TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2479–2482
A novel 13 C-branched isocyanate monomer for resin
amplification—a pseudo PS-PEG high-loading resin
Sylvain Lebreton,a Nicholas Newcombeb and Mark Bradleya,*
aDepartment of Chemistry, University of Southampton, Southampton, Hampshire SO17 1BJ, UK
bAstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
Received 13 November 2001; revised 1 February 2002; accepted 8 February 2002
Abstract—High loading resins (up to 120 nmoles/bead) were preprared by solid-phase dendrimerisation using a novel 13
C-branched isocyanate monomer. © 2002 Published by Elsevier Science Ltd.
1. Introduction
the branching centre and the protected amine.7
Although these proved to work efficiently as a means of
bead-loading enhancement, limitations included the
beads mechanical instability towards Boc removal with
TFA and slow kinetics at high dendrimer generations.
A new isocyanate monomer was designed to increase
the flexibility of the structure. It was anticipated that
this would render reactive sites on the resin more
accessible, therefore allowing higher loadings to be
reached as well as speeding up reaction rates. The
design of the new monomer was supported by observa-
tions made by Newkome et al. who reported a signifi-
cant drop in reactivity when constructing 13
C-branched polyols by triester amidation with 1,1,1-
tris(hydroxymethyl)aminomethane.3 It was observed
that the use of an appropriate spacer (>3 atoms)
between the branching point and the reactive centres
was necessary for dendrimer growth due to steric hin-
drance associated with the carbon centre. The
monomer 5 was therefore synthesised where the chain
length was increased to five atoms (Scheme 1).
Dendritic molecules are highly-branched arborescent
structures which have found applications in many areas
of chemistry.1 Over the past twenty years, an increasing
number of diverse dendrimers have been reported based
on an alteration of structural parameters such as
monomer multiplicity, the distance between successive
branching centres or the flexibility of the structure.2 In
1985, Newkome et al. reported the first example of
divergently constructed dendrimers utilising sp3-carbon
atoms as 13 branching centres.3 These dendritic
assemblies were of great interest due to the high multi-
plicity of branching, but their growth was often found
to be difficult due to steric congestion. As a result, new
13 C-branching monomers were designed as building
blocks for use in the rapid growth of dendritic macro-
molecules.4 Isocyanate-based monomers possessing a
triad of protected functional groups have emerged as
promising candidates for such a task. The isocyanate
moiety allows simple connectivity while the protected
moieties prevent side-reactions.5
The synthesis started with three Michael additions of
1,1,1-tris(hydroxymethyl)aminomethane onto acryloni-
trile in the presence of aqueous potassium hydroxide to
yield the tris(nitrile)amine 1 in 64% yield. The amine
was protected as the benzylcarbamate. Reduction of the
nitrile groups with borane–THF complex afforded the
triamine, which was reacted crude with Boc2O to afford
the tert-butoxycarbonyl-protected triamine 3 in 37%
yield. Removal of the benzyloxycarbonyl group by
hydrogenation gave the tri-(t-butylcarbamate)amine 4
in 92% yield. DMAP-induced isocyanation of the
amine, using a stoichiometric amount of DMAP and
Boc2O, gave the isocyanate 5 in 91% yield.8
2. Results and discussion
In a project aimed at the synthesis of high-loading resin
beads,6 the utilisation of such monomers for rapid
solid-phase dendrimer synthesis appeared attractive. In
the preceding paper7 we reported on the use of a 13
C-branched isocyanate monomer possessing three tris-
(Boc) protected amines with a 3-atom spacer between
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(02)00295-2