Ferrocene-modified amino acids: synthesis and in vivo bioeffects on hippocampus

Article abstract of DOI:10.1007/s11172-017-1711-1

A method for the ferrocene modification of amino acids of natural and synthetic origin has been developed. In the in vivo studies, the hippocampal electrical activity under the action of ferrocenyl(phenylpyrazolyl)glycine (1) was assessed. A meaningful rise (up to 25% compared to the control) in the response amplitudes of the focal potentials of the hippocampal region СА1 after intraperitoneal administration of compound 1 at the dose of 2.0 mg kg^–1 was established.

Full text of DOI:10.1007/s11172-017-1711-1

Russian Chemical Bulletin, International Edition, Vol. 66, No. 1, pp. 136—142, January, 2017
136
Ferroceneꢀmodified amino acids: synthesis and in vivo bioeffects on hippocampus*
А. N. Rodionov,а L. V. Snegur,а А. А. Simenel,а Yu. V. Dobryakova,b and V. А. Markevichb
аA. N. Nesmeyanov Institute of Organoelement Compounds of Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5085. Eꢀmail: snegur@ineos.ac.ru
bInstitute of Higher Nervous Activity and Neurophysiology of Russian Academy of Sciences,
5А ul. Butlerova, 117485 Moscow, Russian Federation.
Fax: +7 (499) 743 0058. Eꢀmail: julkadobr@gmail.com
A method for the ferrocene modification of amino acids of natural and synthetic origin has
been developed. In the in vivo studies, the hippocampal electrical activity under the action of
ferrocenyl(phenylpyrazolyl)glycine (1) was assessed. A meaningful rise (up to 25% compared to
the control) in the response amplitudes of the focal potentials of the hippocampal region СА1
after intraperitoneal administration of compound 1 at the dose of 2.0 mg kg–1 was established.
Кey words: ferrocene, amino acids, synthesis, enantiomers, biological activity, brain,
hippocampus.
Chemistry of ferrocene has been intensively developed
for more that six decades.1,2 However, during the first
decade and a half of the XXI century a special attention
was been given to the synthesis of ferrocene derivatives
bearing pharmacophoric groups, namely, nucleobases, oliꢀ
gonucleotides, various heterocycles, amino acids, peptides,
and sugars.3—8 In vitro and in vivo studies have demonꢀ
strated that many of such ferrocenes display a large range
of biological activity,9 including antianemic,10 antimicroꢀ
bial,11 antibacterial,12 tuberculostatic,13 antimalarial,14
antitumor activities,15—18 etc. Ferroceron (оꢀcarboxybenzoꢀ
ylferrocene), being a ferroceneꢀbased drug, is used effecꢀ
tively for a long time for the treatment of ironꢀdeficiency
pathologies.19
However, a potential of ferrocenylꢀsubstituted amino
acids as drugs for the treatment of neurodegenerative disꢀ
orders is out of view of scientists. At the same time, acꢀ
cording to the projections of the World Health Organizaꢀ
tion20 these are precisely the disorders which will domiꢀ
nate in the nearest future and exceed the incidence of
cancer and cardiovascular diseases.
and improve their lipid membrane penetrating ability.9
Moreover, it allows there compounds to exist both in salt
and neutral forms29 providing their transport in a blood
flow, as well as across the membranes into cytoplasm (polar
medium). An ability of ferrocenylꢀsubstituted compounds
to undergo oxidation and reduction22,27 at physiological
pH values is their substantial advantage, that is to say,
these compounds present a kind of mediators. Therefore,
chemical modification of drugs intended for the treatment
of brain disorders (glycine, gammaꢀaminobutyric acid
(GABA), betaꢀphenyl derivatives of GABA (phenibut),
other amino acids, as well as drugs used to treat Alzheiꢀ
mer´s disease, particularly, memantin) enables one to imꢀ
prove the mediator properties of the existing pharmaꢀ
ceuticals. For instance, it is known that GABA, being
a major mediator involved in the central inhibition proꢀ
cesses activates the energetic processes in the brain, scarcely
penetrates across the bloodꢀbrain barrier (BBB) and only
as small as 8% of GABAꢀcontaining drug aminalon reaches
the brain targets upon oral administration. A ferrocene
moiety which is generally agreed to be a good vehicle,6,9,17
overcomes readily the BBB (though this hypothesis did
nor find sufficient experimental support yet) and can facilꢀ
itate the targeted drug delivery to the brain.
