Chemo-and regiospecific modification of D,L-tryptophan by reaction with α,β-acetylenic γ-hydroxy nitriles

Article abstract of DOI:10.1055/s-0030-1257912

D,L-Tryptophan reacts with α,β-acetylenic γ-hydroxy nitriles, chemo-and regiospecifically, under mild, green conditions via a hydroamination-type process involving the primary amine group. The hydroxycyanopropanyl substituent of the initial adducts underg

Full text of DOI:10.1055/s-0030-1257912

3174
PAPER
Chemo- and Regiospecific Modification of D,L-Tryptophan by Reaction with
a,b-Acetylenic g-Hydroxy Nitriles
C
hemo- and Regi
o
ospecific
M
o
dificatio
i
n
of
D
,
L
-
Tryptophan A. Trofimov,* Anastasiya G. Mal’kina, Angela P. Borisova, Olesya A. Shemyakina, Valentina V. Nosyreva,
Alexander I. Albanov
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch, Russian Academy of Sciences, 1 Favorsky Str., 664033, Irkutsk,
Russian Federation
Fax +7(3952)419346; E-mail: boris_trofimov@irioch.irk.ru
Received 28 April 2010; revised 7 May 2010
tophan units underwent acid-promoted macrocyclization
Abstract: D,L-Tryptophan reacts with a,b-acetylenic g-hydroxy ni-
and oxidation to afford peptides demonstrating unique
triles, chemo- and regiospecifically, under mild, green conditions
via a hydroamination-type process involving the primary amine
group. The hydroxycyanopropanyl substituent of the initial adducts
fluorescent properties.10 In addition, Pictet–Spengler con-
densation of tryptophan with quinoline or quinoline-5,8-
undergoes cyclization to afford a 2,5-dihydro-5-iminofuranyl moi- dione aldehydes has led to the synthesis of the antibiotic,
lavendamycin.11 Amino acids displaying antibacterial and
ety. Several novel amino acids are obtained in almost quantitative
yields (95-98%), which exist in an unusual zwitterionic form where
antifungal properties were obtained by reaction of L-tryp-
the positive charge is located on the remote nitrogen atom of the
tophan with 2-hydroxy-1-naphthaldehydes.12
imino group of the dihydrofuran ring.
In this paper, we report on the modification of D,L-tryp-
Key words: D,L-tryptophan, a,b-acetylenic g-hydroxy nitriles, nu-
tophan (1) by reaction with a,b-acetylenic g-hydroxy ni-
triles 2a–d. The reaction takes place in water under mild
conditions (sodium hydroxide, pH ~10, 40–45 °C, 4–48
hours), and proceeds via nucleophilic addition of the ami-
no function across the triple bond, resulting in the forma-
tion of a novel family of unnatural amino acids 4a–d
containing a 2,5-dihydro-5-iminofuranyl substituent. The
iminofuranyl moiety is assembled by ring-closure involv-
ing the cyano and hydroxy functionalities of the initial ad-
ducts 3. The modified tryptophans 4a–d were formed
chemo- and regioselectively, in almost quantitative yields
(95–98%) (Table 1).
cleophilic addition, hydroamination, amino acids, 2,5-dihydroimi-
nofurans
The indole ring system is a very common scaffold in Na-
ture,1 indeed the large number of known biologically ac-
tive indoles has led to them being employed as key
structural units in many pharmaceuticals.2 Substituted in-
doles can bind selectively to many receptors with high af-
finity.3 The significance of the essential amino acid
tryptophan in human nutrition has been widely recog-
nized.1d,4 In plants, tryptophan is used to synthesize pro-
teins and compounds responsible for control of their
growth.5
Table 1 Synthesis of Amino Acids 4a–d
O
_
Derivatives of tryptophan are able to activate osteoblasts
and amongst these, therapeutic agents for the treatment of
osteoporosis have been found.6 They are also recommend-
ed for the specific treatment of serotonin-producing tu-
mors.7 Certain tryptophan congeners exhibit matrix
metalloproteinase (MMP) inhibitory activity.8 Therefore,
the development of new synthetic strategies for the modi-
fication of tryptophan is important. Furthermore, as tryp-
tophan exists as a polyfunctional molecule, containing
amine, carboxylic acid and indole functional groups, its
chemo- and regioselective modification is an obvious
challenge.
