
m, NH, aromatic), 5.78 (1H, br, NH), 5.08 (1H, d, J 11.9 Hz,
CHaHbOPh), 5.03 (1H, d, J 11.9 Hz, CHaHbOPh), 4.40 (2H, m,
CH2NH), 4.30 (1H, m, CHCH3), 4.08 (4H, m, 2OCH2CH3), 3.73
(4H, m, 2CH2), 3.48 (4H, m, 2CH2), 1.37 (3H, d, J 7.0 Hz,
CHCH3), 1.30 (6H, t, J 7.0 Hz, 2OCH2CH3); δC (CDCl3) 172.7
(C=O), 161.3 (d, J 37.0 Hz, O-C=C-P), 156.0 (C=O), 150.9 (d,
J=21.7 Hz, O-C=N), 136.2, 128.5, 128.2, 128.0, 101.2 (d, J 254.8
Hz, CP), 67.0 (OCH2Ph), 66.2, 62.4 (OCH2CH3), 50.6 (CHCH3),
48.3 (NHCH2), 36.3, 18.6 (CHCH3), 16.3 (OCH2CH3); δP
(CDCl3) 13.0; LCMS: found m/z 525.2 MH+. C23H33N4O8P
requires 524.5. Chiral HPLC: 100%, eluent: hexane-2-propanol
(80:20, v:v), flow rate 0.6 ml/min.
Yield 460 mg, 91% as a yellow viscous oil; [Found: С, 61.69;
H, 8.09; N, 8.14; P, 6.31. C26H40N3O5P requires С, 61.77; H,
7.97; N, 8.31; P, 6.13%]; νmax (ATR) 3309, 1618, 1572, 1259,
1021, 961 cm-1; δH (CDCl3) 7.70 (2Н, d, J 8.3 Hz, aromatic), 7.32
(2Н, d, J 8.3 Hz, aromatic), 7.25 (1Н, br, NH), 4.02 (4Н, m,
2ОСН2), 3.42 (2Н, m, СН2), 3.34 (4Н, m, 2СН2), 2.63 (2Н, m,
СН2), 1.95 (2Н, m, СН2), 1.50 (6Н, m, 3СН2), 1.23 (15Н, m,
2ОСН2СН3, С(СН3)3); δC (CDCl3) 167.4 (С=О), 161.7 (d, J 36.5
Hz, О-С=С-Р), 154.6, 154.0 (d, J 21.7 Hz, О-С=N), 131.5,
126.9, 125.2, 99.8 (d, J 256.8 Hz, CP), 62.0 (ОСН2СН3), 49.4
(СН2), 39.3, 34.7 (С(СН3)3), 31.1 (С(СН3)3), 26.4, 25.5, 25.3,
23.8, 16.2 (ОСН2СН3); δP (CDCl3) 14.5; LCMS: found m/z 506.2
MH+. C26H40N3O5P requires 505.6.
4.9.4. Diethyl (2-[4-[(4-tert-butylphenyl)formamido]butyl]-5-
(piperidin-1-yl)-1,3-oxazol-4-yl)phosphonate (8d).
Yield 483 mg, 93% as a yellow viscous oil; [Found: С 62.33,
H 8.26, N 7.91, P 6.12. C27H42N3O5P requires С 62.41, H 8.15, N
8.09, P 5.96%]; νmax (ATR) 3316, 1618, 1572, 1260, 1022, 962
cm-1; δH (CDCl3) 7.73 (2Н, d, J 8.3 Hz, aromatic), 7.36 (2Н, d, J
8.3 Hz, aromatic), 6.94 (1Н, br, NH), 4.05 (4Н, m, 2ОСН2), 3.40
(6Н, m, 3СН2), 2.60 (2Н, m, СН2), 1.73 (2Н, m, СН2), 1.67-1.52
(8Н, m, 4СН2), 1.27 (15Н, m, 2ОСН2СН3, С(СН3)3); δC (CDCl3)
167.5 (С=О), 161.8 (d, J 37.0 Hz, О-С=С-Р), 154.6, 154.2 (d, J
21.7 Hz, О-С=N), 131.8, 126.9, 125.2, 99.8 (d, J 256.8 Hz, CP),
62.0 (ОСН2СН3), 49.6, 39.3, 34.8 (С(СН3)3), 31.1 (С(СН3)3),
30.3, 29.4, 29.0, 27.4, 25.4, 24.0, 23.9, 16.2 (ОСН2СН3); δP
(CDCl3) 14.5; LCMS: found m/z 520.4 MH+. C27H42N3O5P
requires 519.6.
