Synthesis of α-hydrazino phosphonates from l-amino acid- and l-glutathione-derived hydrazones

Article abstract of DOI:10.1007/s11172-011-0041-y

[Tetra(tert-butyl)phthalocyanine]aluminum chloride catalyzed hydrophosphorylation of cyclic ketone hydrazones, which were derived from hydrazides of l-amino acids and glutathione, resulted in polyfunctional α-hydrazino phosphonates.

Full text of DOI:10.1007/s11172-011-0041-y

Russian Chemical Bulletin, International Edition, Vol. 60, No. 2, pp. 248—253, February, 2011
248
Synthesis of αꢀhydrazino phosphonates from
Lꢀamino acidꢀ and Lꢀglutathioneꢀderived hydrazones
E. D. Matveeva, I. N. Kolesnikova, and N. S. Zefirov
Department of Chemistry, M. V. Lomonosov Moscow State University,
1 Leninskie Gory, 119992 Moscow, Russian Federation.
Fax: +7 (495) 939 0290. Eꢀmail: matveeva@org.chem.msu.ru
[Tetra(tertꢀbutyl)phthalocyanine]aluminum chloride catalyzed hydrophosphorylation of
cyclic ketone hydrazones, which were derived from hydrazides of Lꢀamino acids and glutathione,
resulted in polyfunctional αꢀhydrazino phosphonates.
Key words: Lꢀamino acid hydrazides, Lꢀglutathione dihydrazide, hydrazones, αꢀhydrazino
phosphonates, [tetra(tertꢀbutyl)phthalocyanine]aluminum chloride, diethyl phosphite, the
Pudovik reaction.
Scheme 1
Structural analogs of αꢀamino phosphonates serving
as amino acid mimetics and possessing different biologiꢀ
cal activity,1,2 αꢀhydrazino phosphonates, are still poorly
studied compounds in terms of their synthesis and biologꢀ
ical activity, while αꢀhydrazino phosphonates of amino
acids and peptides are not described in the literature.
Previously, we have developed the approach toward
αꢀamino phosphonates based on threeꢀcomponent Kaꢀ
bachnik—Fields reaction3 in the presence of [tetra(tertꢀ
butyl)phthalocyanine]aluminum chloride (tPcAlCl) as
a catalyst. This method makes it possible to synthesize
αꢀamino phosphonates on the base of Lꢀamino acids and
t
peptides.4 Later, catalysis with PcAlCl was successfully
applied for the synthesis of αꢀhydrazino phosphonates of
azines and hydrazones.5—7 The method involved addition
of diethyl phosphite at the C=N bond of the correspondꢀ
ing hydrazones.
In continuation of this research, in the present work,
hydrazones derived from enantiomerically pure Lꢀamino
acid hydrazides, Lꢀglutathione dihydrazide, and carboꢀ
cyclic ketones were used as the amine component.
Starting hydrazones 1—5 were synthesized by the reꢀ
action of hydrazides of amino acids (in some cases Nꢀproꢀ
tected) with the corresponding cyclic ketones in the yields
of 85—98% (Scheme 1).
Comꢀ
pound
2
R
X
Comꢀ
pound
4
5
R
X
Me
Me
CH2
NBoc
CH2Ph
CH2Ph
CH2
NBoc
Dihydrazone 6 derived from glutathione dihydrꢀ
azide and NꢀBocꢀpiperidone was prepared in 95% yield
(Scheme 2).
3
The hydrazones synthesized were involved in the cataꢀ
lytic phosphorylation. It was shown that diethyl phosphite
adds to both C=N bonds of hydrazono imine 1 to give
diphosphonate 7 in 55% yield within 20 h (Scheme 3).
Chemoselective phosphorylation was achieved with
Nꢀprotected hydrazones 2—5, which gave the corresꢀ
ponding αꢀhydrazino phosphonates 8—11 in 68—75%
yields (Scheme 4).
Taking αꢀhydrazino phosphonate 9 as an example,
both Bocꢀprotecting groups and ethoxy groups at phosꢀ
phorus atom were removed by the action of trimethylsilyl
bromide (TMSBr) followed by quenching with propylene
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 243—248, February, 2011.
1066ꢀ5285/11/6002ꢀ248 © 2011 Springer Science+Business Media, Inc.

Amino acid αꢀhydrazino phosphonates
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 2, February, 2011
249
Scheme 2
oxide in methanol. The reaction afforded αꢀhydrazino
phosphonic acid 12, which may be regarded as a conforꢀ
mationally fixed bioisosteric analog of the natural ligand
to GABACꢀreceptor, γꢀaminobutyric acid, and several
known synthetic ligands8 as well (Scheme 5).
Scheme 5
i. 1) TMSBr; 2)
, MeOH.
Scheme 3
To date, it is known that several synthetic peptides
(e.g., heptapeptide "Semax",9 which is used in clinical
practice, and tripeptide "RER"10—12) can improve brain
cognitive function. Natural tripeptide glutathione is inꢀ
volved in redox processes in the living organisms. Recently,
application of glutathione as a component for neuroproꢀ
tective and antisclerotic pharmaceuticals was documented.13
One of the way to design the promising "twinꢀdrugs" is the
combination of the peptide moiety and phosphonate group
in one molecule. With this aim, we involved hydrazone 6
prepared from Lꢀglutathione hydrazide and NꢀBocꢀpiperiꢀ
done in hydrophosphorylation. The reaction was carried
for 20 h and the corresponding diphosphorylation product
13 was obtained in 46% yield (Scheme 6).
i. tPcAlCl, 80 °C, 20 h.
Scheme 4
Scheme 6
i. (EtO)2P(O)H, tPcAlCl, 80 °C, 8—10 h.
i. (EtO)2P(O)H, tPcAlCl, 80 °C, 20 h.
