10.1002/chem.201804285
Chemistry - A European Journal
COMMUNICATION
seemed promising because neighboring group participation from
2’-acetoxy group is expected. It should also be mentioned that
synthesizing 8 is still a great challenge in general, and
electrosynthetic method is a quite straightforward way to
constructing this skeleton. As summarized in Table 3, we could
finally obtain azanucleosides 7a-d in good yield and with
sufficient -selectivity. 7b was synthesized in dichloroethane at
the reflux temperature because it gave the desired N9-isomer
predominantly (entry 3). When the same reaction was carried
S. is grateful for a Grant-in-Aid for JSPS Research Fellow (No.
16J07350)
Keywords: Electrochemistry • C-H activation • Nucleoside
analogues • Anodic oxidation
[1]
[2]
a) G. Romeo, U. Chiacchio, A. Corsaro, P. Merino, Chem. Rev. 2010,
110, 3337-3370; b) D. Hernández, A. Boto, Eur. J. Org. Chem. 2014, 11,
2201-2220.
out in MeCN, undesired N7-isomer was predominantly generated
a) U. Chiacchio, L. Borrello, L. Crispino, A. Rescifina, P. Merino, B.
Macchi, E. Balestrieri, A. Mastino, A. Piperno, G. Romeo, J. Med. Chem.
2009, 52, 4054-4057; b) G. A. Kicska, L. Long, H. Hörig, C. Fairchild, P.
C. Tyler, R. H. Furneaux, V. L. Schramm, H. L. Kaufman, Proc. Natl.
Acad. Sci. USA. 2001, 98, 4593-4598; c) T. K. Warren, S. Bavari et al.,
Nature, 2014, 508, 402-405; d) V. Boldescu, M. A. M. Behnam, N.
Vasilakis, C. D. Klein, Nat. Rev. Drug. Discov. 2017, 16, 565-586; e) K.
H. Altmann, S. M. Freier, U. Pieles, T. Winkler, Angew. Chem. Int. Ed.
1994, 33, 1654-1657.
[14]
(entry 2).
One-pot synthesis of 7d after electrolysis via SHJ
reaction was also attempted. Although the yield was much lower
and no / selectivity was observed, presumably due to lithium
ions still working as a Lewis acid, the desired product was
obtained (Table 3, entry 6).
In conclusion, we have established an efficient route to
synthesize a variety of ribo-azanucleosides, including novel
compounds 4’-azaguanosine (7b) and 4’-azacytidine (7c) via a
key anodic oxidation step. A mechanistic study suggested that
acetate adduct 9 is the key intermediate in the presence of
AcOH under electrolysis, which is activated by lithium ions in the
electrolytic solution. Although a direct electrochemical approach
[3]
W. A. Fischer, P. Vetter, M. Jacobs et al., Lancet. Infect. Dis. 2018, 18,
e183-192.
[4]
[5]
[6]
K. Sridharan, N. J. Gogtay, Br. J. Clin. Pharmacol. 2016, 82, 659-672.
T. Shoji, S. Kim, K. Chiba, Angew. Chem. Int. Ed. 2017, 56, 4011-4014.
a) V. S. Korneeva, C. E. Cameron, J. Biol. Chem. 2007, 282, 16135-
16145; b) H. Nishimasu, F. A. Ran, P. D. Hsu, S. Konermann, S. I.
Shehata, N. Dohmae, R. Ishitani, F. Zhang, O. Nureki, Cell 2014, 156,
935–949.
gave the desired product in sufficient yields in the case of A(Bz)
,
G(Ib) and C(Bz), the desired -anomers were not enriched well.
We attributed this result to the coordination of lithium ions to the
acetoxy groups at the 2’-position, inhibiting neighboring group
participation. Thus, we changed our strategy to use an
electrochemical method to prepare hydroxy-substituted prolinols,
and then introduced them to the SHJ reaction. In this case, not
only -anomers were obtained with high selectivity, but also U
could be introduced due to improved solubility and
nucleophilicity under the SHJ condition.
[7]
a) E. J. Reist, D. E. Gueffroy, R. W. Blackford, L. Goodman, J. Org.
Chem. 1966, 31, 4025-4030; b) G. Rassu, L. Pinna, P. Spanu, F.
Ulgheri, G. Casiraghi, Tetrahedron. Lett. 1994, 35, 4019-4022.
a) S. Kim, T. Shoji, Y. Kitano, K. Chiba, Chem. Commun. 2013, 49,
6525-6527; b) Y. Okada, K. Chiba, Chem. Rev. 2018, 118, 4592-4630.
F. Cataldo, Eur. Chem. Bull. 2015, 4, 92-97.
[8]
[9]
[10] T. Nokami, A. Shibuya, H. Tsuyama, S. Suga, A. A. Bowers, D. Crich, J.
Yoshida, J. Am. Chem. Soc. 2007, 129, 10922-10928.
[11] D. R. Mootoo, P. Konradsson, U. Udodong, B. Fraser-Reid. J. Am.
Chem. Soc. 1988, 110, 5583-5584.
[12] M.
Miljković,
Carbohydrates:
Synthesis,
Mechanisms,
and
Stereoelectronic Effects, Springer, New York, 2010, pp. 239-240.
Acknowledgements
[13] Y. Imada., Y. Yamaguchi, N. Shida, Y. Okada, K. Chiba, Chem.
Commun. 2017, 53, 3960-3963.
[14] B. Golankiewics, T. Ostrowski, P. Leonard, F. Seela, Helv. Chim. Acta.
2002, 85, pp. 388-398.
This research was supported in part by JSPS KAKENHI through
a Grant-in-Aid for Scientific Research (B; 15H04494) to K. C. N.
This article is protected by copyright. All rights reserved.