A practical process for polymer-supported synthesis

Article abstract of DOI:10.1016/S0040-4039(00)00886-8

Various complex structures can be attached to a polystyrene oligomer using the simple but powerful xanthate transfer technology; the material obtained is soluble in many of the common organic solvents allowing further reactions under homogeneous conditions, but can be precipitated with methanol making this technique especially suitable for conducting parallel syntheses. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00886-8

Tetrahedron Letters 41 (2000) 5673±5677
A practical process for polymer-supported synthesis
Beatrice Quiclet-Sire,a Agnieszka Wilczewskaa and Samir Z. Zarda,b,
*
aInstitut de Chimie des Substances Naturelles, CNRS, 91198 Gif-Sur-Yette, France
Á Â
Laboratoire de Synthese Organique associe au CNRS, Ecole Polytechnique, 91128 Palaiseau, France
b
Received 3 April 2000; accepted 1 June 2000
Abstract
Various complex structures can be attached to a polystyrene oligomer using the simple but powerful
xanthate transfer technology; the material obtained is soluble in many of the common organic solvents
allowing further reactions under homogeneous conditions, but can be precipitated with methanol making
this technique especially suitable for conducting parallel syntheses. # 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: xanthates; radicals; supported reactions; oligomers.
The construction of libraries of compounds using combinatorial and parallel synthesis has
witnessed dramatic development in recent years.1 The need for fast delivery of large numbers of
diverse molecules for high-throughput screening assays has triggered a huge e€ort in industry and
academia aimed at designing and adapting reactions for solid-supported synthesis. Insoluble
polymers of all kinds have thus been examined as possible supports, building on the early
pioneering work of Merri®eld.1 However, working with a substrate ®xed on an insoluble support
has several drawbacks: (i) generally slower kinetics and variations in behaviour, which often
result in a long developmental phase required to adapt a given reaction to a solid-supported
substrate (only a tiny fraction of the reactions in the organic chemist's arsenal can so far be
routinely used); (ii) diculty in following reactions and characterising products still attached to
the polymer (sophisticated and custom-designed techniques are often needed); (iii) the attachment
of the substrate is itself a non-trivial operation (incomplete use of active sites for example);
(iv) mechanical breakdown of the polymeric support upon stirring, heating, etc.; and (v) high cost
of the specially modi®ed polymers.
The use of soluble polymers, i.e. polymers which are soluble in one medium but insoluble in
another and can therefore be precipitated after each operation, have not yet found widespread
use, mainly because of a lack of a suitable support, which allies the desired properties of solubility,
¯exibility for substrate attachment, and compatibility with various reaction types.2 So far,
* Corresponding author. Fax: +33 (0)1 69 33 30 10; e-mail: sam.zard@icsn.cnrs-gif.fr
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00886-8

5674
polyethylene glycol (PEG)-based systems appear to be the most promising. In this preliminary
communication, we describe an alternative strategy, hinging on a new, powerful polymerisation
system, and allowing the custom synthesis of supported substrates (or reagents) in a way not
easily feasible hitherto. Our initial e€orts have centred on polymerising styrene, but the same
approach can be applied in principle to other monomers (or combinations thereof). The use of
linear (as opposed to cross-linked) polystyrene has relied in the past on commercial, high
molecular weight polymer (average MW 200 000), which has to be functionalised, for example by
chloromethylation, as shown in Scheme 1.2,3 Such randomly functionalised material does not
always exhibit the desired solubility pro®le, and its properties can vary from one batch to
another. Moreover, the limited number of reactions for functionalising polystyrene imposes
serious constraints on the type of attachments that can be envisaged.
Scheme 1.
Over the past few years, we have examined the radical transfer of a xanthate (and other
dithiocarbonate derivatives) as a convenient method for the inter- or intramolecular creation of
carbon±carbon bonds.4 The general scheme is outlined in Scheme 2. Upon heating a mixture of
xanthate 1 and ole®n 2 in the presence of a small amount of an initiator such as a peroxide, an
adduct 3 is formed, whereby the elements of the xanthate have added across the ole®nic bond.
This adduct is itself a xanthate and can act as a starting point for another addition to an ole®n
resulting in the ultimate polymerisation of the ole®n (or `monomer') if the ole®n is easily
polymerisable. Moreover, the resulting polymer 4 is also a xanthate that can act as the starting
point of another polymerisation process to give a bloc polymer 6. Thus, depending on the way the
starting materials and reaction conditions are selected, the radical process may be directed
towards the formation of either a small monoadduct 3 or a large macromolecular structure such
as 4 or 6.5
Scheme 2.
This polymerisation system exhibits the characteristics of a controlled living radical
polymerisation, namely the obtention of narrow polydispersity and the possibility of constructing
block copolymers. The rapid exchange of the xanthate group in comparison to addition to
monomer allows the chains to grow throughout the duration of the reaction at a comparable rate,
resulting in an averaging of the molecular weights. Whence the narrow polydispersity.