4.10.2. Benzyl N-[1-([[4-(diethoxyphosphoryl)-5-(morpholin-
4-yl)-1,3-oxazol-2-yl]methyl]carbamoyl)ethyl]carbamate [(R,S)-
9].
Obtained from Z-(R,S)-Ala and oxazole 7k. Yield 1.626 g,
62% as a yellow viscous oil. All spectral and analytical data for
compound (R,S)-9 are identical to those for (S)-9. Chiral HPLC,
2 peaks of equal intensity; eluent, hexane-2-propanol (80:20,
v:v); flow rate, 0.6 ml/min.
4.10.3. Methyl 1-(2-[[(2S)-2-[[(benzyloxy)carbonyl]amino]-4-
carbamoylbutanamido]methyl]-4-(diethoxyphosphoryl)-1,3-oxa-
zol-5-yl)piperidine-4-carboxylate [(S)-11].
Obtained from Z-(S)-Gln and oxazole 7m. Yield 1.435 g, 45%
as a yellow viscous oil; [Found: С, 52.62; H, 6.49; N, 10.81; P,
4.99. C28H40N5O10P requires С, 52.74; H, 6.32; N, 10.98; P,
4.86%]; νmax (CH2Cl2) 3423-3305, 1727, 1679, 1624, 1580, 1233,
1029, 970 cm-1; δH (CDCl3) 7.71 (1H, br, NH), 7.38 (5H, m,
aromatic), 7.13 (1H, br, NH), 6.31 (1H, br, NH), 5.89 (1H, br,
NH), 5.10 (1H, d, J 12.2 Hz, CHaHbOPh), 5.06 (1H, d, J 12.2 Hz,
CHaHbOPh), 4.41 (2H, m, CH2NH), 4.31 (1H, m, CH), 4.08 (4H,
m, 2OCH2CH3), 3.90 (2H, m, CH2), 3.70 (3H, s, OCH3), 3.10
(2H, m, CH2), 2.51 (2H, m, CH2), 2.38 (1H, m, CH), 2.09 (2H,
m, CH2), 1.97 (2H, m, CH2), 1.79 (2H, m, CH2), 1.31 (6H, t, J 7.0
Hz, 2OCH2CH3); δC (CDCl3) 175.7 (C=O), 174.6 (C=O), 171.9
(C=O), 161.2 (d, J 36.0 Hz, O-C=C-P), 155.7 (C=O), 151.0 (d, J
21.7 Hz, O-C=N), 136.3, 128.5, 128.1, 128.0, 100.9 (d, J 256.2
Hz, CP), 67.0 (OCH2Ph), 62.3 (OCH2CH3), 51.8 (CHCO2Me),
48.0 (N(CH2)2), 40.3 (OCH3), 36.3 (CH2NH), 31.2, 31.0, 27.6
[(CH2)2CHCO2Me], 16.3 (d, J 6.9 Hz, OCH2CH3); δP (CDCl3)
12.8.
4.9.5. Diethyl (2-[5-[(4-tert-butylphenyl)formamido]pentyl]-5-
(piperidin-1-yl)-1,3-oxazol-4-yl)phosphonate (8e).
