Cyclin-dependent kinase (CDK) inhibitors: Development of a general strategy for the construction of 2,6,9-trisubstituted purine libraries. Part 1

Article abstract of DOI:10.1016/S0040-4039(01)01751-8

To validate a proposed solid support synthesis strategy for the construction of 2,6,9-trisubstituted purine based CDK inhibitors, the N-9 THP protected 6-benzylthio-2-iodopurine 11 was reacted with piperidine-2-methanol to give 12. Alternatively, intermediate 11 was converted to the C-2 acetylenyl substituted purine 16 in five steps, involving N-9 alkylation (Mitsunobu reaction), a Pd(0)-CuI-catalyzed acetylene coupling, selective activation of the 6-sulfur substituent and its displacement by ArCH₂NH₂.

Full text of DOI:10.1016/S0040-4039(01)01751-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8161–8164
Cyclin-dependent kinase (CDK) inhibitors: development of a
general strategy for the construction of 2,6,9-trisubstituted purine
libraries. Part 1
Virginie Brun, Michel Legraverend* and David S. Grierson
Laboratoire de Pharmacochimie UMR 176 CNRS-Institut Curie, Bat 110 Centre Universitaire, 91405 Orsay, France
Received 2 August 2001; accepted 13 September 2001
Abstract—To validate a proposed solid support synthesis strategy for the construction of 2,6,9-trisubstituted purine based CDK
inhibitors, the N-9 THP protected 6-benzylthio-2-iodopurine 11 was reacted with piperidine-2-methanol to give 12. Alternatively,
intermediate 11 was converted to the C-2 acetylenyl substituted purine 16 in five steps, involving N-9 alkylation (Mitsunobu
reaction), a Pd(0)–CuI-catalyzed acetylene coupling, selective activation of the 6-sulfur substituent and its displacement by
ArCH2NH2. © 2001 Elsevier Science Ltd. All rights reserved.
Cell proliferation is a consequence of (+)-signals
which promote cell division (growth factors, etc.), and
(−)-signals which suppress this process (tumor sup-
pressor factors). Key actors in this signaling cascade,
which play the central role in the ultimate step of
DNA synthesis and cell division (mitosis) are a series
of cyclin dependent kinases (CDKs) (CDK1, 2, 4 and
6). Following the discovery that the purine derivatives
olomoucine 1 and roscovitine 2 are selective ATP
competitive inhibitors of CDK1, CDK2 and CDK5/
cyclin complexes1–4 a great deal of effort has been
devoted to finding other more potent and specific
inhibitors of the CDKs, and in particular inhibitors
of CDK4 and CDK6. Second generation purine
based compounds include purvalanol 35 and the
diaminocyclohexanes 4 and 5 developed by Novartis6
and Hoechst Marion Roussel,7 respectively. Results
from our laboratory have shown that purine systems
such as 6a,b, substituted at C-2 by an acetylene motif
are also amongst the most active CDK1/CDK2
inhibitors known to date.8,9
inhibitors.4,5,10–16 Relatively large libraries, in some
cases up to several thousand members, have been
generated in this way. However, none of these
approaches permit the sequential introduction of
functionality, while on the resin, onto all three crucial
positions on the purine ring. This essentially results
from the problem of orchestrating properly the much
greater reactivity of the C-6 center in 2,6-dihalopuri-
nes relative to the 2-position. This situation can be
circumvented, albeit with a loss in synthetic flexibility/
diversity, by condensation of the amine component to
be introduced at C-6 onto the resin before attachment
of the purine.
To devise a more general strategy on solid support
for the synthesis of 2,6,9-trisubstituted purine libraries
we envisaged that the system wherein the purine scaf-
fold is connected to the resin via a CarbonꢀSulfur
bond at C-6 would offer a number of distinct advan-
tages. The important feature of such an approach is
that the low reactivity of the purine C6ꢀS bond
would provide the possibility to introduce a wide
variety of functionality at the N-9 and C-2 positions
prior to reaction at C-6. Subsequent activation of the
sulfur atom (oxidation, alkylation, etc.), as already
reported in pyrimidines,17,18 would then open the way
to concomitant introduction of a substituent (nucleo-
phile) at C-6 and cleavage of the trisubstituted purine
product from the resin.
To facilitate SAR studies several solid phase strategies
have been developed for the construction of 2,6,9-
trisubstituted purine based libraries of CDK
* Corresponding author. Fax: +33-169-863085; e-mail: michel.
legraverend@curie.u-psud.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01751-8