Comꢀ
pound
2, 8
R
X
Comꢀ
pound
4, 10
5, 11
R
X
Structures of hydrazones 1—6, αꢀhydrazino phosphoꢀ
nates 7—11, 13, and phosphonic acid 12 were established
Me
CH2
CH2Ph
CH2Ph
CH2
NBoc
3, 9
Me NBoc

250
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 2, February, 2011
Matveeva et al.
by IR spectroscopy, NMR 1H, 13C, and 31P spectroscopy
and confirmed by elemental analysis and high resolution
mass spectrometry.
LꢀAlanine hydrazide (LꢀAlaNHNH2). To a solution of Lꢀalaꢀ
nine methyl ester (0.516 g, 5 mmol, prepared from the correꢀ
sponding hydrochloride by treatment with aqueous NaOH) in
MeOH (5 mL), hydrazine hydrate (1.25 mL, 25 mmol) was addꢀ
ed and the reaction mixture was stirred for 18 h. The solvent was
removed in vacuo, purification of the residue by column chroꢀ
matography (silica gel, elution with MeOH—CHCl3, 1 : 1)
afforded LꢀAlaNHNH2 (0.438 g, 85%) as transparent oil,
[α]D23 +14.0 (MeOH). 1H NMR (CDCl3), δ: 1.27 (d, 3 H, Me,
The IR spectra of αꢀhydrazino phosphonates 7—11
and 13 contained absorption bands at 1230—1260 cm–1
corresponding to the P=O group and at 3230—3290 cm–1
attributed to the NH group. The 31P NMR of the comꢀ
pounds synthesized exhibited signals for the phosphorus
atoms in the range of δ 25—30. In the 31P NMR spectra of
diphosphonates 7 and 13, the signals for two phosphorus
atoms were observed at δ 27.73, 30.46 and 25.66, 25.74,
respectively. In case of αꢀhydrazino phosphonates 8—11,
the 31P NMR spectra exhibited two signals for the phosꢀ
phorus atom in the range of δ 26.41—29.28 with relative
intensities 1 : 20, which can probably be explained by the
existence of rotamers.6 This issue is confirmed by the fact
that with an increase in temperature, the signals for the
phosphorus atom of phosphonate 9 are broadened and
approached each other; however, no coalescence of the
signals was achieved. Thus, the NMR 31P (DMSOꢀd6) of
phosphonate 9 at 22 °C exhibited signals for the phosphoꢀ
rus atoms at δ 26.41 and 26.83; at 70 °C these signals were
observed at δ 26.41 and 26.68, while at 120 °C these sigꢀ
nals became closer and appeared at δ 26.41 and 26.56. The
3
3JH,H = 6.6 Hz); 3.41, 3.42 (both q, 1 H, CH, JH,H = 6.8 Hz,
3JH,H = 7.1 Hz); 4.33 (br.s, 5 H, NHNH2, NH2). 13C NMR
(CDCl3), δ: 27.53 (s, Me); 49.20 (s, CH); 176.04 (s, C=O). IR,
ν/cm–1: 1670 (C=O); 3300 (NH). Found (%): C, 34.86; H, 8.61;
N, 40.54. C3H9N3O. Calculated (%): C, 34.94; H, 8.80; N, 40.75.
Synthesis of hydrazides of NꢀBocꢀprotected Lꢀamino acids
(general procedure). To a solution of NꢀBocꢀprotected amino
acid methyl ester (5 mmol) in MeOH (10 mL), hydrazine hyꢀ
drate (2.45 ml, 50 mmol) was added and the reaction mixture
was stirred for 18 h. Removal of the solvent in vacuo afforded the
corresponding hydrazide of NꢀBocꢀprotected amino acid as
colorless crystals.
NꢀtertꢀButoxycarbonylꢀLꢀalanine
hydrazide
(BocꢀLꢀ
23
AlaNHNH2). Yield 0.97 g (60 %), [α]D –28.0 (MeOH); m.p.
95—96 °C (cf. Ref. 15: [α]D20 –25.4 (c 1, MeOH), m.p. 96—97 °C).
NꢀtertꢀButoxycarbonylꢀLꢀphenylalanine hydrazide (BocꢀLꢀ
23
PheNHNH2). Yield 1.23 g (68%), [α]D +9.8 (MeOH); m.p.
20
121—123 °C (cf. Ref. 16: [α]D +9.7 (c 1, MeOH), m.p.
1
NMR H and 13C spectroscopy data confirmed also the
120—122 °C).
structures of αꢀhydrazino phosphonates 7—11 and 13.
In summary, in the present work, hitherto unknown
αꢀhydrazino phosphonates derived from hydrazides of natꢀ
ural Lꢀamino acid and natural tripeptide Lꢀglutathione were
synthesized, opening broad prospects for the design of
compounds of pharmacological value.