5675
The area of controlled radical polymerisation is growing at a tremendous rate.6 For the
purpose of polymer-supported synthesis, one can envisage incorporating the substrate in the R
portion of the xanthate and using this material to accomplish the oligomerisation of styrene
(Y=Ph in Scheme 2). The number of styrene units can be varied at will in order to optimise the
loading capacity and solubility pro®le. A ratio of substrate to styrene of 1:15 appears to be a
reasonable compromise, leading (at least in the cases we have studied) to an easily handleable,
powdery solid that is soluble in many of the common organic solvents but that can be
precipitated by methanol. For a substrate of molecular weight of about 300, this gives a loading
of approximately 0.5 mmol/g, which is quite respectable.
These considerations are illustrated by the preparation of the polymer-bound protected
arabinose 7 (Scheme 3). The preparation of the corresponding xanthate 9 is trivial and involves
the formation of the chlorophenylacetate ester 8 of the free hydroxy group, followed by
displacement of the halide with commercially available potassium O-ethyl xanthate. Heating this
compound with 15 equivalents styrene in re¯uxing toluene for 18 hours in the presence of 12
mol% of lauroyl peroxide, followed by concentration under vacuum and precipitation with
methanol gave the corresponding polymeric derivative 10 in 75% yield as a white powder. This
material is readily soluble in chloroform and may be further analysed by the usual spectroscopic
techniques (we have used IR and NMR, but UV and certain MS techniques are applicable; in the
NMR, the wide region between the aromatic and aliphatic hydrogens or carbons of the styrene
units remains useful).
Scheme 3.
A similar, smooth polymerisation could be achieved starting with various substrates, using
both phenylacetate or propionate derived xanthates. The polymerisation conditions are especially
mild, and complex structures with various functional or protecting groups generally encountered
in organic synthesis are readily tolerated (Fig. 1). Thus, carbohydrates (maltose derived polymer
11), cyclitols (polymer 12), nucleosides (thymine derived polymer 13), steroids (hecogenin and bile
acid derived polymers 14 and 15) were easily prepared. Other types of substrates, belonging to
other families may also, in principle, be attached in the same way: b-lactams, amino acids, and
various aromatic, heteroaromatic, and heterocyclic derivatives may be easily manipulated using
this new radical chemistry of xanthates.4,7
The linking directly through the phenylacetate or propionate group serves to illustrate the
technique. These are quite hindered esters, close to the bulky polystyrene residue, but can
nevertheless be saponi®ed. For example, the bile acid fragment in derivative 15 could be detached
in 75% yield by treatment with KOH in a mixture of methanol and THF. It is also possible to

