Light MPEG Supports for the Synthesis of Arrays

In order to discover new drugs, large numbers of compounds have to be synthsized and tested in biological screens. With the advent of high throughput screening, the pressure is on to produce libraries of drug-like compounds in a quick, efficient and cost-effective way. This requires automation. Attaching compounds to solid supports makes them easy to handle by machines and resin-bound materials have found great use in synthesis for easing purification and allowing automation. They have been widely employed in solid-phase synthesis (SPS), and in polymer-assisted organic synthesis (PAOS) as solid-supported reagents, catalysts and scavengers. Unfortunately, solid supports have several serious drawbacks: (a) Reactivity is reduced on going from solution phase to solid phase, and this affects both SPS and PAOS. (b) In SPS, there is sometimes a build up of undesired products on resin and monitoring of reactions is difficult. (c) Resins are expensive, and this is particularly problematic for PAOS as several different resin-bound materials may be used in each step, and because of slow reaction, an excess of the solid-supported materials is often employed. These chemical and economic problems limit the use of resins and prevents the resynthesis of hits (compounds that are identified as interesting by the biological screen) by large-scale SPS or PAOS. We propose that using low molecular weight poly(ethyleneglycol)monomethyl ether (MPEG) as the support will overcome these problems. MPEG is extremely cheap and is produced on a massive scale for use in adhesives, in paints, coatings, cosmetics and household products. We aim to show that MPEG is the best support for the everyday needs of synthetic chemists, and to demonstrate its potential as a support in array synthesis by exemplifying and exploiting its potential advantages: (a) MPEG-supported compounds should be soluble in most organic solvents allowing solution-phase synthesis with the advantage of good kinetics so that fewer equivalents of reagents are necessary. (b) Purification from unPEGylated material should be straightforward using solid-phase extraction on silica and alumina. (c) MPEG is very cheap and it should be possible to scale-up resynthesis of hits using the original MPEG-supported synthesis. (d) Characterization of MPEG-supported compounds should be straightforward using all the standard techniques and the methyl signal in the 1H NMR spectra could be used to assess purity. Therefore, unlike solid-supported reagents, it should be easy to check whether MPEG-supported reagents are still good if they have been stored. (e) Orthogonal purification and recovery systems (e.g. solid supports) could be used with MPEG-supported compounds, e.g. ion-exchange columns or scavenger resins could be used to separate MPEG-supported compounds bearing different functionality, and resin-bound reagents and catalysts could also be used.