Our own results17,21—29 as well as literature data30—33
suggest that it is ferroceneꢀmodified amino acids that can
have a considerable impact on the neurodegenerative proꢀ
cesses. It is known, that ironꢀcontaining ferrocene moiety
endows the modified compounds with a number of useful
properties. First, it significantly decreases their toxicity7,17
Based on the commercially available ferrocene, we have
developed a unique synthetic procedure and obtained
a series of hitherto unknown ferrocenylꢀsubstituted amino
acids, namely, glycine, alanine, valine, tyrosine, and proꢀ
line ones. This approach to ferrocenylꢀsubstituted amino
acids comprises modification of synthetically available
ferrocenyl azoles8 wellꢀaccepted in terms of biological
activity. On the basis of a ferroceneꢀpyrazol building block
*Based on the materials of the International Conference "Orgaꢀ
nometallic and Coordination Chemistry: Achievements and
Challenges" (VI Razuvaev Lecture) (September 18—23, 2015,
Nizhny Novgorod).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 0136—0142, January, 2017.
1066ꢀ5285/17/6601ꢀ0136 © 2017 Springer Science+Business Media, Inc.

Ferroceneꢀmodified amino acids and hippocampus
Russ.Chem.Bull., Int.Ed., Vol. 66, No. 1, January, 2017
137
the aminoꢀacid moiety was attached. For this purpose,
selective approaches to obtain isomeric ferrocenyl pyrazol
carbaldehydes were proposed.34,35 Their subsequent funcꢀ
tionalization via the reductive amination with the amino
acid methyl esters of both natural (including both Lꢀ, Dꢀ or
DLꢀforms), and synthetic origin using sodium triacetoxyꢀ
borohydride as a reducing agent affords the ferroceneꢀ
pyrazolꢀamino acid building block (Scheme 1). As a reꢀ
sult, various ferroceneꢀsubstituted amino acids were obꢀ
tained. It should be noted that all the above reactions are
well scaled up, allowing one to obtain these compounds in
amounts sufficient to perform biological assays.
It should be emphasized that biological activity of the
ferroceneꢀbased compounds in an enantiomerically pure
(or enriched) form earlier has virtually not been studied.
Moreover, chemistry of such compounds is presently
scarcely investigated. At the same time, these are precisely
enantiomers which optimize the state of the nervous sysꢀ
tem, and are involved in the most important methylation
and demethylation processes. Furthermore, the so called
"thalidomide tradegy" which has been associated with the
use of the drug thalidomide in a racemic form and resulted
in severe birth defects, forced the world community to
revise its attitude to the enantiomeric purity of drug forꢀ
mulations and to make the corresponding supplements to
the State Pharmacopoeias. Therefore, a need in additional
studies of the biological effects of individual stereomers is
inspired by the requirements of the Pharmaceutical Comꢀ
mittee of the Russian Federation to enantiomeric purity36
and the studies logic.
In the Institute of Higher Nervous Activity and Neuꢀ
rophysiology of Russian Academy of Sciences primary
studies of a biological action of the first representative of
a series of ferrocenyl amino acids, namely, ferrocenylꢀ
(phenylpyrazolyl)glycine (1), on the hippocampus which
is a part of a temporal lobe of the brain, have been perꢀ
formed. A significant (up to 15%) rise of the amplitude of
the hippocampal focal potentials upon intraperitoneal adꢀ
ministration of compound 1 at a dose of 2.0 mg kg–1 was
established. Further we are planning to screen the activity
of the ferrocene compounds using both racemic mixtures
and the individual enantiomers.
Scheme 1
Reagents and conditions: i. NaBH(OAc)3, C2H4Cl2, Δ, 3 h; ii. NaBH(OAc)3, C2H4Cl2, Δ, 1 h.
