Novel synthetic routes to N-(2-amino-9H-purin-6-yl)-substituted amino acids

Article abstract of DOI:10.1016/j.mencom.2013.12.011

Reaction of N²-protected 2-amino-6-chloropurine with tert-butyl (S)-phenylalaninate, (R)- and (S)-valinates followed by deprotection affords 2-aminopurines bearing at 6-position the corresponding amino acid moieties, whose chiral centre is part

Full text of DOI:10.1016/j.mencom.2013.12.011

Mendeleev
Communications
Mendeleev Commun., 2014, 24, 35–36
Novel synthetic routes to N-(2-amino-9H-purin-6-yl)-substituted amino acids
Alexey Yu. Vigorov, Viktor P. Krasnov,* Dmitry A. Gruzdev, Alisa A. Men’shikova,
Alexander M. Demin, Galina L. Levit and Valery N. Charushin
I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
620990 Ekaterinburg, Russian Federation. Fax: +7 343 369 3058; e-mail: ca@ios.uran.ru
DOI: 10.1016/j.mencom.2013.12.011
Reaction of N2-protected 2-amino-6-chloropurine with tert-butyl (S)-phenylalaninate, (R)- and (S)-valinates followed by deprotection
affords 2-aminopurines bearing at 6-position the corresponding amino acid moieties, whose chiral centre is partially racemized.
Cl
Currently a lot of attention is paid to the synthesis and study of
nucleoside analogues, among which the compounds exhibiting
antiviral and anticancer activity have been found.1–3 For instance,
Nelarabine [2-amino-9-(b-d-arabinofuranosyl)-6-methoxy-9H-
purine]4 and Fludarabine [9-(b-d-arabinofuranosyl)-2-fluoro-
adenine]5 are used for treatment of lymphoblastic leukemias.
Modification of various biologically active compounds by
introduction of amino acid moieties into their structure is one of
the most important approaches to achieve the optimal pharmaco-
kinetic and pharmacodynamic characteristics of potential drugs.6–14
The 9H-purine-based nucleoside analogues with amino acids
fragments exhibit cytostatic,15 antimicrobial16 and antiviral17,18
activity. The published synthetic routes to such compounds are
based on the introduction of amino acid residues in N9-substituted
purines.15,16,19,20 This approach makes it impossible to vary the
structures of substituents in 9-position of purine fragment.
The purpose of this study was to develop the synthetic routes
to the purine derivatives containing amino acid residues at C6-
position. Particular attention has been given to the preparation
of purine derivatives with free functional groups in the amino
acid and purine moieties available for further modification.
Attempted reactions of 2-amino-6-chloro-9H-purine 1 with
tert-butyl (S)-phenylalaninate [(S)-PheOBut], (R)-valinate [(R)-
ValOBut] and (S)-valinate [(S)-ValOBut] as well as methyl (S)-
phenylalaninate [(S)-PheOMe] [Et3N as the base, N,N-dimethyl-
acetamide (DMA), 100°C] did not afford the target products.
Probably, a positive mesomeric effect of amino group at C2 atom
deactivated the purine derivative to attack by nucleophiles.21
Therefore, we turned to N2-protected 2-amino-6-chloropurines
2–5, such as N-acetyl, N-formyl, N-Boc and N-trifluoroacetyl
derivatives. Reactions of compounds 2–5 with (S)-PheOBut hydro-
chloride were carried out at a 1:3 molar ratio in the presence
of Et3N in DMA at 100°C for 12 h (Scheme 1). In the case of
N-acetyl derivative 2 the product of nucleophilic substitution
of chlorine; compound 7,† was isolated as acetate in 63% yield.
1 R = H
2 R = C(O)Me
3 R = CHO
N
N
4 R = C(O)OBut
5 R = C(O)CF3
R
N
H
N
N
H
Reactions of derivatives 3–5 with (S)-PheOBut hydrochloride
under the same conditions were accompanied by the removal of
N2-protection resulting in tert-butyl N-(2-amino-9H-purin-6-yl)-
(S)-phenylalaninate 8‡ in 40, 35, and 50% yields, respectively.