NꢀtertꢀButoxycarbonylꢀLꢀglutathione dihydrazide was syntheꢀ
sized according to the general procedure using twoꢀfold excess
of hydrazine hydrate per 1 mol of NꢀtertꢀbutoxycarbonylꢀLꢀglutaꢀ
thione dimethyl ester. Yield 1.48 g (64%), m.p. 170—171 °C;
[α]D –230.5 (H2O). 1H NMR (D2O), δ: 1.33 (s, 9 H, But);
23
1.80—188, 1.90—2.02 (both m, 1 H each, CHCH2CH2);
2.34—2.36 (m, 2 H, CHCH2CH2); 2.85—2.91, 3.15—3.19 (both
m, 1 H each, CH2SH); 3.82 (AB system, HA, 1 H, CH2, Gly,
2JH,H = 16.7 Hz); 3.86 (AB system, HB, 1 H, CH2, Gly, 2JH,H
=
Experimental
= 16.7 Hz); 3.86—3.92 (m, 1 H, CHCH2CH2); 4.60—4.64 (m, 1 H,
CHCH2SH). 13C NMR (D2O), δ: 26.95 (s, CH2SH); 27.62 (Me,
But); 31.34 (s, CHCH2CH2); 38.25 (s, CHCH2CH2); 41.39
(s, NHCH2); 52.60 (s, CHCH2CH2); 52.92 (s, CHCH2SH);
81.51 (s, C, But); 157.15 (s, C=O, C(O)OBut); 169.97, 172.74;
173.06; 175.12 (C=O, C(O)NH). IR, ν/cm–1: 1640—1690 (C=O,
Boc, C(O)NH); 2290—3340 (NH, NH2). Found (%): C, 41.29;
H, 6.50; N, 22.38. C15H29N7O6S. Calculated (%): C, 41.37;
H, 6.71; N, 22.51.
Synthesis of hydrazones 1, 2, and 4 derived from Lꢀamino acid
hydrazides (general procedure). A mixture of cyclohexanone
(9 mmol) and the corresponding hydrazide (3 mmol) was reꢀ
fluxed for 1—3 h, the reaction mixture was cooled to room temꢀ
perature, the precipitate that formed was filtered off, washed
with diethyl ether and dried in vacuo.
NMR 1H (400.13 MHz), 13C (100.61 MHz), and 31P
(161.98 MHz) were run on a «Bruker Avance 400» instrument in
CDCl3 and D2O relative to Me4Si (1H and 13C, internal stanꢀ
dard) and 85% aqueous H3PO4 (31P, external standard). IR specꢀ
tra were recorded on a URꢀ20 spectrophotometer in CCl4. Eleꢀ
mental analysis was carried out on a VarioꢀII CHN analyzer.
Mass spectra were recorded on a Finnigan Mat Incos 50 quadruꢀ
pole mass spectrometer (EI, 70 eV, direct inlet). High resolution
mass spectra were run on a micrOTOF II instrument (Bruker
Daltonics) in the positive ion mode (electrospray ionization (ESI)),
scanning mass range was 50—3000 Da, capillary cap voltage was
4.5 kV). The sample was injected via syringe pump, MeCN was
used as a solvent, flow rate was 3 μL min–1, chamber temperaꢀ
ture was 180 °C, carrier gas was nitrogen (4.0 L min–1). Specific
rotation was measured on a EPOꢀ1 AVNIEKIPRODMASh
polarimeter at 23 °C in MeOH or H2O at concentrations
c 1 g (100 mL)–1. Diethyl phosphite (Aldrich) was used as
purchased. [Tetra(tertꢀbutyl)phthalocyanine]aluminum chloꢀ
ride was synthesized by the known procedure.14 The course
of the reaction and purity of compounds were monitored by
TLC on ALUGRAM SIL G/UV254 plates. Column chromaꢀ
tography was performed on silica gel (MN Kieselgel 60,
0.04—0.063 mm).
(S)ꢀN´ꢀCyclohexylideneꢀ2ꢀ(cyclohexylideneamino)propaneꢀ
23
hydrazide (1). Yield 85%, m.p. 103—105 °C; [α]D +36.4
(MeOH). 1H NMR (CDCl3), δ: 1.11—1.22 (m, 1 H, CH2, cycl.);
3
1.36 (d, 3 H, Me, JH,H = 7.1 Hz); 1.40—1.52 (m, 3 H, CH2,
cycl.); 1.54—1.69 (m, 9 H, CH2, cycl.); 1.75—1.87 (m, 3 H,
CH2, cycl.); 1.92—1.99 (m, 1 H, CH2, cycl.); 2.11—2.18 (m, 1 H,
CH2, cycl.); 2.22—2.33 (m, 1 H, CH2, cycl.); 2.37—2.50 (m, 2 H,
CH2, cycl., NH); 3.50 (q, 1 H, CH, 3JH,H = 6.8 Hz). 13C NMR
(CDCl3), δ: 17.91 (s, Me); 22.31, 22.83, 24.88, 25.61, 26.71,

Amino acid αꢀhydrazino phosphonates
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 2, February, 2011
251
27.65, 30.74, 31.61, 35.87, 37.51 (all s, CH2, cycl.); 53.07
(s, CH); 168.98 (s, C=N), 173.63 (s, C=NNH); 178.25 (s, C=O).
IR (CCl4), ν/cm–1: 1630 (C=N); 1680 (C=O); 3270 (NH).
Found (%): C, 68.37; H, 9.83; N, 15.89. C15H25N3O. Calculatꢀ
ed (%): C, 68.40; H, 9.57; N, 15.95.
mixture was cooled to room temperature, the precipitate that
formed was filtered off, washed with diethyl ether, and dried
23
in vacuo. Yield 98%, m.p. 163—165 °C; [α]D +40.0 (MeOH).