R = H (glycine) (1); Me (alanineꢀDL, L, D) (2a, 2b, 2c, respectively); isoꢀPro (valineꢀDL, L, D) (3a, 3b, 3c); 4ꢀHOC6H4CH2 (tyrosineꢀDL, L, D)
(4a, 4b, 4c); βꢀalanine (2d); proline (DL, L) (5a, 5b).

138
Russ.Chem.Bull., Int.Ed., Vol. 66, No. 1, January, 2017
Rodionov et al.
First ferrocenyl derivatives of amino acids such as ferroꢀ
try. In particular, in animal (rodent) studies it was estabꢀ
lished30 that oral (e.g. dietary) administration of (3,5,5ꢀ
trimethylhexanoyl)ferrocene did not result in accumulaꢀ
tion of iron in the brain tissues. In a recent work,44
Nꢀphenylferrocene carboxamide FcC(O)NHꢀPh was used
only as a starting compound to be radiolabeled with 99mТс
through substituting iron for 99mТс. Ironꢀfree technetiumꢀ
labeled compound was subsequently administrated to anꢀ
esthesized animals (rats) with the purpose to investigate
the accumulation of the radioactive product in different
parts on the brain.
The influence of ferrocenylꢀsubstituted amino acids
obtained by us on the efficiency of interneuronal interacꢀ
tions was studied by the in vivo recording the hippocampal
focal potentials. Hippocampus is a key structure involved
in the learning and memory processes.45 One of the comꢀ
mon model of processes taking place in the hippocampus
during learning is a development of a longꢀterm potentiaꢀ
tion of the synaptic transmission in the hippocampal
sector CA1.46
Electrophysiological studies were carried out on the
anesthesized Wistar rats weighting 350 g. The animals were
anesthesized with ethylcarbamate (1.75 g kg—1; IP). Elecꢀ
trodes for the electric stimulation were implanted accordꢀ
ing to the following stereotaxic coordinates: hippocampal
sector CA1 AP 2.7, L is 1.5; ventral hippocampal comꢀ
missura (VHC) AP 1.3, L is 1.0 with the rat´s skull posiꢀ
tion at the same horizontal level. Bipolar electrodes made
from 80 μm diameter nichrome wire were used for recordꢀ
ing and stimulation. Penetration depth of the stimulation
and recording electrodes was assessed from the recorded
response measurements (optimal ratio of an amplitude
and stimulating current). To record the focal potentials of
the field CA1 VHС was stimulated with 50—100 μs rectꢀ
angular pulses. A series of ten paired stimili presentations
was applied (interstimulus interval in a pair was 30 ms,
pulse pair interval was 20 s). Optimal parameters for the
stimulating current varied from 100 to 400 μА. Efficiency
of the synaptic transmission was assessed from the change
in the amplitude characteristics of the induced responces
of the hippocampal field CA1 on the testing stimulation of
the VHC. Long term potentiation presenting an interneuꢀ
ronal synaptic transmission was induced by the highꢀfreꢀ
quency stimulation of the ventral hippocampal commissuꢀ
ra (five stimulus sets each comprising four repeats of five
stimuli with the 100 Hz stimulation frequency and an inꢀ
terval of 200 μs; an interval between the stimulus sets was
30 s). Electrophysiological study was performed 30 min
before the drug treatment, within 1 h after the injection
and within 1 h after the highꢀfrequency stimulation (Fig. 1).
During the testing of the ferrocenyl(phenylpyrazolyl)ꢀ
glycine methyl ester (1) at a dose of 2.0 mg kg–1 (in
a DMSO—Н2О solution) two groups of animals were studꢀ
ied. It was shown that response amplitudes of the focal
cenyl alanine (FcꢀAla) and ferrocenyl phenyl alanine
(FcꢀPheAla) were obtained in several steps as far back as
1957.37 Systematic studies started in the end of 1990s and
are performed nowadays though less actively (see reꢀ
views4,6 and a book9).
