Polymer backbone disassembly: Polymerisable templates and vanishing supports in high loading parallel synthesis

Article abstract of DOI:10.1039/a806331a

In the synthesis of a library of N-alkyl-3-aza-8-oxabicyclo[3.2.l]octane-6,7-dimethanol derivatives, prepared from an 7-oxabicyclo[2.2.1]hept-2-ene-5,6-dimethanol derivative via ring opening metathesis polymerisation using Cl₂(Cy₃P)<

Full text of DOI:10.1039/a806331a

Polymer backbone disassembly: polymerisable templates and vanishing
supports in high loading parallel synthesis
Christopher P. Ball, Anthony G. M. Barrett,* Lydie F. Poitout, Marie L. Smith* and Zoë E. Thorn
Department of Chemistry, Imperial College of Science, Technology and Medicine, London, UK SW7 2AY.
E-mail: m.stow@ic.ac.uk
Received (in Liverpool, UK) 7th August 1998, Accepted 6th October 1998
In the synthesis of a library of N-alkyl-3-aza-8-oxabi-
X
X
X
cyclo[3.2.1]octane-6,7-dimethanol derivatives, prepared
from an 7-oxabicyclo[2.2.1]hept-2-ene-5,6-dimethanol
derivative via ring opening metathesis polymerisation using
Cl2(Cy3P)2RuNCHPh, selective alkylation, ozonolytic scis-
sion of the polymer backbone and reductive alkylation,
purification was facilitated by the differential solubility of
the polymer intermediates.
ROMP
modification
n
n
1
2
Y-X
Y-X
Y-X
cleavage
n
The emergence of combinatorial methodologies and parallel
syntheses have dramatically accelerated synthetic chemistry
and the quest for novel pharmaceuticals and other specialty
chemicals.1 Many state-of-the-art parallel syntheses rely upon
polymer-supported procedures in which the substrate is at-
tached to a support throughout a synthetic sequence. Assay is
either carried out on the support or following late release. Such
supported syntheses are aided by the ‘polymer advantage’
which allows (i) solid phase reactions to be driven to completion
by the addition of excess solution phase reagents which are
simply removed by filtration techniques and (ii) the separation
of reaction products from the polymer post-cleavage. There is
clear merit in maximising substrate loading so that for any given
synthesis, sufficient substrate is produced at a minimum resin
weight such that compound authentication, bioassay and
compound archiving are facilitated. As such there is need to
maximise the loadings yet to also facilitate on-support analysis.
The use of PEG supports clearly addresses the need for easy
solution-based analyses but these supports are not ideal in terms
of loadings. On the other hand, the preparation of polymer
supported dendritic materials2 leads to improved loadings yet
does not greatly facilitate analysis. The use of insoluble
polymers often necessitates the utilisation of time-consuming,
non-standard analytical techniques, e.g. solid state NMR
spectroscopy, in order to determine the character of the
polymer-bound substrates.
A
B
n
3
4
Scheme 1
polymers may be precipitated by the correct choice of solvent to
afford solids which can be washed to remove excess reagents. In
this respect ROMP polymers show similar behaviour to the
PEG polymers recently further developed by Janda et al.,4 after
the pioneering work by Bayer, Mutter and Shemyakin.5
Norbornene, 7-oxanorbornene and cyclobutene ROMP mon-
omers containing functional groups which are either hydro-
philic or hydrophobic in nature are readily available and many
offer the opportunity for post-polymerisation chemical mod-
ification required for library generation. 7-Oxanorbornene 6
was chosen for initial study as depicted in Scheme 2. The
monomer 6 is readily prepared from diol 5 via mono-silylation
followed by tetrahydropyranyl protection. The use of orthogo-
nal protecting groups6 allows for a stepwise hydroxy group
modification strategy to be utilised in library synthesis.
Polymerisation of 6 using the Grubbs catalyst 137 and chain
PCy3
Cl
Ph
Ru
H
Cl
PCy3
Herein, we report the concept of polymer backbone dis-
assembly for the preparation of synthetic libraries. In this
approach the substrate is also the monomer building block for
the polymer. As such the polymer loading should ideally
approach quantitative. The polymerisation of an appropriate
monomer (starting material) to form an insoluble (or differ-
entially soluble) polymeric material is followed by substrate
modification for the introduction of chemical diversity. Finally
oxidative disassembly generates the modified monomers which
are in fact the small molecules of interest. Polymers derived
from ring opening metathesis polymerisation (ROMP)3 fulfil
these criteria and were chosen for initial evaluation in the
strategy outlined in Scheme 1. ROMP polymers are, unlike
cross-linked polystyrene resins, generally soluble in a range of
organic solvents yet insoluble in others. Thus, chemical
modifications may be carried out in a homogenous environment
thereby avoiding poor solvation which often inhibits reactions
carried out with insoluble solid supports. Moreover, reactions
may be probed using standard solution phase spectroscopic
techniques and the ability to rapidly determine the nature of the
attached substrate offers a significant advantage over standard
solid-phase organic synthesis. Following synthesis, the ROMP
13
termination with ethyl vinyl ether8 gave polymer 7 as an off-
white foam which was most conveniently isolated (90%)
following repeated precipitation from 1,2-dichloroethane solu-
tion with MeOH. Both 1H and 13C NMR spectra were consistent
with polymer 7 having a 1:1 trans:cis stereochemistry.8
Selective desilylation of polymer 7 gave the corresponding
polyol 8 as a THF-insoluble precipitate which was washed with
THF and Et2O and dried in vacuo, whereupon 1H and 13C NMR
spectra (acetone-d6) indicated complete removal of the tert-
butyldimethylsilyl residues. Alkylation of polymer 8 using MeI
or 4-bromobenzyl bromide (R1X) in the presence of NaH in
THF gave the corresponding THF-soluble polymeric ethers 9
which were precipitated from MeOH. In turn, cleavage of the
tetrahydropyranyl ether of 9 using TsOH in a MeOH–THF–
CH2Cl2 (1:2:1) mixture and precipitation from THF followed
by further alkylation with MeI or 4-bromobenzyl bromide
(R2X) afforded the polyethers 10 which were isolated in the
same way as 9. All polymers were isolated cleanly and with
high recovery.
Chem. Commun., 1998, 2453–2454
2453