R2
O
NaOH, H2O (pH ~10)
R1
CN
+
+
NH3
40–45 °C, 4–48 h
N
H
OH
1
2a–d
O
O
_
OH
CN
O
HN
R2
HN
N
H
N
R2
+
NH2
H
R1
O
OH
R1
3
4a–d
Product
4a
R1
R2
Me
Et
Yield (%)
For example, the reaction of tryptophan residues of en-
zymes with N-halosuccinimide has been reported.9 The
complex transformations of tryptophan in foods, and the
significant diversity of its derivatives, have been re-
viewed. Carbolines have been obtained from tryptophan
and carbonyl compounds.5a Peptides containing two tryp-
Me
Me
98
96
95
95
4b
4c
–(CH2)5–
–(CH2)6–
4d
SYNTHESIS 2010, No. 18, pp 3174–3178
x
x.
x
x
.
2
0
1
0
Advanced online publication: 04.08.2010
DOI: 10.1055/s-0030-1257912; Art ID: Z11110SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Chemo- and Regiospecific Modification of D,L-Tryptophan
3175
O
7
It is clear that the true catalyst here is the sodium salt of
D,L-tryptophan. The role of the base is to increase the con-
centration of the non-zwitterionic form of the amino acid.
The latter, possessing an uncharged amino group, is able
to undergo nucleophilic addition at the triple bond of the
hydroxy nitrile.
11
_
9
12
13
10a
8
10
O
HN 6
R2
15
H
16
3
2
4
5
14a
14
N
H
+
NH2
O
R1
4a–d
It should be noted that, in this case, the amino group of the
indole ring remained completely inactive towards the
highly electrophilic acetylenes 2a–d. This is surprising as
the latter typically undergo addition to a number of di-
verse NH-containing heterocycles, such as imidazole,13
benzimidazole,13c,e,14 pyrazole, triazole,13c–e and tetra-
zole,15 to furnish the corresponding adducts without un-
dergoing cyclization into iminodihydrofurans.
Figure 1 The atom numbering used for NMR assignments in com-
pounds 4a–d
O
_
O
H
HN
H3C
H3C
N
H
+
NH2
The amino acids 4a–d exist, both in solid and solution
states, in peculiar zwitterionic forms, protonated at the re-
mote nitrogen atom of the iminodihydrofuran residue in-
stead of at the expected tryptophan amino group. Similar
long-range proton transfer has been observed in adducts
O
Figure 2 Diagnostic cross peaks in the HMBC (1H–13C) spectrum
of amino acid 4a
of aliphatic amino acids16 and 2-aminobenzoic acid17 with The zwitterionic form of amino acids 4a–d was supported
a,b-acetylenic g-hydroxy nitriles.
by their IR (KBr) spectra in which strong, broad absorp-
tions were apparent in the region 3500–2600 cm–1 (with
peaks at 3405–3219, 3115–3049, 2985–2930 and 2876–
2865 cm–1). These bands were attributed to the NH,
=N+H2, C=CH and CH groups. The carboxylate anion was
evident as a broad absorption in the region 1700–1500
cm–1, overlapping with the stretching vibration of the C=C
bond at 1611–1618 cm–1, and the bending vibrations of
the =N+H2 moiety at 1572–1535 cm–1. Stretching vibra-
tions due to the =N+H2 fragment were present as weak,
broad absorption bands at 2205–2216 cm–1.
The reaction time depends on the structure of the starting
acetylenes 2a–d: aliphatic acetylenes 2a,b underwent the
reaction in four hours, while in the case of acetylenes 2c,d
possessing cycloalkyl substituents, the reaction was com-
plete after two days. This was probably due to the steric
effects of the cyclic substituents in 2c,d, and also due to
the lower solubility of these acetylenes in water. Amino
acids 4a–d were obtained as light-yellow powders which
were highly soluble in water, methanol and ethanol, but
were insoluble in most organic solvents.
The zwitterionic structures of amino acids 4a–d follow by
analogy to the previously reported addition of glycine16
and 2-aminobenzoic acid17 to a,b-acetylenic g-hydroxy
nitrile 2a, where the transfer of positive charge to the
iminodihydrofuran ring was confirmed, unambiguously,
by single crystal X-ray structure analysis.