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V. Brun et al. / Tetrahedron Letters 42 (2001) 8161–8164
As for the development of any solid support synthesis
strategy, it was necessary to first validate the synthetic
plan in solution. Toward this end (Scheme 1), the
reaction of 6-chloropurine 7 with dihydropyran/H+,
followed by treatment of the derived N-9 THP deriva-
tive 819 with strong base and n-Bu3SnCl according to
Tanaka et al. proved to be a convenient high yielding
three step route to the N-9 THP protected 6-chloro-2-
iodopurine 10.20,21 Condensation of 10 with benzyl thiol
occurred under mild conditions to give the C-6 sulfur
substituted purine 11 (82%). This key transformation
served to mimic the attachment of compound 10 to a
resin support. In the first of the transformations we
ultimately want to achieve on solid support, purine 11
was reacted in DMA at 110°C with piperidine-2-
methanol as a representative secondary-amine. No
undesired reaction at the C-6 sulfur substituted center
was observed, as compound 12 was isolated in essen-
tially quantitative yield.
strongly suggested that the corresponding cleavage of a
sulfone intermediate from a resin support will be simi-
larly efficient. It was not immediately obvious that the
oxidation method for sulfur activation in 14 could be
transposed to the corresponding activation of com-
pound 12. However, the difference in reactivity of the
sulfur and nitrogen atoms in this molecule was suffi-
ciently large to permit formation of 17 in high yield.
Overall, the condensation of 2-iodo-6-chloropurine
derivative 10 with benzyl thiol, and the sequential intro-
duction of the 9-iso-propyl group, an acetylene function
at C-2 and a benzylamine motif at C-6 was achieved in
six steps. With the exception of the Mitsunobu based
alkylation at N-9, which requires further optimization,
the remaining operations, including those to obtain
compounds 12 and 17, all proceeded in high yield.
Having shown that the major reactions to be trans-
posed onto solid phase all proceed in high yield in
solution, the next stage was thus set for the study of the
construction of 2,6,9-trisubstituted purine libraries
using a resin bound 6-thio substituted purine intermedi-
ate analogous to 11 as the starting scaffold. The results
of this work, oriented respectively toward the prepara-
tion of purine libraries bearing an amine function or an
acetylene motif at C-2, are presented in the two follow-
ing communications.24
In the next operation, N-deprotection of 11 (50% TFA,
rt) and Mitsunobu reaction22 of the liberated amine
with isopropanol gave the N-9 alkylated product 13
(60%), as the sole product. Introduction of the acetyl-
ene unit to give 14 was then achieved by reaction of
intermediate 13 with 3-butyn-1-ol in the presence of
Pd(0) 20% CuI 5% at 20°C for 5 h. The success of this
Sonogashira coupling was crucial to our strategy, and it
was satisfying to again observe that the 6-benzylthio
substituent was unreactive under these conditions.
Selective activation of the sulfur atom was then
achieved by oxidation of 14 with predried m-CPBA in
CH2Cl2. Final reaction of sulfone 15 with p-chloroben-
zyl amine also occurred very readily, resulting in loss of
the sulfur substituent and quantitative conversion to
the target 2,6,9-trisubstituted purine product 16.23 The
ease with which this transformation could be effected
Acknowledgements
This work has been generously financed by ARC (Asso-
ciation pour la Recherche sur le Cancer, Grant no.
5713), and by an MENRT scholarship for V.B.

V. Brun et al. / Tetrahedron Letters 42 (2001) 8161–8164
8163
Scheme 1.
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