Synthetic approaches to the ferrocene modification of
amino acids are rather simple. They comprise the synthesis
of Schiff bases from acetylferrocene and an amino acid.38
However, such ferrocenyl imines are unstable compounds.
They are usually reduced and then isolated as methyl or
ethyl esters of the corresponding acids.39
To obtain ferrocenylꢀmodified amino acids we have
previously used an approach developed for ferrocenylꢀ
(alkyl)azoles. Starting from ferrocenyl alcohols
FcCH(OH)R and ethyl esters of glycine and βꢀalanine
under acidic catalysis in aqueous organic medium the corꢀ
responding products were obtained.40
In the present work we propose an approach to ferꢀ
roceneꢀsubstituted amino acids based on modification of
synthetically available ferrocenyl pyrazoles.35,41 Reducꢀ
tive amination reactions between ferrocenyl pyrazoles
bearing an aldehyde group in the pyrazole moiety, and
esters of amino acid such as glycine, alanine, βꢀalanine,
valine, tyrosine, and proline using sodium triacetoxyboroꢀ
hydride under reflux in dichloroethane afforded the target
products 1, 2a—c, 2d, 3a—c, 4a—c, and 5a,b, correspondꢀ
ingly, in 90% yields after chromatographic purification
(see Scheme 1).
It is known that sodium triacetoxyborohydride
NaBH(OAc)3 is often used in the reductive aminations.
Being a milder reductive agent compared to, e.g., sodium
borohydride or lithium aluminium hydride, it is effective
in the carbonyl and aldehyde group reduction, with the
С=С multiple bonds, cyano or nitro groups remaining
intact.42 We have found that NaBH(OAc)3 effectively reꢀ
duces Fcꢀformylpyrazol in reaction with monoaminotetꢀ
raphenyl porphyrine to form the —СН2—NH— bond in
the corresponding ferrocenyl porphyrine.43
Thus, ferrocenyl pyrazol derivatives of amino acids
were synthesized via the reductive amination using sodiꢀ
um triacetoxyborohydride according to Scheme 1. As
a result, starting from methyl esters of amino acids such as
glycine, alanine, βꢀalanine, valine, tyrosine, and proline,
a variety of ferrocenylꢀsubstituted amino acids both in
a racemic forms and in Lꢀ and Dꢀforms were obtained in
high yields.
Antitumor activity of ferrocene compounds is presently
under active investigation,5,15—18 and the authors have
also succeeded in this field.17,21 However, for the moment
there are only few publications concerning the influence of
the ferrocenylꢀsubstituted compounds on the brain.30—33,44
This subject is only beginning to attract the attention of
scientists working in the field of organometallic chemisꢀ

Ferroceneꢀmodified amino acids and hippocampus
Russ.Chem.Bull., Int.Ed., Vol. 66, No. 1, January, 2017
139
A (%)
180
1
2
160
140
120
100
S
I
–40 –30 –20 –10
10 20 30 40 50 60 70 80 90 100 110 120 130
t/min
Fig. 1. A change in the amplitude of the focal potentials of the hippocampal field CA1as a response on the VНС testing stimulation
within 60 min after administrating the ferroceneꢀcontaining preparation (compound 1, a dose of 2 mg kg–1, IP) and within 60 min after
highꢀfrequency stimulation; 1 is a ferroceneꢀmodified preparation, 2 is a saline solution, I is a preparation administration, S is a highꢀ
frequency stimulation, t is a duration of a test, A is a response amplitude as a percentage of the background level (AM SEM are
presented). Meaningful values (p < 0.05) are designated (*) in assessment of the group differences according to the tꢀtest.
potentials of the hippocampal field CA1 in the tested aniꢀ
mals injected with a ferroceneꢀcontaining preparation
(compound 1) at the concentration of 2 mg kg–1 (n = 5)
rised from 15% to 25% compared to the salineꢀtreated
control animals (n = 3) (see Fig. 1). Within 60 min after
the beginning of recordings in the group of rats injected
with the preparation, the response amplitude following
the highꢀfrequency stimulation was significanty higher
compared to that for the salineꢀinjected control group anꢀ
imals (157.7 7.9% и 132.25 9.3%, respectively; p < 0.05
according to the tꢀtest).