1H NMR (CDCl3), δ: 1.31, 132 (both s, 9 H, But); 1.39, 1.41
(both s, 9 H, But); 1.98—2.42 (m, 4 H, CH2, cycl.); 2.85—3.06
(m, 2 H, CH2Ph); 3.29—3.52 (m, 4 H, CH2, cycl.); 4.35—4.40,
5.28—5.33 (both m, 1 H, CH); 5.17, 5.37 (both br.d, 1 H, NH,
tertꢀButyl Nꢀ[(S)ꢀ1ꢀmethylꢀ2ꢀoxoꢀ2ꢀ(2ꢀcyclohexylideneꢀ
hydrazino)ethyl]carbamate (2). Yield 85%, m.p. 110—112 °C;
[α]D23 +21.4 (MeOH). 1H NMR (CDCl3), δ: 1.34, 1.37 (both d,
3
3JH,H = 9.4 Hz, JH,H = 7.0 Hz); 7.10—7.22 (m, 5 H, Ph); 9.25
3
3
3 H, Me, JH,H = 6.8 Hz, JH,H = 7.0 Hz); 1.41, 1.42 (both s,
9 H, But); 1.57—1.69 (m, 6 H, CH2, cycl.); 2.24—2.37 (m, 4 H,
CH2, cycl.); 4.22—4.29, 5.02—5.10 (both m, 1 H, CH); 5.29,
5.39 (br.s, d, 1 H, NHBoc, 3JH,H = 8.1 Hz); 9.11, 9.70 (both br.s,
1 H, NH). 13C NMR (CDCl3), δ: 17.91, 18.72 (Me, CHMe);
25.56, 25.88, 25.95, 26.11, 26.91, 27.03 (CH2, cycl.); 28.28, 28.35
(Me, But); 35.50 (CH2, cycl.); 47.13, 48.78 (CH); 79.30, 80.36
(C, But); 155.16, 156.24 (C=N); 156.84, 161.55 (C=O, Boc);
169.22, 175.41 (C=O, C(O)NH). IR, ν/cm–1: 1645 (C=N),
1660—1690 (C=O, C(O)NH, C=N); 1720 (C=O, Boc), 3230
(NH). Found (%): C, 59.46; H, 8.90; N, 14.89. C14H25N3O3.
Calculated (%): C, 59.34; H, 8.89; N, 14.83.
(br.s, 1 H, NHC(O)). 13C NMR (CDCl3), δ: 26.46, 27.02 (CH2,
cycl.); 28.28 (Me, But), 28.40 (Me, But); 33.74, 33.88 (CH2,
cycl.); 38.19, 38.71 (CH2Ph); 41.13 (CH2, cycl.); 43.60 (CH2,
cycl.); 52.20, 55.01 (CH); 79.58, 80.13, 80.43 (C, But, NBoc,
NHBoc); 126.61, 126.84, 128.18, 128.61, 129.42, 129.57 (CH,
Ph); 136.85 (C, Ph); 152.45, 154.55 (C=N); 155.19, 156.06
(C=O, NHBoc); 157.68 (C=O, NBoc); 168.10, 173.98 (C=O,
C(O)NH). IR, ν/cm–1: 1650—1710 (C=O, Boc, C=O, C(O)NH,
C=N), 3300 (NH). Found (%): C, 62.65; H, 7.98; N, 12.20.
C24H36N4O5. Calculated (%): C, 62.59; H, 7.88; N, 12.16.
(2S,7R)ꢀ1,11ꢀBis[2ꢀ(1ꢀtertꢀbutoxycarbonylpiperidinꢀ4ꢀylꢀ
idene)hydrazino]ꢀ2ꢀtertꢀbutoxycarbonylaminoꢀ7ꢀsulfanylmethylꢀ
6,9ꢀdiazaundecaneꢀ1,5,8,11ꢀtetraone (6). A mixture of NꢀBocꢀ
piperidone (0.796 g, 4 mmol) and NꢀtertꢀbutoxycarbonylꢀLꢀglutaꢀ
thione dihydrazide (0.870 g, 2 mmol) in DMF (2 mL) was heatꢀ
ed at 70 °C for 3 h. The solvent was removed in vacuo, the
precipitate that formed was washed with diethyl ether and dried
tertꢀButyl Nꢀ[(S)ꢀ1ꢀbenzylꢀ2ꢀoxoꢀ2ꢀ(2ꢀcyclohexylidenehydrꢀ
23
azino)ethyl]carbamate (4). Yield 85%, m.p. 124—125 °C; [α]D
+ 25.0 (MeOH). 1H NMR (CDCl3), δ: 1.37 (s, 9 H, But);
1.50—1.68 (m, 6 H, CH2, cycl.); 1.97—2.04 (m, 1 H, CH2,
cycl.); 2.20—2.38 (m, 3 H, CH2, cycl.); 2.88—3.16 (m, 2 H,
CH2Ph); 4.44—4.48, 5.35—5.41 (both m, 1 H, CH); 5.28, 5.46
(d, 3JH,H = 8.3 Hz, br.s, 1 H, NHBoc); 7.20—7.27 (m, 5 H, CH,
Ph); 9.31, 9.51 (both br.s, 1 H, NH). 13C NMR (CDCl3),
δ: 25.47, 25.55, 25.90, 26.18, 26.74, 26.84, 26.96 (CH2, cycl.);
28.25, 28.31 (Me, But); 35.44, 35.55 (CH2, cycl.); 38.36, 38.58
(CH2Ph); 52.25, 54.95 (CH); 79.36, 80.25 (C, But); 126.54,
126.75 (CH, Ph); 128.16, 128.58, 129.41, 129.57 (CH, Ph);
136.94 (C, Ph); 155.19, 155.96 (C=N); 157.29, 162.16 (C(O)NH);
167.97, 173.99 (C=O, Boc). IR, ν/cm–1: 1660—1880 (C=O,
C(O)NH, C=N); 1710 (C=O, Boc); 3260 (NH). Found (%):
C, 66.70; H, 7.99; N, 11.58. C20H29N3O3. Calculated (%):
C, 66.83; H, 8.13; N, 11.69.
23
in vacuo. Yield 95%, m.p. 142—144 °C; [α]D –14.7 (MeOH).
