Tetrahedron Letters
Selectivity between N-1 and N-7 nucleosides: regioselective synthesis
of BMK-Y101, a potent cdk7 and 9 inhibitor
⇑
Young-Jong Kim, Soon Ho Kwon, Il Hak Bae, B. Moon Kim
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, South Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
BMK-Y101 is a new pyrrolo[2,3-d]pyrimidine-based potent cdk7 and 9 inhibitor, which is characterized
by an intriguing structural feature of N-1 nucleoside, departing from previously reported N-7 nucleoside
Cdk inhibitor, xylocydine. Though N-1 nucleosides have appeared in the literature, they have often been
considered as kinetic products and thus intermediates of N-7 glycosylation. In the course of the synthetic
studies of xylocydine derivatives, we have developed a highly regioselective method to obtain the N-1
nucleoside. The origin of the selectivity is apparently based on the reactivity of the silylated nucleobase
and the stability of the resulting N-1 nucleoside. The choice of BSA as a silylating agent was critical in
securing the N-1 nucleoside, BMK-Y101. On the other hand, proper selection of reaction conditions pro-
moting transglycosylation provides an efficient route to N-7 nucleosides.
Received 20 June 2013
Revised 23 July 2013
Accepted 26 July 2013
Available online 2 August 2013
Keywords:
Nucleosides
Cdk inhibitor
Regioselective
Pyrrolopyrimidine
Glycosylation
Ó 2013 Elsevier Ltd. All rights reserved.
Pyrrolo[2,3-d]pyrimidine nucleosides1 have been isolated from
nature and found both as monomers and as constituents of nucleic
acids.2,3 Due to their similarity to the purine structure, pyrrolo[2,3-
d]pyrimidine nucleosides are often called as 7-deazapurines
(throughout this discussion, systematic numbering is only used).
ester-type prodrug ibulocydine (4b) were identified as potential
candidates for preclinical evaluation against liver cancer (Fig. 1).
BMK-Y101 (4a) was first obtained as a minor N-1 glycosylation
product in the synthesis of xylocydine, which is an N-7 nucleo-
side.15,16 Typically N-1 nucleosides14,15,17,18 have been reported to
be unstable due to disrupted aromaticity within the purine sys-
tem,19,20 produced as intermediates during convergent nucleoside
synthesis under kinetically controlled conditions, and rearranged
to the thermodynamically more stable N-7 isomers.21 Most reports
on the synthesis of the N-1 nucleoside have been concerned with
SN2 type nucleophilic substitution reactions of bases with furano-
syl22–25 or alkyl halides26–28 under basic conditions. It was also
found in the reaction of chloromercury derivative of bases with
ribofuranosyl chloride,29 but only a few cases have been reported
on the syntheses of N-1 nucleosides employing bases and furanosyl
acetates in the presence of trimethylsilyl trifluoromethanesulfo-
nate (TMSOTf)30–32 as a Lewis acid under Vorbruggen conditions.
Since we were in need of a large quantity of BMK-Y101 for a ser-
ies of in vivo evaluations, we searched for an efficient and general
method for the synthesis of N-1 nucleosides. Since a majority of
synthetic efforts on pyrrolo[2,3-d]pyrimidine nucleosides has been
focused on the N-7 isomer, methods for selective N-1 nucleoside
synthesis have not been thoroughly explored. In the previous
A
number of natural and unnatural pyrrolo[2,3-d]pyrimidine
nucleosides have been reported, exhibiting antibacterial, anti-
fungal, antiviral, or anticancer activities.4,5 Toyocamycin (1) and
sangivamycin (2) are such deazapurine ribonucleosides, which
are produced from Streptomyces toyocaensis or Streptomyces
strains.6,7 They have been shown to inhibit RNA synthesis in mam-
malian cells.8 Due to high cell toxicity9 of toyocamycin, various
analogues of toyocamycin have been synthesized and evaluated
as anticancer and antiviral agents.10–13
Xylocydine (3), a xylose analogue of toyocamycin and sangiva-
mycin, was identified as a novel inhibitor of cyclin-dependent ki-
nases (cdks), especially cdk1 and cdk2/cyclin A activity (IC50 = 1.4
and 61 nM, respectively).14,15 However, low solubility in water,
low cell-permeability, and cytotoxicity of xylocydine hindered us
from further developing as an anti-tumor agent. Therefore we have
continued our efforts to investigate various xylocydine derivatives
for enhanced efficacy and selectivity, and desirable physicochemi-
cal properties. Among them, BMK-Y101 (4a), a structural isomer of
xylocydine, was identified as a potent cdk7 and 9 selective inhibi-
tor inducing apoptosis in hepatocellular carcinoma cells with no
apparent toxic side effects.16 Therefore compound 4a and its
synthesis of xylocydine, 1-O-acetyl-2,3,5-tri-O-benzoyl-L-xylofura-
nose (6) was used as the furanose counterpart for the
glycosylation, which was prepared in several steps.18 Rendle and
co-workers33 reported an efficient synthesis of furanosyl tetraace-
tates from hexoses or pentoses in a ‘one-pot’ procedure using boric
acid, and this method was applicable to glucose, idose, and xylose.
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Corresponding author. Tel.: +82 2 880 6644; fax: +82 2 872 7505.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.