Experimental
1Н and 13C NMR spectra were recorded on a Bruker DRXꢀ500
spectrometer at 500.13 and 125.76 MHz, respectively, in
CDCl3. Mass spectra were recorded on a Finnigan Polaris Q
spectrometer (ionization energy 70 eV, the ionization chamꢀ
ber temperature 250 °С). IR spectra were recorded on a URꢀ20
(Karl Zeiss) spectrometer (KBr pellets). Sodium triacetꢀ
oxyborohydride NaBH(OAc)3 and amino acids (Acros Orꢀ
ganics) were used without preliminary purification. Amino
acid methyl and ethyl ester hydrochlorides were obtained by
reaction of amino acids with SOCl2 in methanol or ethanol,
respectively.47
Synthesis of ferroceneꢀsubstituted pyrazolyl amino acids (genꢀ
eral procedure). To a solution of 1ꢀphenylꢀ3ꢀ(ferrocenyl)pyrazolꢀ
4ꢀcarbaldehyde (1.0 mmol) and an amino acid ester hydrochlorꢀ
ide (1.2 mmol) in dried 1,2ꢀdichloroethane (35 mL) Et3N
(0.17 mL, 1.2 mmol) was added followed by sodium triacetoxyꢀ
borohydride (0.3 g, 1.4 mmol). The reaction mixture was heated
under reflux for 1—3 h. After cooling it for 20 °C, 30 mL of the
saturated aqueous NaHCO3 solution was added. The product
was extracted with dichloromethane (2×30 mL). Organic fracꢀ
tions were combined and washed with 30 mL of the saturated
sodium chloride solution and dried over the anhydrous Na2SO4.
The solvent was removed under the reduced pressure. The resiꢀ
due was purified by chromatography on silica gel, eluent CHCl3—
MeOH (9 : 1). Below are given the elemental analysis data, IR,
1Н and 13С NMR spectroscopy as well as massꢀspectrometry
data for the racemic mixtures, which are similar to the data for
the individual enantiomers.
In such a manner a pronouced response of the hippoꢀ
campal region of the brain to the ferroceneꢀcontaining
preparation was detected. Naturally, there is a need in
further studies with varying the dose and the ferrocene
preparations per se to accumulate the statistical data and
to review the results. However, it should be noted that the
chosen class of the ferroceneꢀmodified amino acids disꢀ
plays a biological action on the most important region of
the brain, i.e. hippocampus. The biological model was
well chosen and a significant change (an increase of 15—25%
compared to the control) in the amplitude of the focal
potentials in the hippocampal region СА1 was detected.
The result obtained on choosing a dose (2.0 mg kg–1
)
based on a considerable experience of other biological studꢀ
ies performed by us suggests that the ferrocenyl compounds
act in a low dose range.
Primary biological studies revealed the involvement of
the ferrocene based compounds in the synaptic plasticity
of a brain region.
Methylꢀ2ꢀ[(1ꢀphenylꢀ3ꢀferrocenylꢀ1Нꢀpyrazolꢀ4ꢀyl)methylꢀ
amino]acetate or ferrocenyl(phenylpyrazolyl)glycine methyl ester (1).
Yield 90%. Yellow powder, m.p. 102 °С. Found (%): С, 64.25;

140
Russ.Chem.Bull., Int.Ed., Vol. 66, No. 1, January, 2017
Rodionov et al.
Н, 5.38; N, 9.80. С23Н23FeN3O2. Calculated (%): С, 64.35; Н, 5.40;
N, 9.79. MS, m/z (Irel (%)): 429 [M]+ (100). 1Н NMR (CDCl3),
δ: 1.69 (br.s, 1 Н, NН); 3.64 (s, 2 Н, СН2); 3.77 (s, 3 Н, Me);
4.13 (s, 2 Н, СН2); 4.17 (s, 5 Н, Fc); 4.33, 4.82 (both s, by 2 Н,
Fc); 7.28 (t, 1 Н, Рh, J = 7.5 Hz); 7.45 (m, 2 Н, Рh); 7.75 (d, 2 Н,
Рh, J = 8.0 Hz); 8.12 (s, 1 Н, CH). 13С NMR (CDCl3), δ: 42.9,
48.9, 52.1, 67.6, 68.8, 69.4, 77.9, 116.9, 118.6, 125.9, 127.6,
129.3, 139.9, 150.1, 171.4.