Yield 507 mg, 95% as a yellow viscous oil; [Found: С, 62.95;
H, 8.42; N, 7.69; P, 5.96. C28H44N3O5P requires С, 63.02; H,
8.31; N, 7.87; P, 5.80%]; νmax (ATR) 3315, 1619, 1572, 1260,
1023, 960 cm-1; δH (CDCl3) 7.70 (2Н, d, J 8.3 Hz, aromatic), 7.38
(2Н, d, J 8.3 Hz, aromatic), 6.60 (1Н, br, NH), 4.07 (4Н, m,
2ОСН2), 3.40 (6Н, m, 3СН2), 2.57 (2Н, m, СН2), 1.69 (2Н, m,
СН2), 1.59 (8Н, m, 4СН2), 1.39 (2Н, m, СН2), 1.28 (15Н, m,
2ОСН2СН3, С(СН3)3); δC (CDCl3) 167.4 (С=О), 161.8 (d, J 37.0
Hz, О-С=С-Р), 154.6, 154.4 (d, J 21.7 Hz, О-С=N), 131.9,
126.8, 125.3, 99.7 (d, J 256.8 Hz, CP), 62.1 (ОСН2СН3), 49.5,
39.7, 34.8 (С(СН3)3), 31.2 (С(СН3)3), 29.3, 27.7, 26.5, 25.4, 23.9,
16.2 (ОСН2СН3); δP (CDCl3) 14.6; LCMS: found m/z 534.4
MH+. C28H44N3O5P requires 533.6.
4.10. General procedure for the preparation of (S)-9,
(R,S)-9, and (S)-11.

ACCEPTED MANUSCRIPT
12
Tetrahedron
4.11. General procedure for the preparation of
(CDCl3) 174.8, 174.3, 173.4, 172.5, 169.0, 164.2, 156.4, 137.5,
peptidomimetics. Oxazole ring opening.
128.3, 128.2, 128.1, 66.9, 66.0, 65.9, 63.6, 63.3, 54.9, 52.0, 51.4,
48.2, 47.7 (d, J 147.1 Hz, CP), 45.9, 45.4, 42.3, 41.9, 41.6, 41.0,
40.7, 33.8, 32.0, 31.4, 28.7, 28.3, 28.2, 27.9, 25.8, 24.9, 24.8,
21.5, 16.7 (dd, J 12.0, 5.0 Hz, OCH2CH3); δP (DMSO-d6) 18.3.
The compounds were obtained as described in the literature.5a
Heating one of oxazoles [(S)-9, (R,S)-9 or (S)-11] (1 mmol) in a
5:1 AcOH-H2O mixture (20 mL) for 8 h at 75°C followed by
evaporation to dryness in vacuo yielded analytically pure
products.
References and notes
1. (a) Aminophosphonic and Aminophosphinic Acids; Kukhar, V. P.,
Hudson, H. R., Eds.; John Wiley & Sons: Chichester, 2000; (b)
Kukhar, V. P.; Soloshonok, V. A.; Solodenko, V. A. Phosphorus,
Sulfur, and Silicon 1994, 92, 239-264; (c) Palacios, F.; Alonso, C.;
de los Santos, M. Chem. Rev. 2005, 105, 899–931; (d) Wardle, N.
J.; Bligh, S. W. A.; Hudson, H. R. Curr. Org. Chem. 2007, 11,
1635–1651; (e) Lejczak, B.; Kafarski, P. Top. Heterocycl. Chem.