The spectroscopic data of adducts 4a–d [multinuclear 1H,
13C and 2D (HMBC) NMR, IR and UV] were in agree-
ment with the proposed structures. The 1H NMR spectra
of compounds 4a–d exhibited an alkene proton (H-4) sig-
nal at 4.63–4.76 ppm (Figure 1). The CH and CH2 protons
of the propanoyl chain appeared as three doublet of dou-
blets (three-spin ABX system) in the regions 4.06–4.10, An advantage of these modified tryptophans is the combi-
3.48–3.49 and 3.11–3.16 ppm, respectively. The aromatic nation of an indole amino acid and a 2,5-dihydro-5-imino-
protons were present as two doublets (7.61–7.67 and furanyl moiety in their structures. The dihydrofuran
7.20–7.29 ppm) and two doublet of doublets (6.99–7.06 moiety is present in numerous biologically active com-
and 6.98–7.06 ppm), or as a multiplet at 7.06 ppm (in the pounds, for example, tetronic acids and their thiol ana-
case of 4c), assigned to the benzene ring, and as a singlet logs,18 vitamin C,19 penicillic acid, and in anti-AIDS drugs
1
(7.05–7.08 ppm) due to the pyrrole moiety. In the H such as 1-(2¢,3¢-dideoxy-g-D-glyceropent-2-enofurano-
NMR spectrum of 4a in DMSO-d6, the NH (H-15) proton syl)thymine (d4T) and 1-[4-azido-5-(hydroxymethyl)tet-
of the indole and those of the =N+H2 fragment appeared at rahydrofuran-2-yl]-5-methylpyrimidine-2,4-(1H,3H)-dione
10.78 and 8.99 ppm, respectively. In the case of 4b, dou- (AZT).20 The dihydrofuran structural unit also occurs in
bling of the alkyl and alkene hydrogen signals, corre- cardenolides21 (cardioactive steroid lactones), dysidiolide
sponding to a 1:1 [R,R(S,S):R,S(S,R)] diastereomeric (the only known natural inhibitor of the protein phos-
mixture was observed. The 13C NMR spectra further con- phatase cdc25A22), as well as in many other natural mole-
firmed the structures of amino acids 4a–d. The carbon sig- cules such as sesquiterpenes23 and pulvinic acid
nals of the COO–, HN-C=CH and C=N+H2 groups were derivatives.24 In strigol and its analogs, the dihydrofura-
assigned using 1H–13C HMBC spectroscopy. The HMBC none unit is primarily responsible for the germination of
spectrum of adduct 4a showed cross peaks between the seeds.25
alkene proton (H-4) and the quaternary carbons at C-2 and
C-5 of the iminodihydrofuran ring, and between the meth-
yl group protons and carbon C-3 (Figure 2).
The starting a,b-acetylenic g-hydroxy nitriles 2a–d are
readily available compounds which are prepared from
acetylenic alcohols in two simple steps13e,26 (Scheme 1).
Synthesis 2010, No. 18, 3174–3178 © Thieme Stuttgart · New York

3176
B. A. Trofimov et al.
PAPER
3
3
2JAB = 14.9 Hz, JAX = 4.2 Hz, JBX = 9.4 Hz, 3 H, CH2CH), 1.52
R2
R2
Br2, NaOH, H2O
and 1.29 (s, 6 H, 2 × CH3).
R1
H
R1
Br
80–85%
1H NMR (400.13 MHz, DMSO-d6): d (selected resonances) = 10.78
OH
OH
(s, 1 H, H-15), 8.99 (br s, 2 H, =N+H2).
R2
CuCN, DMF
58–62%
13C NMR (100.62 MHz, CD3OD): d = 178.2 (COO–), 177.4 (HN-
C=CH), 176.7 (C=N+H2), 138.0 (C-14a), 128.9 (C-10a), 124.6,
122.4, 119.8, 119.4 (C-11, C-12, C-13, C-14), 112.3 (C-16), 111.7
(C-10), 92.2 (C-2), 76.6 (C-4), 63.7 (CH2CH), 29.5 (CH2CH), 25.0,
24.7 (2 × CH3).
R1
CN
2a–d
OH
R1, R2 = alkyl; R1–R2 = cycloalkyl
UV/Vis (EtOH): lmax (log e) = 222 (4.65), 273 (4.61), 291 (shoul-
der, 4.24), 372 nm (3.26).
Scheme 1 Synthesis of a,b-acetylenic g-hydroxy nitriles 2a–d
Anal. Calcd for C17H19N3O3: C, 65.16; H, 6.11; N, 13.41. Found: C,
65.40; H, 6.33; N, 13.38.
These powerful building blocks have attracted significant
attention in organic synthesis.13c,e,26b,27
2-[(2-Ethyl-5-iminio-2-methyl-2,5-dihydrofuran-3-yl)amino]-3-
(1H-indol-3-yl)propanoate (4b)
Light-yellow powder; yield: 314 mg (96%); mp 194–200 °C (dec.).