(DL)ꢀMethylꢀ2ꢀ[(1ꢀphenylꢀ3ꢀferrocenylꢀ1Нꢀpyrazolꢀ4ꢀyl)ꢀ
methylamino]propanoate or (DL)ꢀferrocenyl(phenylpyrazolyl)ꢀ
alanine methyl ester (2a). Yield 90%. Yellow powder, m.p. 94 °С.
Found (%): С, 64.91; Н, 5.65; N, 9.29. С24Н25FeN3O2. Calꢀ
culated (%): С, 65.02; Н, 5.45; N, 9.48. MS, m/z (Irel (%)):
443 [M]+ (87), 378 [M – Ср]+ (100). IR, ν/cm–1: 1731
(СООМе). 1Н NMR (CDCl3), δ: 1.31 (d, 3 Н, Me, J = 6.7 Hz);
2.02 (br.s, 1 Н, NН); 3.43 (q, 1 Н, СН, J = 6.7 Hz); 3.68 (s, 3 Н,
Me); 3.70, 3.88 (both d, by 1 Н, СН2, J = 13.1 Hz); 4.02 (s, 5 Н,
Fc); 4.23, 4.75 (both s, by 2 Н, Fc); 7.12 (t, 1 Н, Рh, J = 7.2 Hz);
7.31 (m, 2 Н, Рh); 7.61 (d, 2 Н, Рh, J = 7.9 Hz); 7.80 (s, 1 Н,
Pz). 13С NMR (CDCl3), δ: 19.2, 42.3, 51.9, 56.2, 67.2, 67.3,
68.6, 69.3, 78.0, 118.4, 119.1, 125.7, 126.8, 129.3, 140.0,
149.7, 176.0.
(D)ꢀMethylꢀ2ꢀ[(1ꢀphenylꢀ3ꢀferrocenylꢀ1Нꢀpyrazolꢀ4ꢀyl)ꢀ
methylamino]ꢀ3ꢀmethylbutanoate (3c). Yield 90%. Yellow powꢀ
der, m.p. 137 °С, [α]D +17.9 (с 1.0; CHCl3).
25
(DL)ꢀMethylꢀ2ꢀ[(1ꢀphenylꢀ3ꢀferrocenylꢀ1Нꢀpyrazolꢀ4ꢀyl)ꢀ
methylamino]ꢀ3ꢀ(4ꢀhydroxyphenyl)propanoate or (DL)ꢀferroꢀ
cenyl(phenylpyrazolyl)tyrosine methyl ester (4a). Yield 90%. Yellow
powder, m.p. 170 °С. Found (%): С, 67.40; Н, 5.40; N, 7.85.
С30Н29FeN3O3. Calculated (%): С, 67.30; Н, 5.46; N, 7.85.
MS, m/z (Irel (%)): 535 [M]+ (34), 470 [M – Ср]+ (58). IR, ν/см–1
:
1
1732 (СООМе). Н NMR (CDCl3), δ: 1.95 (br s, 1 Н, NН);
2.83 (dd, 1 Н, СН2, J1 = 8.0 Hz, J2 = 13.5 Hz); 2.97 (dd, 1 Н,
СН2, J1 = 5.3 Hz, J2 = 13.5 Hz); 3.64 (m, 1 Н, СН); 3.63 (s, 3 Н,
Me); 3.78, 3.96 (both d, by 1 Н, СН2, J = 13.7 Hz); 4.06 (s, 5 Н,
Fc); 4.26, 4.72 (both s, by 2 Н, Fc); 6.69, 7.03 (both d, by 2 Н,
Ar, J = 7.8 Hz); 7.18 (t, 1 Н, Рh, J = 7.2 Hz); 7.37—7.42 (m, 2 Н,
Рh); 7.55 (s, 1 Н, Pz); 7.57 (d, 2 Н, Рh, J = 7.0 Hz). 13С NMR
(CDCl3), δ: 29.8, 38.9, 42.5, 52.1, 62.5, 67.3, 67.6, 68.8, 69.4,
77.8, 115.7, 118.8, 118.9, 126.0, 127.3, 128.5, 129.4, 130.4, 139.0,
150.1, 155.3, 175.3.