Methyl (S)-phenylalaninate proved to be less suitable for
the preparation of N-(2-amino-9H-purin-6-yl) derivatives. For
example, the nucleophilic substitution of chlorine in compound
2 under the action of (S)-PheOMe was complicated by formation of
the corresponding diketopiperazine derivative as by-product.22
To obtain the unprotected C6-derivatives of 2-amino-9H-purine,
we carried out the hydrolysis of tert-butyl N-(2-acetamido-9H-
CO2But
NH
CO2But
NH
Ph
Ph
ii
i
2
N
N
N
N
·
AcOH
N
H
N
H
AcHN
N
AcHN
N
6
7
63% (2 steps)
CO2But
3
Ph
40%
NH
i
4
5
N
35%
50%
N
N
H
H2N
N
8
Scheme 1 Reagents and conditions: i, (S)-PheOBut·HCl, TEA, DMA,
100°C, 12 h; ii, AcOH, hexane.
†
tert-Butyl N-(2-acetylamino-9H-purin-6-yl)-(S)-phenylalaninate acetate
7: colourless crystals, mp 118–125°C, [a]D20 –2.85 (c 1.0, CHCl3). 1H NMR
(DMSO-d6, 100°C) d: 1.34 (s, 9H, But), 1.90 (s, 3H, MeCO2H), 2.25 (s,
3H, MeCO), 3.21 (d, 2H, CH2-Phe, J 6.5 Hz), 5.10 (br.s, 1H, CH-Phe),
6.92 (br.s, 1H, C6'NH), 7.17 (m, 1H, Ph), 7.25 (m, 4H, Ph), 7.90 (s, 1H,
C8' H), 9.16 (s, 1H, NHAc), 11.99 (br.s, 2H, N9'H, MeCO2H). 13C NMR
(DMSO-d6) d: 20.96 (MeCO2H), 24.61 (MeCONH), 27.47 (CMe3), 36.53
(CH2-Phe), 54.95 (CH-Phe), 80.61 (CMe3), 115.75 (C5'), 126.31 (p-Ph),
128.08 (o-Ph), 129.11 (m-Ph), 137.78 and 138.39 (C8' and i-Ph), 150.70
and 152.39 (C4' and C2'), 153.81 (C6'), 169.40, 171.12 and 171.88 (C=O
in AcNH, AcOH and CO2But). Found (%): C, 58.06; H, 6.12; N, 18.60.
Calc. for C22H28N6O5 (%): C, 57.89; H, 6.18; N, 18.41.
‡
tert-Butyl N-(2-amino-9H-purin-6-yl)-(S)-phenylalaninate 8: yellowish
powder, mp 123°C, [a]D25 –4.54 (c 1.0, CHCl3). 1H NMR (DMSO-d6) d:
1.33 (s, 9H, But), 3.03–3.23 (m, 2H, CH2-Phe), 4.77 (br.s, 1H, CH-Phe),
5.69 (s, 2H, C2'NH2), 7.03 (br.s, 1H, C6'NH), 7.20 (m, 1H, Ph), 7.24–7.31
(m, 4H, Ph), 7.68 (s, 1H, C8'H), 12.12 (br. s, 1H, N9'H). 13C NMR
(DMSO-d6) d: 27.52 (CMe3), 36.97 (CH2-Phe), 54.63 (CH-Phe), 80.46
(CMe3), 112.68 (C5'), 126.31 (p-Ph), 128.07 (o-Ph), 129.16 (m-Ph), 135.89
(C8'), 137.72 (i-Ph), 152.46 and 153.75 (C4' and C2'), 159.66 (C6'), 171.36
(CO2But). HRMS, m/z: 355.1877 [M+H]+ (calc. for C18H23N6O2, m/z:
355.1882).