IR (KBr): 3500–2600 with peaks at 3397, 3249 (NH, =N+H2), 3056
(C=CH), 2973, 2931, 2876 (CH), 2205 (br w, =N+H2), 1700–1500
with peaks at 1680 (C=O), 1616 (C=C), 1570 (=N+H2) cm–1.
In summary, a new synthetic strategy for the chemical
modification of D,L-tryptophan into unnatural derivatives
containing a 2,5-dihydro-5-iminofuranyl moiety, and dis-
playing an unusual zwitterionic distribution (where the
most distal NH basic center is protonated) has been devel-
oped. The strategy involves the chemo- and regiospecific
addition of D,L-tryptophan to a,b-acetylenic g-hydroxy
nitriles in water under gentle heating. These unnatural
amino acids represent potential pharmaceuticals, and
promising building blocks and auxiliaries for drug design,
proteomics and controlled peptide modification.
1H NMR (400.13 MHz, CD3OD): d (1:1 mixture of diastereomers) =
7.67 and 7.64 (d, 3J = 8.0 Hz, 2 H, H-14), 7.29 (d, 3J = 8.3 Hz, 2 H,
H-11), 7.08 (s, 2 H, H-16), 7.06 (dd, 3J13–12 ~ 3J11–12 = 8.3 Hz, 2 H,
H-12), 6.99 (dd, 3J13–14 ~ 3J13–12 = 8.0 Hz, 2 H, H-13), 4.76 and 4.68
(s, 2 H, H-4), 4.09, 3.49, 3.15 (ABX, dd, 2JAB = 14.7 Hz, 3JAX = 3.8
3
Hz, JBX = 10.4 Hz, 3 H, CH2CH), 4.07, 3.49, 3.11 (ABX, dd,
3
3
2JAB = 14.7 Hz, JAX = 4.2 Hz, JBX = 9.4 Hz, 3 H, CH2CH), 1.90
and 1.74 (dq, 2J = 6.7 Hz, 3J = 7.3 Hz, 4 H, CH2CH3), 1.53 and 1.28
(s, 6 H, CH3), 0.77 and 0.32 (t, 3J = 7.3 Hz, 6 H, CH2CH3).
Melting points were obtained using a Kofler micro hot stage appa-
ratus. IR spectra were recorded using a Bruker Vertex-70 instru-
ment. 1H and 13C NMR spectra were recorded on a Bruker DPX-400
spectrometer in CD3OD or DMSO-d6 at room temperature. The
NMR signals were assigned using 2D NMR techniques (HMBC
1H–13C). 1H and 13C NMR assignments are made according to the
numbering system shown in Figure 1. UV/Vis spectra were mea-
sured on a Perkin-Elmer Lambda 35 spectrometer at room temper-
ature (EtOH, d = 0.1, 1.0 cm). Elemental analyses were performed
on a FLASH EA 1112 Series instrument. The reaction was moni-
tored by TLC on neutral Al2O3 (Merck) (eluent: CHCl3–benzene–
EtOH, 20:4:1). D,L-Tryptophan (1) was commercially available
(Merck). a,b-Acetylenic g-hydroxy nitriles 2a–d were prepared ac-
cording to the literature.26
13C NMR (100.62 MHz, CD3OD): d (1:1 mixture of diastereomers) =
177.9a (COO–), 177.0a (HN-C=CH), 176.8 and 176.7 (C=N+H2),
138.2 and 138.0 (C-14a), 128.9 and 128.7 (C-10a), 124.5, 124.4,
122.4,a 119.8,a 119.4, 119.3 (C-11, C-12, C-13, C-14), 112.3a (C-
16), 111.8 and 111.7 (C-10), 94.8a (C-2), 78.0 and 77.9 (C-4), 63.9
and 63.7 (CH2CH), 31.7 and 31.4 (CH2CH), 29.6 and 29.5
(CH3CH2), 23.9 and 23.5 (CH3), 7.3 and 6.8 (CH3CH2). a The car-
bon signals for the two diastereomers are equivalent.
UV/Vis (EtOH): lmax (log e) = 222 (4.50), 272 (4.42), 291 (shoul-
der, 4.06), 371 nm (3.44).
Anal. Calcd for C18H21N3O3: C, 66.04; H, 6.47; N, 12.84. Found: C,
65.95; H, 6.33; N, 13.03.