1H NMR (CDCl3) δ: 1.35, 1.39, 1.40 (all s, 9 H each, But);
1.82—1.95, 1.99—2.12 (both m, 1 H each, CHCH2CH2); 2.29—2.48
(m, 10 H, CHCH2CH2, CH2, cycl.); 2.98—3.06 (br.m, 2 H,
CH2SH); 3.15 (s, 2 H, NHCH2C(O)); 3.42—3.56 (m, 8 H, CH2,
cycl.); 4.08—4.16 (m, 1 H, CHCH2CH2); 4.71—5.02 (m, 1 H,
CHCH2SH). 13C NMR (CDCl3), δ: 26.58, 27.25 (CH2, cycl.);
27.68 (CH2SH); 28.20 (Me, But); 31.78, 33.36, 43.57 (CH2, cycl.);
33.70 (CHCH2CH2); 41.20 (CHCH2CH2); 41.98 (NHCH2);
52.32 (CHCH2CH2); 52.76 (CHCH2SH); 80.32 (C, But); 154.70,
156.26 (C=O, C(O)OBut); 159.46, 166.16 (C=N); 169.20,
170.82, 171.38, 173.15 (C=O, C(O)NH). IR, ν/cm–1: 1650—1720
(C=O, Boc, C(O)NH, C=N); 2250—3320 (NH, NH2).
Found (%): C, 52.76; H, 7.27; N, 15.55, S, 3.90. C35H59N9O10S.
Calculated (%): C, 52.68; H, 7.45; N, 15.80; S, 4.02.
(S)ꢀ1ꢀtertꢀButoxycarbonylꢀ4ꢀ({2ꢀ[(tertꢀbutoxycarbonyl)ꢀ
amino]propanoyl}hydrazino)piperidine (3). A mixture of NꢀBocꢀ
piperidone (0.398 g, 2 mmo) and BocꢀLꢀAlaNHNH2 (0.406 g,
2 mmol) was heated at 100 °C for 1.5 h. A reaction mixture was
cooled to room temperature, the precipitate that formed was
filtered off, washed with diethyl ether, and dried in vacuo. Yield
Synthesis of αꢀhydrazino phosphonates derived from hydrꢀ
azides of Lꢀamino acids and Lꢀglutathione 7—11 and 13 (general
procedure). Diethyl phosphite (5 mmol) and tPcAlCl (0.05 mmol)
were added to hydrazone (1 mmol) and the reaction mixture was
stirred under argon at 80 °C until completion of the reaction
(TLC monitoring). The volatiles were removed in vacuo, the
residue was dissolved in small amount of CH2Cl2—MeOH (70 : 1)
and subjected to column chromatography (silica gel, column
height 15 cm, diameter 1.5—2.0 cm).
23
97%, m.p. 138—140 °C; [α]D +47.0 (MeOH). 1H NMR
3
(CDCl3), δ: 1.23, 1.27 (both d, 3 H, CHMe, JH,H = 7.0 Hz);
1.31, 1.32 (both s, 9 H, But); 1.34, 1.35 (both s, 9 H, But);
2.30—2.41 (m, 4 H, CH2, cycl.); 3.37—3.52 (m, 4 H, CH2,
cycl.); 4.11—4.18, 4.92—4.96 (both m, 1 H, CH); 5.23 (br.d,
3
1 H, NHBoc, JH,H = 8.4 Hz); 9.18, 9.78 (both br.s, 1 H,
NHC(O)). 13C NMR (CDCl3) δ: 17.07, 18.59 (Me, CHMe);
25.56, 27.36 (CH2, cycl.); 28.36 (Me, But); 33.79, 33.91, 41.10,
43.67 (CH2, cycl.); 47.09, 48.87 (CH); 79.45, 80.09, 80.14, 80.50
(C, But, NBoc, NHBoc); 152.12, 154.55 (C=N); 155.18, 156.37
(C=O, NHBoc); 157.02 (C=O, NBoc); 169.22, 175.41 (C=O,
C(O)NH). IR, ν/cm–1: 1650—1690 (C=O, C(O)NH, C=N),
1710 (C=O, Boc); 3300 (NH). Found (%): C, 56.20; H, 8.53;
N, 14.35. C18H32N4O5. Calculated (%): C, 56.23; H, 8.39; N, 14.57.
(S)ꢀ1ꢀtertꢀButoxycarbonylꢀ4ꢀ(2ꢀ{2ꢀ[(tertꢀbutoxycarbonyl)ꢀ
amino]ꢀ3ꢀphenylpropanoyl}hydrazino)piperidine (5). A mixture of
NꢀBocꢀpiperidone (0.398 g, 2 mmo) and BocꢀLꢀPheNHNH2
(0.558 g, 2 mmol) was heated at 30 °C for 1.5 h. The reaction
Diethyl (S)ꢀ{1ꢀ[2ꢀ(2ꢀ{[1ꢀ(diethoxyphosphoryl)cyclohexyl]ꢀ
amino}propanoyl)hydrazino]cyclohexyl}phosphonate (7) was synꢀ
thesized from hydrazone 1, reaction time was 20 h. Yield 55%;
[α]D23 –16.9 (MeOH). 1H NMR (CDCl3), δ: 1.12—1.21 (m, 2 H,
CH2, cycl.); 1.26—1.31 (m, 12 H, 4 Me, POEt); 1.34 (d, 3 H,
3
Me, JH,H = 7.1 Hz); 1.40—1.94 (m, 18 H, CH2, cycl.); 2.39
(br.s, 1 H, NH); 3.69 (q, 1 H, CH, 3JH,H = 6.6 Hz); 4.03—4.18
3
(m, 8 H, 4 OCH2); 5.20 (br.d, 1 H, NHNHC(O), JH,H
=
= 23.0 Hz); 9.21 (br.s, 1 H, NHNHC(O)). 13C NMR (CDCl3),
δ: 16.42—16.55 (m, Me, POEt); 19.51 (d, Me, 4JC,P = 11.7 Hz);
19.78 (d, JC,P = 10.3 Hz); 19.89 (d, JC,P = 10.9 Hz); 20.24
(d, JC,P = 11.7 Hz); 21.49, 25.07, 25.44, 26.42, 27.37, 28.26,
3
3
3

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Matveeva et al.
