The Use of Polymer-Assisted Solution-Phase Synthesis and Automation for the High-Throughput Preparation of Biologically Active Compounds

STEVEN V. LEY, MARK LADLOW AND EMMA VICKERSTAFFE

1 Introduction

In recent years, the drug discovery process has been revolutionised by progress in the areas of proteomics and genomics, together with advances in high-throughput screening (HTS) of compounds for activity in various biological assays. This in turn has created a much higher demand for the rapid production of novel and functionally diverse compounds, thereby driving chemists to look for new ways to simplify, expedite and automate the process of organic synthesis. The importance of synthe-sising high-quality arrays of discrete compounds, from which meaningful structure activity relationships can be derived and also act as assets for future screening protocols is now well recognised.

The origins of high-throughput organic chemistry can be traced back to the work of Merrifield who pioneered solid-phase peptide synthesis. The development of this approach enabled the subsequent automation of peptide synthesis. Early attempts at high-throughput chemistry utilised this strategy, exploiting the advantages of solid-phase chemistry, which facilitates reaction work-up and rapid sample processing.

Today, although solid-phase organic synthesis (SPOS) remains a powerful technique for some aspects of high-throughput chemistry, there are a number of limitations that restrict its application. For example, while in some instances, by-product formation on the resin can be monitored without cleavage from the resin, separation of these materials from the desired product is not feasible until the end of the reaction sequence. The consequences are often cumulative, resulting in a complex final purification step. Additionally, even though a number of well-established methods for monitoring resin-bound intermediates have been developed, accurate quantitative measurement of immobilised material still represents a major challenge. Techniques such as magic angle spinning (MAS)-NMR and IR enable the analysis of molecules covalently bound to the resin, whereas MS techniques or the use of analytical constructs, require that the analyte be cleaved from the resin. The development of new chemistry on the solid support is therefore difficult and often protracted, requiring extended reaction rehearsal and optimisation.

Although SPOS is well suited to the synthesis of large, but relatively simple compound libraries, typically using combinatorial methods, the time required for route development and limitations as to the synthetic transformations that can be reliably performed is often restrictive. Increasingly, therefore, higher quality, smaller arrays are being synthesised by employing a much wider range of precedented solution-phase chemistries. Historically, attempts to increase the throughput of solution-phase chemistries have been confounded by the need for extensive work-up and purification procedures. An increasingly popular approach to circumvent many of these drawbacks involves the use of supported reagents." In this way, the advantages of performing chemistry in solution, namely, straightforward reaction monitoring and optimisation, are maintained. Excess reagents and their associated by-products may be readily separated from the desired solution-phase reaction product by simple filtration. A wide variety of reagents and scavenger resins have been developed in recent years to extend the scope of this new paradigm.

The concept of a reagent being immobilised on a solid-support was first exploited in catalytic applications as early as 1946. However, it was not until the end of the twentieth century that solid-supported nucleophiles and electrophiles immobilised on a polystyrene (PS) support were applied to the rapid purification of compounds prepared using standard solution-phase procedures. This application and its subsequent extension to the immobilisation of reagents has stimulated an explosion in the number of publications describing the development of novel polymer-bound reagents, catalysts and scavengers. As an ever-increasing number of these reagents becomes commercially available, interest in applying polymer-assisted solution-phase (PASP) techniques within industrial settings escalates.

PASP synthesis can be divided into two main approaches; these being (a) the use of supported reagents and scavengers, and (b) the adoption of a catch-and-release strategy (Figure 1). Both of these techniques allow the production of clean products, without the need to resort to traditional purification techniques, such as column...