Amino Acids 4a–d; General Procedure
2-[(2-Iminio-1-oxaspiro[4.4]non-3-en-4-yl)amino]-3-(1H-indol-
3-yl)propanoate (4c)
Light-yellow powder; yield: 321 mg (95%); mp 164–166 °C (dec.).
IR (KBr): 3500–2600 with peaks at 3405, 3258 (NH, =N+H2), 3054
(C=CH), 2964, 2936, 2874 (CH), 2216 (br w, =N+H2), 1700–1500
with peaks at 1680 (C=O), 1617 (C=C), 1572 (=N+H2) cm–1.
A soln of NaOH (20 mg, 0.5 mmol) in H2O (2 mL) was added to a
suspension of D,L-tryptophan (1) (204 mg, 1.0 mmol) in H2O (5
mL), and the mixture heated at 40–45 °C. The appropriate acetylene
2a–d (1.0 mmol) was added and the resulting mixture stirred for 4
h (2a,b) or 48 h (2c,d). The H2O was evaporated, the residue filtered
through neutral Al2O3 [2–3 cm, eluent: 50–70 mL of hot EtOH (50–
60 °C)] and the solvent evaporated under reduced pressure to afford
amino acids 4a–d.
1H NMR (400.13 MHz, CD3OD): d = 7.61 (d, 3J = 7.7 Hz, 1 H, H-
14), 7.29 (d, 3J = 8.2 Hz, 1 H, H-11), 7.06 (m, 1 H, H-13), 7.05 (s,
1 H, H-16), 6.98 (dd, 3J13–12 ~ 3J11–12 = 8.0 Hz, 1 H, H-12), 4.72 (s,
2-[(5-Iminio-2,2-dimethyl-2,5-dihydrofuran-3-yl)amino]-3-
(1H-indol-3-yl)propanoate (4a)
Light-yellow powder; yield: 307 mg (98%); mp 232–236 °C (dec.).
2
3
1 H, H-4), 4.10, 3.49, 3.16 (ABX, dd, JAB = 15.0 Hz, JAX = 4.0
Hz, 3JBX = 9.2 Hz, 3 H, CH2CH), 2.00–1.60 [m, 8 H, (CH2)4].
13C NMR (100.62 MHz, CD3OD): d = 176.0 (COO–), 175.4 (HN-
C=CH), 174.3 (C=N+H2), 136.7 (C-14a), 127.6 (C-10a), 123.2,
121.1, 118.4, 118.0 (C-11, C-12, C-13, C-14), 110.9 (C-16), 110.4
(C-10), 100.7 (C-2), 76.6 (C-4), 62.3 (CH2CH), 37.6 (CH2CH),
37.1, 28.0, 24.2, 24.1 (4 × CH2).
IR (KBr): 3500–2600 with peaks at 3272, 3226 (NH, =N+H2), 3115,
3058 (C=CH), 2985, 2932, 2871 (CH), 1700–1500 with peaks at
1698 (C=O), 1618 (C=C), 1535 (=N+H2) cm–1.
1H NMR (400.13 MHz, CD3OD): d = 7.64 (d, 3J = 7.8 Hz, 1 H, H-
14), 7.20 (d, 3J = 8.1 Hz, 1 H, H-11), 7.08 (s, 1 H, H-16), 7.05 (dd,
3J13–14 ~ 3J13–12 = 7.8 Hz, 1 H, H-13), 7.00 (dd, 3J13–12 ~ 3J11–12 = 8.0
Hz, 1 H, H-12), 4.65 (s, 1 H, H-4), 4.08, 3.49, 3.15 (ABX, dd,
UV/Vis (EtOH): lmax (log e) = 223 (4.56), 274 (4.45), 291 (shoul-
der, 4.12), 375 nm (3.64).
Anal. Calcd for C19H21N3O3: C, 67.24; H, 6.24; N, 12.38. Found:
C, 67.40; H, 6.50; N, 12.28.
Synthesis 2010, No. 18, 3174–3178 © Thieme Stuttgart · New York

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Chemo- and Regiospecific Modification of D,L-Tryptophan
3177
2-[(2-Iminio-1-oxaspiro[4.5]dec-3-en-4-yl)amino]-3-(1H-indol-
3-yl)propanoate (4d)
Light-yellow powder; yield: 355 mg (95%); mp 194–196 °C (dec.).
1579. (c) Carlier, P. R.; Lam, P. C.-H.; Wong, D. M. J. Org.