32.27 (CH2, cycl.); 51.50 (s, CH); 56.07 (d, C, 1JC,P = 142.0 Hz);
58.51 (d, C, 1JC,P = 164.6 Hz); 61.69, 61.95, 62.12, 63.38 (all d,
62.65, 62.83 (both d, OCH2, 2JC,P = 7.3 Hz); 79.97 (s, C, But);
126.82, 128.58, 129.26, 136.48 (C, Ph); 155.14 (s, C=O, Boc);
167.87 (s, C(O)NH). 31P NMR (CDCl3), δ: 28.15, 28.84. IR,
ν/cm–1: 1040, 1060 (P—O—C); 1235 (P=O); 1645 (C=N), 1670
(C=O, C(O)NH); 1710 (C=O, Boc), 3270 (NH). Found (%):
C, 57.63; H, 8.08; N, 8.29. C24H40N3O6P. Calculated (%):
C, 57.93; H, 8.10; N, 8.45.
2
2
2
2
OCH2, JC,P = 7.3 Hz, JC,P = 8.1 Hz, JC,P = 7.4 Hz, JC,P
=
= 8.0 Hz); 172.64 (s, C=O). 31P NMR (CDCl3), δ: 27.73, 30.46.
IR, ν/cm–1: 1030, 1070 (P—O—C); 1230 (P=O); 1660 (C=O);
3330 (NH). Found (%): C, 51.26; H, 8.47; N, 7.56. C23H47N3O7P2.
Calculated (%): C, 51.20; H, 8.78; N, 7.79.
Diethyl (S)ꢀ[1ꢀ(2ꢀ{2ꢀ[(tertꢀbutoxycarbonyl)amino]propanoꢀ
yl}hydrazino)cyclohexyl]phosphonate (8) was synthesized from
hydrazone 2, the reaction time was 8 h. Yield 75%, m.p. 79—81 °C;
[α]D23 –22.5 (MeOH). 1H NMR (CDCl3), δ: 1.27, 1.28 (both t,
(S)ꢀ1ꢀtertꢀButoxycarbonylꢀ4ꢀ(2ꢀ{2ꢀ[(tertꢀbutoxycarbonyl)ꢀ
amino]ꢀ3ꢀphenylpropanoyl}hydrazino)ꢀ4ꢀ(diethoxyphosphoryl)ꢀ
piperidine (11) was synthesized from hydrazone 5, the reaction
23
time was 10 h. Yield 68%; [α]D –13.2 (MeOH). 1H NMR
3
3
6 H, 2 Me, POEt, JH,H = 7.1 Hz); 1.29 (d, 3 H, Me, JH,H
=
(CDCl3), δ: 1.29, 1.30 (both t, 6 H, 2 Me, POEt, 3JH,H = 7.1 Hz);
1.41, 1.45 (both s, 18 H, Me, But); 1.57—1.68 (m, 2 H, CH2,
cycl.); 1.71—1.80 (m, 1 H, CH2, cycl.); 2.98—3.30 (m, 4 H,
CH2Ph, CH2, cycl.); 3.69—3.80 (m, 2 H, CH2, cycl., NHBoc);
4.03—4.14 (m, 4 H, 2 OCH2, CH); 4.26—4.31 (br.m, 1 H, CH);
5.01 (d, 1 H, NHNHC(O), 3JH,H = 7.3 Hz); 7.19—7.24 (m, 3 H,
Ph); 7.28—7.32 (m, 2 H, Ph); 8.15 (br.s, 1 H, NHNHC(O)).
= 7.1 Hz); 1.37 (s, 9 H, Me, But); 1.41—1.64 (m, 8 H, CH2,
cycl.); 1.73—1.79 (m, 2 H, CH2, cycl.); 4.05—4.14 (m, 5 H,
2 OCH2, CH); 4.88 (br.s, 1 H, NHNHC(O)); 5.07 (d, 1 H,
3
NHBoc, JH,H = 6.9 Hz); 8.34 (br.s, 1 H, NHNHC(O)).
3
13C NMR (CDCl3), δ: 16.51 (d, Me, POEt, JC,P = 4.0 Hz);
3
3
18.64 (s, Me); 19.76 (d, JC,P = 10.4 Hz); 19.86 (d, JC,P
=
= 10.5 Hz); 25.13, 27.28, 27.70 (CH2, cycl.); 28.27 (s, Me, But);
49.23 (s, CH); 58.61 (d, C, 1JC,P = 160.7 Hz); 62.70, 62.86 (both d,
OCH2, 2JC,P = 7.2 Hz, 2JC,P = 8.0 Hz); 79.81 (s, C, But); 155.18
(s, C=O, Boc); 169.69 (s, C(O)NH). 31P NMR (CDCl3),
δ: 28.23, 29.28. IR, ν/cm–1: 1030, 1070 (P—O—C); 1240 (P=O);
1670 (C=O, C(O)NH); 1720 (C=O, Boc), 3280 (NH). Found (%):
C, 51.22; H, 8.50; N, 9.81. C18H36N3O6P. Calculated (%):
C, 51.30; H, 8.61; N, 9.97.