© 2014 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2014, 24, 35–36
purin-6-yl)-(S)-phenylalaninate acetate 7 in 1 n NaOH at 60°C
The enantiomeric excess (ee) of compounds (R)-11 and (S)-11
was 81 and 86%, respectively, according to the chiral HPLC.
The structures of the compounds obtained were confirmed
(Scheme 2). Under these conditions the simultaneous removal
of both N2-acetyl and tert-butyl ester group occurred to yield
N-(2-amino-9H-purin-6-yl)-(S)-phenylalanine 9.§
1
by the H and 13C NMR spectroscopy, elemental analyses (or
HRMS) and LC-MS.
CO2But
NH
CO2H
NH
In conclusion, the prepared N-(2-amino-9H-purin-6-yl) deriva-
tives of amino acids, which are not substituted at N9-position,
can be suitable for further synthesis of novel nucleosides thereof.
The starting material is readily available 2-amino-6-chloropurine.
Ph
Ph
1 N NaOH
60 °C, 3 h
N
N
N
N
·
AcOH
N
H
N
H
AcHN
N
H2N
N
The authors are grateful to Dr. A. A. Tumashov and M. S.
Toporova for performing HPLC analyses, Dr. I. N. Ganebnykh for
registration of LC-MS spectra, and Dr. M. I. Kodess for registra-
tion of NMR spectra. This work was supported by the Russian
Foundation for Basic Research (grant no. 12-03-33029), the Ural
Branch of the Russian Academy of Sciences (grant no. 12-P-3-1030)
and the State Program for Supporting of Leading Scientific Schools
of the Russian Federation (grant no. NSh-5505.2012.3).
7
9 (61%)
Scheme 2
This approach is also suitable for the synthesis of other
N-(2-amino-9H-purin-6-yl) amino acids, e.g., N-(2-amino-9H-
purin-6-yl)-(R)- and (S)-valines, (R)-11 and (S)-11 (Scheme 3).¶
Preparation of compounds (R)-11 and (S)-11 starting from com-
pound 2 and (R)- or (S)-valinates 10, respectively, made it possible
to evaluate the degree of racemization of the chiral center in the
amino acid moiety that occurred during the two-step process.
Online Supplementary Materials
Supplementary data associated with this article (details of
synthetic procedures and characteristics of compounds) can be
found in the online version at doi:10.1016/j.mencom.2013.12.011.
Me
Me
CO2But
NH
CO2H
NH
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Me
Me
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H2N
N
(S)-10
(S)-11
Scheme 3 Reagents and conditions: i, (R)- or (S)-ValOBut·AcOH, TEA,
DMA, 100°C, 12 h; ii, 1 n NaOH, 60°C, 3 h.
§
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7.00 (br.s, 1H, C6'NH), 7.17 (m, 1H, Ph), 7.26 (m, 4H, Ph), 7.67 (s, 1H,
C8'H), 12.2 (br.s, 2H, N9'H and CO2H). 13C NMR (DMSO-d6) d: 36.57
(CH2-Phe), 53.77 (CH-Phe), 112.23 (C5'), 126.26 (p-Ph), 128.09 (o-Ph),
129.07 (m-Ph), 135.94 (C8'), 138.06 (i-Ph), 152.22 (C4'), 153.79 (C2'),
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¶
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J 6.8 Hz), 0.97 (d, 3H, Me-Val, J 6.7 Hz), 2.22 (m, CbH-Val), 4.64 (br.s,
1H, CaH-Val), 5.86 (s, 2H, NH2), 6.68 (br.s, 1H, C6'NH), 7.75 (s, 1H,
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272°C (decomp.), ee 86%. Chiral RP HPLC [ChiraDex, MeCN–H2O
(8:2), 0.8 ml min–1] tR: 6.8 min. NMR spectra were identical to those for
compound (R)-11.
Received: 19th August 2013; Com. 13/4187
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