5676
Figure 1.
intercalate a linker separating the polymer units from the actual substrate. This is illustrated by
the bile acid derivative 16 (Scheme 4). This compound is easily prepared from 3a-hydroxy-11-
oxo-cholanic acid by treatment with 11-(a-bromophenylacetoxy)undecanoyl chloride, followed
by displacement of the bromide with potassium O-ethyl xanthate in acetone. The usual reaction
with 15 equivalents of styrene then provides the polymer bound steroid 17 in 85% yield.
Scheme 4.
The xanthate group at the other terminus of the polymer represents an additional but di€erent
site for substrate attachment or for the placement of a label.1 The xanthate may for instance be
cleaved by base or an amine to give a thiol, which may be alkylated by the substrate (or a
labelling) molecule. Alternatively, to improve compatibility with subsequent reactions one wishes
to use, it may be desirable to remove the xanthate group. Thus, exposure of 17 to sulfuryl

5677
chloride in acetic acid caused the formation of the corresponding benzylic sulfonyl chloride,8
which underwent elimination of sulfur dioxide and HCl to give 18 in 91% yield. Elemental
microanalysis showed the absence of sulfur in the product whereas ole®nic hydrogens appeared in
the NMR spectrum. Treatment of 18 ®rst with oxalyl chloride in CH2Cl2 then with
cyclopropylamine furnished N-cyclopropylamide 19 (89%), after precipitation with methanol.
Free amide 20 was obtained in 62% yield by saponi®cation with KOH in methanol/THF. This
sequence illustrates an application of the present approach for polymer-supported synthesis.
In summary, this preliminary work shows that it is possible to attach complex molecules to a
polystyrene oligomer, cheaply and in a ¯exible manner. One molecule of the substrate is linked to
one terminus of the linear oligomeric unit. Fairly large amounts of polymer bound material can
be obtained rapidly and the properties may be tailored by adjusting the ratio of substrate to
styrene (or even another monomer if desired). The polystyrene subunit is reasonably inert to most
reaction conditions: it may be viewed as just a bulky protecting group which modi®es the
solubility properties of the substrate. In the same way, a given reagent (or a ligand for a transition
metal catalyst) may in principle be grafted on such an oligomeric backbone. Further studies
aimed at exploring and extending the scope of this technology are in progress.
Acknowledgements
We wish to thank Rhodia Chimie for generous ®nancial support to one of us (A.W.) and Drs
Dominique Charmot and Mathias Destarac for many friendly discussions.
References
1. (a) Obrecht, D.; Villalgordo, J. M. Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-
Weight Compound Libraries; Pergamon Press: Oxford, 1998.
2. (a) Gravert, D. J.; Janda, K. D. Chem. Rev. 1997, 97, 489±509.
3. Enholm, E. J.; Gallagher, M. E.; Moran, K. M.; Lombardi, J. S.; Schulte, J. P. Org. Lett. 1999, 1, 689±691.
4. For a review of our work on xanthates, see: Zard, S. Z. Angew. Chem., Int. Ed. Engl. 1997, 36, 672±685.
5. Charmot, D.; Corpart, P.; Michelet, D.; Zard, S. Z.; Biadatti, T. WO 9858974 Priority June 23, 1997 (to Rhodia
Chimie). This polymerisation process has been named MADIX (for MAcromolecular Design via Interchange of
Xanthate). A mechanistically similar system using dithioesters was concomittantly developed by CSIRO chemists
and termed RAFT: Chiefari, J.; Chong, Y. K.; Ercole, F.; Kristina, J.; Je€rey, J.; Le, T. P. T.; Mayadunne,
R. T. A.; Meijs, G. F.; Moad, G.; Moad, C. L.; Rizzardo, E.; Thang, S. H. Macromolecules 1998, 31, 5559±5561.
6. Hawker, C. J. Acc. Chem. Res. 1997, 30, 373±382.
7. (a) Boiteau, L.; Boivin, J.; Quiclet-Sire, B.; Saunier, J.-B.; Zard, S. Z. Tetrahedron 1998, 54, 2087±2098.
(b) Biadatti, T.; Quiclet-Sire, B.; Saunier, J.-B.; Zard, S. Z. Tetrahedron Lett. 1998, 39, 19±22
8. London, J. D.; Shulman, N. J. Chem. Soc. 1938, 1618±1621.