2009, 20, 31–63; (g) Ordonez, M.; Rojas-Cabrera, H.; Cativiela,
C. Tetrahedron 2009, 65, 17–49; (f) Orsini, F.; Sello, G.; Sisti, M.
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4.11.1. Benzyl N-[(1S)-1-[N-([N-[1-(diethoxyphosphoryl)-2-
(morpholin-4-yl)-2-oxoethyl]carbamoyl]methyl)carbamoyl]-
ethyl]carbamate [(S,R),(S,S)-10]
Obtained from (S)-9. Yield 537 mg, 99% as a yellow viscous
oil; [Found: С, 50.81; H, 6.66; N, 10.21; P, 5.89. C232H0 35N4O9P
requires С, 50.92; H, 6.50; N, 10.33; P, 5.71%]; [a]D -12.1 (c
1.5, EtOH); νmax (ATR) 3295, 1637, 1518, 1238, 1013, 975 cm-1;
δH (CDCl3) 7.64 (1H, br, NH), 7.38 (5H, m, Ph), 7.18 (1H, br,
NH), 5.88 (1H, br, NH), 5.48 (1H, dd, J 17.9, 7.8 Hz, CHP), 5.14
(1H, d, J 11.9 Hz, CHaHbOPh), 5.07 (1H, d, J 11.9 Hz,
CHaHbOPh), 4.36 (1H, m, CHCH3), 4.22-3.99 (6H, m, 3CH2),
3.81-3.42 (8H, m, 4CH2), 1.41 (3H, m, CHCH3), 1.30 (6H, m,
2OCH2CH3); δC (CDCl3) 173.0 (C=O), 168.3 (C=O), 164.1
(C=O), 156.1 (C=O), 136.3, 128.5, 128.2, 128.0, 67.0 (OCH2Ph),
66.5 (OCH2), 63.8 (OCH2CH3), 50.5 (CHCH3), 47.8 (d, J 147.5
Hz, CP), 46,8 (NCH2), 43.1 (NCH2), 42.9 (NCH2), 18.7
(CHCH3), 16.4 (OCH2CH3); δP (CDCl3) 17.1; LCMS: found m/z
543.2 MH+. C23H35N4O9P requires 542.5. Chiral HPLC: 2 peaks
with equal intensivity, eluent: hexane-2-propanol (60:40, v:v),
flow rate 0.5 ml/min.
4.11.2
Benzyl
N-[1-[N-([N-[1-(diethoxyphosphoryl)-2-
(morpholin-4-yl)-2-oxoethyl]carbamoyl]methyl)carbamoyl]-
ethyl]carbamate [(R,R),(R,S),(S,R),(S,S)-10].
Obtained from (R,S)-9. Yield 537 mg, 99% as a yellow
viscous oil. All spectral and analytical data for the mixture of
diastereomers (R,R),(R,S),(S,R),(S,S)-10 are identical to those
for (S,R),(S,S)-10. Chiral HPLC, 4 peaks with equivalent
intensity; eluent, hexane-2-propanol (60:40, v:v); flow rate, 0.5
ml/min.
4.11.3. Methyl 1-(2-[2-[(2S)-2-[[(benzyloxy)carbonyl]amino]-
4-carbamoylbutanamido]acetamido]-2-(diethoxyphosphoryl)-
acetyl)piperidine-4-carboxylate [(S,R),(S,S)-12].
Obtained from (S)-11. Yield 649 mg, 99% as a yellow viscous
oil; [Found: С, 51.18; H, 6.57; N, 10.52; P, 4.88. C28H42N5O11P
requires С, 51.29; H, 6.46; N, 10.68; P, 4.72%]; νmax (CH2Cl2)
3303, 1725, 1682, 1645, 1506, 1250, 1023, 980 cm-1; δH (DMSO-
d6) 8.38 (1H, br, NH), 8.16 (1H, br, NH), 7.47 (1H, br, NH),
7.42-7.28 (5H, m, Ph), 7.25 (1H, br, NH), 6.76 (1H, br, NH),
5.48 (dd, 1H, J 19.5, 8.3 Hz, CHP), 5.05 (2H, m, OCH2Ph), 4.33
and 4.23 (1H, m, CH), 4.05 (4H, m, 2OCH2CH3), 3.90 (1H, m,
CH), 3.79 (1H, m, CH), 3.62 (2H, m, CH2), 3.36 (3H, s, OCH3),
3.19 (1H, m, CH), 2.82 (1H, m, CH), 2.65 (1H, m, CH), 2.14
(2H, m, CH2), 1.89 (2H, m, CH2), 1.73 (2H, m, CH2), 1.50 (1H,
m, CH), 1.40 (1H, m, CH), 1.22 (6H, m, 2OCH2CH3); δC
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