Solid-Supported Reagents and Scavengers

Other examples include reactions, such as the Mitsunobu condensation, where polystyrene-diphenylphos-phine can be used instead of triphenylphosphine, avoiding production of the difficult-to-remove by-product, triphenylphosphine oxide. 

Sohd-phase scavengers can also be used both for removal of excess reagents and trace impurities, such as metal residues, for example palladium from cross-coupling reactions. A range of resins is available to remove a variety of metal residues, usually involving binding to a thiol or amino group. 

While all the above methods have been used very successfully on standard laboratory scale, they also have significant potential for rapid synthesis on medium scale (up to several kg) and possibly even larger. High-loading resins can bind an equal weight of substrate and so are efficient in terms of volume.  

At the other end of the scale, products can be isolated on single beads of resin produced by combinatorial chemistry, involving sequential splitting and mixing batches of beads between reaction steps such that single beads contain only one product. Spectroscopic methods have been developed for the non-destructive characterisation of products while still on the bead.  

---

Baxendale, I.R., Brusotti, G., Matsuoka, M., Ley, S.V. (2002) Synthesis of Nornicotine, Nicotine, and Other Functionalised Derivatives Using Solid-supported Reagents and Scavengers. Journal of the Chemical Society Perkin Transactions 1, 143-154. 

Baxendale IR, Lee A-L, Ley SV (2001) A concise synthesis of the natural product carpanone using solid-supported reagents and scavengers. Synlett 482-484... 

Storer RI, Takemoto T, Jackson PS, Ley SV (2003) A total synthesis of epo-thilones using solid-supported reagents and scavengers. Angew Chem Int Ed 42 2521-2525... 

Fig. 2.2 The concept of combining solid-supported reagents and scavengers in chemical synthesis.

Ley, S.V., Baxendale, I.R., Bream, R.N., Jackson, P.S., Leach, A.G. etal, Multi-step organic synthesis using solid-supported reagents and scavengers a new paradigm in chemical library generation, J. Chem. Soc, Perkin Trans. 1, 2000, 3815. 

Baxendale, I.R., Ley, S.V. and Piutti, C., Total Synthesis of the Amaryllidaceae Alkaloid (+)-plicamine and its unnatural enantiomer by using solid-supported reagents and scavengers in a multistep sequence of reactions, Angew. Chem., Int. Ed. Engl., 2002, 41, 2194. 

It should be highlighted that in some cases the distinction between a traditional solid-phase synthesis and a process involving solid-supported reagents is often difficult. The reader is advised to refer also to the chapter on the integration of microwave-assisted synthesis with solid supported reagents and scavengers (Chapter 6). 

Solid-supported reagents and scavengers have increasingly been employed in organic chemistry during recent years, since they allow the simplification of both synthetic procedures and isolation or purification steps (Scheme 15.1) [4],... 

Caldarelli et al. (240) have recently reported a five-step synthesis of substituted p)Trole libraries L22 and L23 using solid-supported reagents and scavengers. The synthesis involved oxidation of benzyl alcohols Mi to aldehydes (step a, Fig. 8.46), Henry reaction of aldehydes 8.91 with nitroalkanes M2 (step b), and acylation and elimination of nitroalcohols 8.93 (steps c and d) to give the nitrostyrenes 8.94, which were subjected to 1,3-dipolar cycloaddition with an isocyanoacetate (step e) to give the pyrroles 8.95. N-alkylation of these pyrroles with alkyl halides (step f) and final library-from-a-library hydrolysis/decarboxylation of L22 gave a library of trisub-stituted pyrroles L23 (step g. Fig. 8.46). 

Oxaziridine 313 was prepared by Ley and co-workers using solid-supported reagents and scavengers <2002T6285>. Reaction of imine 312 with MCPBA followed by treatment with a solid-supported amine afforded the oxaziridine in 95% yield. 

The current interest in solid-phase synthesis has led to a renewed interest in a complementary technique in which solid-supported reagents and scavengers are used in solution-phase chemistry. These reagents have proven to be useful for a wide variety of transformations important to chemists in general, and particularly to medicinal chemists. A comprehensive and clear review on this topic has recently appeared [34]. To exemplify, in Fig. 13 is documented the use of polymer-bound 4-hydroxy-3-nitrobenophenone to synthesize a library of herbici-.dal amides [35]. 

---