Cyclin-dependent kinase (CDK) inhibitors: Development of a general strategy for the construction of 2,6,9-trisubstituted purine libraries. Part 3

Article abstract of DOI:10.1016/S0040-4039(01)01753-1

Experiments to effect Sonogashira (Ph₃P)₂Cl₂Pd-CuI-based coupling of 3-methylpentyn-3-ol at C-2 of a 2-iodo-6-thiopurine derivative, bound via the sulfur atom to a Merrifield resin failed. In contrast, the analogous reaction with Pd(dppe)Cl₂ and trans-di(μ-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium catalysts were successful (20-25%), indicating that (Ph₃P)₂Pd(0) loses its ligands irreversibly on contact with the resin bound purine. The coupling yield was improved considerably (58%) using a Merrifield resin in which a valeric acid linker is interposed between the purine and the resin.

Full text of DOI:10.1016/S0040-4039(01)01753-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8169–8171
Cyclin-dependent kinase (CDK) inhibitors: development of a
general strategy for the construction of 2,6,9-trisubstituted purine
libraries. Part 3
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—Experiments to effect Sonogashira (Ph3P)2Cl2Pd–CuI-based coupling of 3-methylpentyn-3-ol at C-2 of a 2-iodo-6-thio-
purine derivative, bound via the sulfur atom to a Merrifield resin failed. In contrast, the analogous reaction with Pd(dppe)Cl2 and
trans-di(m-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium catalysts were successful (20–25%), indicating that (Ph3P)2Pd(0)
loses its ligands irreversibly on contact with the resin bound purine. The coupling yield was improved considerably (58%) using
a Merrifield resin in which a valeric acid linker is interposed between the purine and the resin. © 2001 Elsevier Science Ltd. All
rights reserved.
In the two preceding communications we described the
first stages in the development of a solid-phase synthe-
sis strategy for the construction of 2,6,9-trisubstituted
purine libraries of CDK inhibitors based upon the
reactivity of a 6-thio substituted purine scaffold.1–8 The
objective is to develop methodology which will permit
sequential introduction of substituents at the N-9, C-2
and C-6 positions of the purine ring on the solid phase.
This strategy was validated in solution and subse-
quently applied to the synthesis of a small library of
purines bearing amine functionality at the 2,6-positions.
Herein, the Sonogashira Pd(0)–CuI palladium coupling
of acetylenes to the C-2 position of 2-iodo-6-thiopurine
bound resins is described. The success of this reaction is
crucial to SAR studies on a family of potent 2-
acetylenylpurine based CDK1/CDK2 inhibitors cur-
rently under investigation in our laboratory.9,10
mation of purine 3 would be problematic. Indeed, the
reaction of 3 [Merrifield resin; 35–75 mm; 1 mmol/g]
under conditions ranging from those used to prepare 2
[20% Cl2(Ph3P)2Pd-5% CuI] up to those in which
greater than 1 equiv. of the palladium reagent and a
large excess of CuI and the acetylene were employed
did not proceed (Scheme 1). In each case the resin
rapidly turned black, indicating that palladium metal
was precipitating onto the resin surface. Furthermore,
we were unable to demonstrate that coupling even
partially occurred, as the purine product/starting mate-
rial was not recovered after carrying out the two-step
procedure (S-oxidation and reaction with benzylamine)
used for product release.1,2 However, in subsequent
experiments in which the more strongly coordinating
bidentate phosphine ligand ‘dppe’ was employed, only
slight coloration of the resin was observed, and com-
pound 4 was isolated in 25% overall yield. This reaction
was further improved upon in terms of the amount of
palladium reagent, CuI and acetylene employed using
trans-di(m-acetato)bis[o-(di-o-tolylphosphino)benzyl]-
dipalladium(II) (Strem) catalyst under conditions
described by Finn12 for a Stille reaction. From these
results it was clear that in the resin bound reaction
using (Ph3P)2Cl2Pd the active catalyst was losing its
phosphine ligands in an irreversible manner, causing
the metal to fall out of solution. It is known that Pd(0)
complexes to purines via the heteroatom at C-6 and the
N-7 nitrogen.13 In solution the equilibrium would be
displaced to the left, but on the solid phase it is
envisaged that initial complexation of the catalyst with
In the model study using a 2-iodo-6-thiobenzylpurine
derivative 1 this transformation was found to give 2 in
80% yield. However, although there is an increasing
number of palladium(0) reactions which have been
adapted to the solid phase, the efficiency of these
processes appear in many cases to be dependent upon
the nature of the resin/linker, and require the use of
large quantities of palladium ‘catalyst’.11 We were thus
prepared for the eventuality that the desired transfor-
* Corresponding author. Fax: 33 (0) 169 86 30 85; 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)01753-1

8170
V. Brun et al. / Tetrahedron Letters 42 (2001) 8169–8171
Scheme 1.
the purine in 3 would result in facile loss of the phos-
phine ligands (steric decompression), and that subse-
quent interaction of the phosphines with the
purine–palladium complex 5 would be a more energy
expensive process due to the more crowded environ-
ment. By using the two other catalysts, and in particu-
lar Pd(dppe)Cl2 there is less of a tendency for the
palladium to complex the purine.
More interestingly, the corresponding reaction using a
catalytic quantity of Herrmann’s catalyst19 (20 mol%
based on 718) was equally efficient, as compound 10 was
isolated in 50% yield after the three sequential
operations.
These experiments to optimize the Sonogashira cou-
pling to prepare 2-acetylenyl substituted purines
brought to light the nature of the factors that compli-
cate this process on the simple 6-thiobenzyl linked
Merrifield resin. They further demonstrated the advan-
tage in incorporating a linker between the resin and the
purine substrate. Further development of our approach
to purine libraries using solid-phase methodology is in
progress.
To diminish the effect of steric crowding on the yield of
the coupling reaction the 6-chloro-2-iodopurine sub-
strate 6 was connected to the Merrifield-Cl resin (35–75
mm; 1 mmol/g) in two steps via a 5-thiovaleric acid14,15
linker (Scheme 2). Recent work by Waldman et al. has
demonstrated the efficacy of such linkers on Pd(0)-cata-
lyzed reactions.16 After condensation of intermediate 7
to the resin via Cs2CO3 promoted ester formation,17,18
the resin bound substrate 8 was reacted with 3-methyl-
1-pentyn-3-ol using the Pd(dppe)Cl2–CuI system. By
cleavage of the coupling product 9 from the resin via
S-oxidation with m-CPBA and reaction of the derived
sulfone with p-methoxybenzylamine, the trisubstituted
purine derivative 10 was isolated in 58% overall yield.
Acknowledgements
This work has been generously financed by ARC (Asso-
ciation pour la Recherche sur le Cancer, Grant no.
5713), and by a MENRT scholarship for V.B.

V. Brun et al. / Tetrahedron Letters 42 (2001) 8169–8171
8171
Scheme 2.
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