(L)ꢀMethylꢀ2ꢀ[(1ꢀphenylꢀ3ꢀferrocenylꢀ1Нꢀpyrazolꢀ4ꢀyl)methꢀ
ylamino]ꢀ3ꢀ(4ꢀhydroxyphenyl)propanoate (4b). Yield 90%.
Yellow powder, m.p. 182 °С, [α]D25 –11.2 (с 0.81; CHCl3).
(D)ꢀMethylꢀ2ꢀ[(1ꢀphenylꢀ3ꢀferrocenylꢀ1Нꢀpyrazolꢀ4ꢀyl)ꢀ
methylamino]ꢀ3ꢀ(4ꢀhydroxyphenyl)propanoate (4c). Yield 89%.
(L)ꢀMethylꢀ2ꢀ[(1ꢀphenylꢀ3ꢀferrocenylꢀ1Нꢀpyrazolꢀ4ꢀyl)ꢀ
methylamino]propanoate (2b). Yield 90%. Yellow powder, m.p.
75 °С, [α]D25 –27.2 (c 1.0; МеCN).
25
Yellow powder, m.p. 182 °С, [α]D +11.1 (с 0.74; CHCl3).
(D)ꢀMethylꢀ2ꢀ[(1ꢀphenylꢀ3ꢀferrocenylꢀ1Нꢀpyrazolꢀ4ꢀyl)ꢀ
(DL)ꢀMethylꢀ1ꢀ[(1ꢀphenylꢀ3ꢀferrocenylꢀ1Нꢀpyrazolꢀ4ꢀyl)ꢀ
methylamino]propanoate (2c). Yield 90%. Yellow powder, m.p.
74—75 °С, [α]D +26.4 (с 1.0; МеCN).
methyl]pyrrolidineꢀ2ꢀcarboxylate or
ferrocenyl(phenylpyrꢀ
25
azolyl)proline methyl ester (5a). Yield 80%. Yellow powder, m.p.
140 °С. Found (%): С, 66.51; Н, 5.85; N, 8.90. С26Н27FeN3O2.
Calculated (%): С, 66.53; Н, 5.80; N, 8.95. MS, m/z (Irel (%)):
469 [M]+ (100). IR, ν/cm–1: 1744 (СООМе). 1Н NMR
(CDCl3), δ: 1.92—2.09 (m, 3 Н); 2.21—2.32 (m, 1 Н);
2.54—2.63 (m, 1 Н); 3.22—3.27 (m, 1 Н); 3.38—3.43 (m, 1 Н);
3.75 (s, 3 Н, Me); 3.81 (d, 1 Н, СН2, J = 13.5 Hz); 4.08 (d, 1 Н,
СН2, J = 13.5 Hz); 4.17 (s, 5 Н, Fc); 4.36 (s, 2 Н, Fc); 4.95,
4.98 (both s, by 1 Н, Fc); 7.28 (t, 1 Н, Ph, J = 7.5 Hz);
7.48—7.53 (m, 2 Н, Ph); 7.76 (d, 2 Н, Ph, J = 7.8 Hz); 7.92
(s, 1 Н, Pz). 13С NMR (CDCl3), δ: 219, 28.3, 47.0, 47.1, 52.8,
64.0, 66.7, 68.5, 69.2, 111.2, 118.4, 126.0, 129.0, 130.2, 139.0,
150.2, 167.0.