Chem. 2002, 67, 6256. (d) Horton, D. A.; Bourne, G. T.;
Smythe, M. L. Chem. Rev. 2003, 103, 893; and references
cited therein. (e) de la Herrán, G.; Segura, A.; Csákÿ, A. G.
Org. Lett. 2007, 9, 961.
IR (KBr): 3500–2600 with peaks at 3371, 3219 (NH, =N+H2), 3114,
3049 (C=CH), 2930, 2865 (CH), 2212 (br w, =N+H2), 1700–1500
with peaks at 1687 (C=O), 1611 (C=C), 1562 (=N+H2) cm–1.
1H NMR (400.13 MHz, CD3OD): d = 7.62 (d, 3J = 7.7 Hz, 1 H, H-
14), 7.29 (d, 3J = 8.1 Hz, 1 H, H-11), 7.06 (dd, 3J13–12 ~ 3J11–12 = 8.0
Hz, 1 H, H-12), 7.05 (s, 1 H, H-16), 6.99 (dd, 3J13–14 ~ 3J13–12 = 7.7
Hz, 1 H, H-13), 4.63 (s, 1 H, H-4), 4.06, 3.48, 3.13 (ABX, dd,
2JAB = 14.9 Hz, 3JAX = 4.0 Hz, 3JBX = 9.3 Hz, 3 H, CHCH2), 1.80–
1.20 [m, 10 H, (CH2)5].
13C NMR (100.62 MHz, CD3OD): d = 176.9 (COO–), 176.3 (HN-
C=CH), 175.5 (C=N+H2), 136.8 (C-14a), 127.7 (C-10a), 123.3,
121.1, 118.5, 118.2 (C-11, C-12, C-13, C-14), 111.0 (C-16), 110.4
(C-10), 92.5 (C-2), 75.6 (C-4), 62.4 (CH2CH), 33.3 (CH2CH), 32.9,
28.2, 23.6, 21.6 (5 × CH2).
(4) Conigrave, A. D.; Quinn, S. J.; Brown, E. M. Proc. Natl.
Acad. Sci. U.S.A. 2000, 97, 4814.
(5) (a) Friedman, M.; Cug, J.-L. J. Agric. Food Chem. 1988, 36,
1079. (b) Lee, D. G.; Cho, N. J.; Choi, J. D. J. Biochem. Mol.
Biol. 1996, 29, 321. (c) Murch, S. J.; KrishnaRaj, S.;
Saxena, P. K. Plant Cell Rep. 2000, 19, 698. (d) Hirasawa,
M.; Nakayama, M.; Kim, S.-K.; Hase, T.; Knaff, D. B.
Photosynth. Res. 2005, 86, 325. (e) Bender, J.; Celenza, J.
L. Phytochem Rev. 2009, 8, 25.
(6) Somei, M.; Hattori, A.; Suzuki, N.(National University
Corporation, Kanazawa University, Japan, National
University Corporation, Tokyo Medical and Dental
University, Japan) WO 2007010723, 2007; Chem. Abstr.
2007, 146, 163392.
UV/Vis (EtOH): lmax (log e) = 222 (4.64), 273 (4.54), 291 (shoul-
der, 4.19), 375 nm (3.70).
(7) Walther, D.; Bader, M., (Max-Delbruck-Centrum fuer
Moleculare Medizin, Germany) WO 2002074309, 2002;
Chem. Abstr. 2002, 137, 242150.
Anal. Calcd for C20H23N3O3: C, 67.97; H, 6.56; N, 11.89. Found: C,
67.57; H, 6.50; N, 12.18.
(8) Watanabe, F., (Shionogi and Co., Ltd., Japan) US 6727266,
2001; Chem. Abstr. 2001, 135, 137709.
(9) (a) Ybarra, J.; Prasad, A. R. S.; Nishimura, J. S.
Biochemistry 1986, 25, 7174. (b) Tsubota, T.;Hagiwara, Y.;
Murakami, N.; Ohno, T. Diamond Relat. Mater. 2009, 18,
1174.
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Acknowledgment
This work was supported by the Russian Foundation for Basic Re-
search (Grant No. 08-03-00156), Presidium of RAS (Program 24),
Presidium of the Department of Chemical Sciences and Materials
RAS (Grant No. 5.1.3.) and Integration Projects No. 93, 5.9.
(11) (a) Seradj, H.; Cai, W.; Erasga, N. O.; Chenault, D. V.;
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