13C NMR (CDCl3), δ: 16.51 (d, Me, POEt, JC,P = 5.1 Hz);
3
26.79, 27.30 (CH2, cycl.); 28.24 (s, Me, But); 28.31 (s, Me, But);
37.89, 37.90 (CH2, cycl.); 38.28 (s, CH2Ph); 55.03 (s, CH);
1
56.60 (d, C, JC,P = 158.8 Hz); 62.89, 63.01 (both d, OCH2,
2JC,P = 6.6 Hz, 2JC,P = 7.3 Hz); 79.54 (C, But), 80.18 (C, But);
126.98, 128.71, 129.26, 136.36 (C, Ph); 154.62, 155.20 (C=O,
NBoc, NHBoc); 169.04 (s, C(O)NH). 31P NMR (CDCl3), δ:
26.41, 26.58. IR, ν/cm–1: 1030, 1050 (P—O—C); 1250 (P=O);
1650—1710 (C=O, C(O)NH, Boc), 3300 (NH). Found (%):
C, 56.10; H, 8.13; N, 9.27. C28H47N4O8P. Calculated (%):
C, 56.17; H, 7.91; N, 9.36.
(S)ꢀ1ꢀtertꢀButoxycarbonylꢀ4ꢀ(2ꢀ{2ꢀ[tertꢀbutoxycarbonyl)ꢀ
amino]propanoyl}hydrazino)ꢀ4ꢀ(diethyxyphosphoryl)piperidine (9)
was synthesized from hydrazone 3, the reaction time was 8 h.
23
1
Yield 70%; [α]D –25.9 (MeOH). H NMR (CDCl3), δ: 1.32,
(2S,7R)ꢀ1,11ꢀBis[2ꢀ(1ꢀtertꢀbutoxycarbonylꢀ4ꢀdiethoxyphosꢀ
phorylpiperidinꢀ4ꢀyl)hydrazino]ꢀ2ꢀtertꢀbutoxycarbonylaminoꢀ7ꢀ
sulfanylmethylꢀ6,9ꢀdiazaundecaneꢀ1,5,8,11ꢀtetraone (13) was
synthesized from hydrazone 6, the reaction time was 20 h. Yield
3
1.33 (both t, 6 H, 2 Me, POEt, JH,H = 7.1 Hz); 1.34 (d, 3 H,
Me, 3JH,H = 6.8 Hz); 1.42 (s, 9 H, Me, But); 1.43 (s, 9 H, But);
1.70—1.88 (m, 4 H, CH2, cycl.); 3.18—3.24 (m, 2 H, CH2,
cycl.); 3.78—3.38 (m, 2 H, CH2, cycl.); 4.06—4.09 (br.m, 2 H,
CH, NHNHC(O)); 4.11—4.20 (m, 4 H, 2 OCH2); 5.06 (d, 1 H,
46%; [α]D –31.8 (MeOH). 1H NMR (CDCl3), δ: 1.25—1.29
23
(m, 12 H, 2 Me, POEt); 1.35, 1.36, 1.37 (all s, 9 H each, Me,
But); 1.60—1.88 (m, 8 H, CH2, cycl.); 1.92—2.07 (m, 2 H,
CHCH2CH2); 2.22—2.44 (m, 2 H, CHCH2CH2); 3.04—3.27,
3.64—3.85 (both m, 4 H each, CH2, cycl.); 3.93—3.98 (br.m,
2 H, NHCH2C(O)); 4.05—4.10 (m, 4 H, 2 OCH2); 4.61—4.89
(m, 2 H, CHCH2CH2, CHCH2SH). 13C NMR (CDCl3), δ: 16.50
(s, Me, POEt); 27.34 (br.m, CH2, cycl.); 28.39 (s, Me, But);
29.62 (s, CH2SH); 31.73 (s, CHCH2CH2); 37.99, 38.37 (CH2,
3
NHBoc, JH,H = 7.1 Hz); 8.40 (br.s, 1 H, NHNHC(O)).
3
13C NMR (CDCl3), δ: 16.53 (d, Me, POEt, JC,P = 5.1 Hz);
18.43 (s, Me); 27.09, 27.49 (CH2, cycl.); 28.25 (s, Me, But);
28.39 (s, Me, But); 37.96 (CH2, cycl.); 49.35 (s, CH); 56.97
1
2
(d, C, JC,P = 158.8 Hz); 62.94, 63.03 (both d, OCH2, JC,P
=
= 9.6 Hz, JC,P = 8.7 Hz); 79.52 (s, C, But); 79.96 (s, C, But);
154.63, 155.28 (C=O, NBoc, NHBoc); 170.87 (s, C(O)NH).
31P NMR (CDCl3), δ: 26.41, 27.07. IR, ν/cm–1: 1030, 1050
(P—O—C); 1250 (P=O); 1660 (C=O, C(O)NH, C=N);
1660—1710 (C=O, C(O)OBut), 3280 (NH). Found (%): C, 50.60;
H, 8.41; N, 10.88. C22H43N4O8P. Calculated (%): C, 50.56;
H, 8.29; N, 10.72.
2
cycl.); 41.08 (s, CHCH2CH2); 42.35 (s, NHCH2); 52.22
1
(s, CHCH2CH2); 52.46 (s, CHCH2SH); 56.72 (d, C, JC,P
=
1
= 154.2 Hz); 56.97 (d, C, JC,P = 156.2 Hz); 62.98 (s, OCH2);
79.46, 79.75, 79.86 (all s, C, But); 154.66, 155.36 (both s, C=O,
C(O)OBut); 167.09, 170.17, 171.23, 173.06 (all s, C=O, C(O)NH).
31P NMR (CDCl3), δ: 25.66, 25.74. IR, ν/cm–1: 1040, 1060
(P—O—C); 1250 (P=O); 1650—1720 (C=O, Boc, C(O)NH);
2250—3330 (NH). Found (%): C, 48.34; H, 7.64; N, 11.60.
C43H81N9O16P2S. Calculated (%): C, 46.08; H, 7.60; N, 11.74.