Ethylꢀ3ꢀ[(1ꢀphenylꢀ3ꢀferrocenylꢀ1Нꢀpyrazolꢀ4ꢀyl)methylꢀ
amino]propanoate or ferrocenyl(phenylpyrazolyl)ꢀβꢀalanine ethyl
ester (2d). Yield 87%. Yellow powder, m.p. 112 °С. Found (%):
С, 65.70; Н, 5.85; N, 9.10. С25Н27FeN3O2. Calculated (%):
С, 65.65; Н, 5.95; N, 9.19. MS, m/z (Irel (%)): 457 [M]+ (67),
1
392 [M – Ср]+ (100). IR, ν/cm–1: 1732 (СООEt). Н NMR
(CDCl3), δ: 1.25 (t, 3 Н, Me, J = 7.0 Hz); 1.70 (br s, 1 Н, NН);
2.59, 3.05 (both t, by 2 Н, СН2, J = 6.5 Hz); 3.97 (s, 2 Н, СН2);
4.12 (s, 5 Н, Fc); 4.14 (m, 2 Н, СН2); 4.32, 4.82 (both s, by 2 Н,
Fc); 7.22 (t, 1 Н, Рh, J = 7.7 Hz); 7.42 (m, 2 Н, Рh); 7.71 (d, 2 Н,
Рh, J = 7.8 Hz); 7.90 (s, 1 Н, Pz). 13С NMR (CDCl3), δ: 14.0,
30.6, 41,4, 41.7, 61.3, 68.1, 68.9, 69.5, 76.7, 110.2, 118.7, 126.5,
129.3, 129.7, 139.3, 150.7, 170.2.
(DL)ꢀMethylꢀ2ꢀ[(1ꢀphenylꢀ3ꢀferrocenylꢀ1Нꢀpyrazolꢀ4ꢀyl)ꢀ
methylamino]ꢀ3ꢀmethylbutanoate or (DL)ꢀferrocenyl(phenylꢀ
pyrazolyl)valine methyl ester (3a). Yield 93%. Yellow powder, m.p.
116 °С. Found (%): С, 69.40; Н, 5.65; N, 8.15. С26Н29FeN3O2.
Calculated (%): С, 69.37; Н, 5.63; N, 8.09. MS, m/z (Irel (%)):
471 [M]+ (70), 406 [M – Ср]+ (100). IR, ν/cm–1: 1726 (СООМе).
1Н NMR (CDCl3), δ: 1.02 (d, 6 Н, Me, J = 6.8 Hz); 1.96 (br s,
1 Н, NН); 2.00—2.07 (m, 1 Н, СН); 3.21 (d, 1 Н, СН, J = 6.0 Hz);
3.74, 3.97 (both d, by 1 Н, СН2, J = 13.2 Hz); 3.79 (s, 3 Н, Me);
4.12 (s, 5 Н, Fc); 4.32, 4.89 (both s, by 2 Н, Fc); 7.31 (t, 1 Н, Рh,
J = 7.4 Hz); 7.43—7.48 (m, 2 Н, Рh); 7.72 (d, 2 Н, Рh, J = 7.8 Hz);
7.89 (s, 1 Н, Pz). 13С NMR (CDCl3), δ: 18.7, 19.5, 31.7, 42.8,
51.5, 66.7, 67.3, 67.4, 68.5, 69.2, 78.1, 118.4, 119.3, 125.7, 126.9,
129.3, 140.0, 149.9, 175.6.
(L)ꢀMethylꢀ1ꢀ[(1ꢀphenylꢀ3ꢀferrocenylꢀ1Нꢀpyrazolꢀ4ꢀyl)ꢀ
methyl]pyrrolidineꢀ2ꢀcarboxylate or ferrocenyl(phenylpyrazolꢀ
yl)proline methyl ester (5b). Yield 80%. Yellow powder, m.p. 140 °С,
25
[α]D +20.6 (с 1.07; CHCl3).
This work was financially supported by the Russian
Foundation for Basic Research (Project Nos. 14ꢀ03ꢀ00980
and 16ꢀ03ꢀ00881).
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der, m.p. 136 °С, [α]D25 –18.0 (с 1.0; CHCl3).

Ferroceneꢀmodified amino acids and hippocampus
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