O
O
We have demonstrated the utility and advantage of polymer
backbone disassembly for the rapid generation of small
molecule targets using polymer 7. Advantages include ease of
intermediate purification and facile reaction monitoring. The
modification of polymer 7 for library construction with different
chemistry is ongoing and will be reported in due course.
We thank Rhône-Poulenc Rorer for the most generous
support of our programs on parallel and combinatorial syntheses
under the auspices of the TeknoMed project. In addition we
thank GlaxoWellcome Research Ltd. for their endowment (to
A. G. M. B.), the Royal Society for a Dorothy Hodgkin
fellowship (to M. L. S.), the EPSRC for a studentship (to
Z. E. T.), Professor Vernon Gibson (for the kind donation of
Grubbs catalyst 13) and the Wolfson Foundation for establish-
ing the Wolfson Centre for Organic Chemistry in Medical
Science at Imperial College.
i,ii
OH
OH
OTBDMS
OTHP
6
5
iii
H
H
H
H
O
O
iv
n
n
THPO
H
OH
H
THPO
H
OTBDMS
7
8
v
H
O
O
Notes and references
vi,vii
† All new compounds were fully characterised by spectroscopic data and
microanalysis and/or high resolution mass spectrometry.
n
n
THPO
OR1
R2O
OR1
9
1 N. K. Terrett, M. Gardner, D. W. Gordon, R. J. Kobylecki and J. Steele,
Tetrahedron, 1995, 51, 8135; E. M. Gordon, R. W. Barrett, W. J. Dower,
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G. Jung, Angew. Chem., Int. Ed. Engl., 1996, 35, 17; D. J. Gravert and
K. D. Janda, Chem. Rev., 1997, 97, 489.
10
viii
O
O
O
O
OR1
OR2
OR1
OR2
ix
2 V. Swali, N. J. Wells, G. J. Langley and M. Bradley, J. Org. Chem., 1997,
62, 4902.
H
H
R3
N
3 V. C. Gibson, Adv. Mater., 1994, 6, 37; B. M. Novak and R. H. Grubbs,
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Kozhevnikova, Tet. Lett., 1965, 2323; M. Mutter and E. Bayer, Angew.
Chem., Int. Ed. Engl., 1974, 13, 88; E. Bayer, I. Gatfield, H. Mutter and
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12
11
Scheme 2 Reagents and conditions: i, NaH, THF, TBDMSCl, 78%; ii,
dihydropyran, cat. PPTS, CH2Cl2, 92%; iii, 13, ClCH2CH2Cl, then
EtOCHNCH2 quench, 90%; iv, Bu4NF, THF; v, NaH, THF, R1X; vi, TsOH,
MeOH–THF–CH2Cl2 (1:2:1); vii, NaH, THF, R2X; viii, O3, CH2Cl2, 278
°C, then EtOH, Me2S; ix, NaBH(OAc)3, R3NH2.
The three functionalised polymers 10 were disassembled by
ozonolysis with a Me2S work-up to reveal the corresponding
dialdehydes 11 which were not isolated. Direct in situ reductive
amination9 with BnNH2, BuNH2 and (cyclohexylmethyl)amine
gave the corresponding 3-aza-8-oxabicyclo[3.2.1]octanes 12 in
overall yields of around 30% from the starting polymer 7. The
same nine 3-aza-8-oxabicyclo[3.2.1]octane derivatives 12 were
prepared from monomer 6 by sequential double deprotection
and monoalkylation, ozonolysis and reductive amination.
Overall yields in these reactions were comparable (30–40%).
Communication 8/06331A
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Chem Commun., 1998, 2453–2454