(S)ꢀ{4ꢀ[2ꢀ(2ꢀAminopropanoyl)hydrazino]piperidinꢀ4ꢀyl}phosꢀ
phonic acid (12). To a solution of αꢀhydrazino phosphonate 9
(404 mg, 0.8 mmol) in anhydrous MeCN (2 mL), trimethylsilyl
bromide (5 mL, 5 mol, freshly distilled) was added. The reaction
mixture was stirred at room temperature for 24 h, the volatiles
were removed in vacuo. To the residue, MeOH (3 mL) was
added and the mixture was stirred for 2 h, then propylene oxide
(0.5 mL) was added. The precipitate that formed was filtered off
and washed with MeOH (3×2 mL) to give compound 12 (160 mg,
75%), m.p. 265—268 °C; [α]D23 –22.5 (H2O). 1H NMR (D2O),
Diethyl (S)ꢀ[1ꢀ(2ꢀ{2ꢀ[(tertꢀbutoxycarbonyl)amino]ꢀ3ꢀphenylꢀ
propanoyl}hydrazino)cyclohexyl]phosphonate (10) was syntheꢀ
sized from hydrazone 4, the reaction time was 10 h. Yield 72%;
[α]D23 –20.3 (MeOH). 1H NMR (CDCl3), δ: 1.08—1.19 (m, 1 H,
CH2, cycl.); 1.26, 1.27 (both t, 6 H, 2 Me, POEt, 3JH,H = 7.1 Hz);
1.37 (s, 9 H, Me, But); 1.41—1.61 (m, 8 H, CH2, cycl.);
1.70—1.75 (m, 1 H, CH2, cycl.); 3.00—3.03 (m, 2 H, CH2Ph);
3.99—4.10 (m, 5 H, 2 OCH2, NHNHC(O)); 4.31 (br.m, 1 H,
CH); 5.04 (d, 1 H, NHBoc, 3JH,H = 7.1 Hz); 7.16—7.19 (m, 3 H,
Ph); 7.23—7.26 (m, 2 H, Ph); 8.20 (br.s, 1 H, NHNHC(O)).
3
13C NMR (CDCl3), δ: 16.48 (d, Me, POEt, JC,P = 5.1 Hz);
3
19.79 (d, CH2, cycl., JC,P = 10.2 Hz); 25.08 (s, CH2, cycl.);
27.21 (d, CH2, cycl., 2JC,P = 16.8 Hz); 28.21 (s, Me, But); 38.30
1
(s, CH2Ph); 54.84 (s, CH); 58.25 (d, C, JC,P = 160.3 Hz);

Amino acid αꢀhydrazino phosphonates
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 2, February, 2011
253
3
δ: 1.45 (d, 3 H, Me, JH,H = 7.1 Hz); 1.78—1.88, 1.99—2.05,
5. E. D. Matveeva, T. A. Podrugina, I. N. Kolesnikova, N. S.
Zefirov, Izv. Akad. Nauk, Ser. Khim., 2010, 403 [Russ. Chem.
Bull., Int. Ed., 2010, 59, 411].
6. E. D. Matveeva, T. A. Podrugina, I. N. Kolesnikova, M. V.
Prisyazhnoi, G. G. Karateev, N. S. Zefirov, Izv. Akad. Nauk,
Ser. Khim., 2010, 409 [Russ. Chem. Bull., Int. Ed., 2010,
59, 418].
7. E. D. Matveeva, T. A. Podrugina, I. N. Kolesnikova, N. S.
Zefirov, Izv. Akad. Nauk, Ser. Khim., 2010, 571 [Russ. Chem.
Bull., Int. Ed., 2010, 59, 584].
3.16—3.20, 3.30—3.40 (all m, 2 H each, CH2, cycl.); 4.03 (q, 1 H,
CH, JH,H = 7.0). 13C NMR (D2O), δ: 16.36 (s, Me); 24.95
3
(d, CH2, 2JC,P = 28.5 Hz); 38.57 (d, CH2, 3JC,P = 9.5 Hz); 49.17
1
(s, CH); 53.97 (d, C, JC,P = 144.1 Hz); 170.16 (s, C=O).
31P NMR (D2O), δ: 19.83, 20.32. IR, ν/cm–1: 1220 (P=O);
1710 (C=O); 3270 (NH). MS (EI), m/z: 266 [M]+, 201
[M – P(O)(OH)2]+, 82 [Ppy – H]+, 65 [P(O)(OH)2]+. MS
(ESI): [M + H]+, found 267.1217, calculated 267.1217,
C8H19N4O4P.
8. M. Chebib, G. A. R. Johnston, J. Med. Chem., 2000, 43, 1427.
9. USSR Inventor's Certificate 939440; Byull. Izobret. [Bulletin
of Invention], 1982, 24 (in Russian).
10. R. Mileusnic, C. L. Lancashire, S. P. R. Rose, Ann. N. Y.
Acad. Sci., 2005, 1048, 149.
11. R. Mileusnic, C. L. Lancashire, S. P. R. Rose, Eur. J. Neuroꢀ
sci., 2004, 19, 1933.
12. US Pat. 20080153759, 2008; www.freepatentsonline.com/
20080153759.pdf.
13. I. Greenwell, Life Extension Magazine, 2001, 7, No. 2, 41.
14. S. A. Mikhalenko, S. V. Barkanova, O. L. Lebedev, E. A.
Luk´yanets, Zh. Obshch. Khim., 1971, 41, 2735 [J. Gen. Chem.
USSR, 1971, 41, No. 12].
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 08ꢀ03ꢀ00611),
the Council on Grants at the President of the Russian
Federation (the Program for the State Support of Leading
Scientific Schools of the Russian Federation, Grant
NShꢀ65546.2010.3), the Russian Academy of Sciences
(the Division of Chemistry and Materials Sciences, Proꢀ
grams Nos 1 and 9), and the Presidium of the Russian
Academy of Sciences (Program 9P).
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Received July 6, 2010;
in revised form December 7, 2010