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  • Review Article
  • Published:

New tools and concepts for modern organic synthesis

Nature Reviews Drug Discovery volume 1, pages 573–586 (2002)Cite this article

Key Points

  • Supported reagents are reactive species that are associated with a support material. They transform a substrate (or substrates) into a new chemical product (or products), and the excess or spent reagent can then be easily removed by filtration. In a similar fashion, impurities can be removed from solution using a 'scavenger' immobilized on a support,

  • This concept of immobilizing reagents on a solid support has several advantages over conventional solution-phase and solid-phase preparative synthesis, and combines many of the best attributes of both approaches:

  • Excess reagents can be used to force the reaction to completion without causing problems with work-up.

  • Toxic, noxious or hazardous reagents and their by-products can also be immobilized and thereby removed from solution.

  • Standard analytical techniques can be easily applied to monitor reactions, allowing rapid optimization.

  • Convergent syntheses are possible.

  • Multiple reagents that would otherwise be incompatible can be used simultaneously.

  • The technique can be easily adapted for automation.

  • The value of the solid-supported-reagent approach has been shown in the synthesis of novel chemical arrays, and in the targeted synthesis of natural products and other complex molecules.

Abstract

The increasing need to efficiently assemble small molecules as potential modulators of therapeutic targets that are emerging from genomics and proteomics is driving the development of novel technologies for small-molecule synthesis. Here, we describe some of the general applications and approaches to synthesis using one such technology — solid-supported reagents — that has been shown to significantly improve productivity in the generation of combinatorial libraries and complex target molecules.

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Figure 1: Polymer supports in organic synthesis.
Figure 2: Some advantages of solid-supported reagents.
Figure 3: Opportunities for solid-supported reagents in clean synthesis.
Figure 4
Figure 5: Scavenging protocols.
Figure 6: Preparation and purification of small molecules using metal tagging — the phase-switch technique.
Figure 7: Construction of molecular diversity from simple monomers.
Figure 8: Polymer-supported total synthesis of alkaloid natural products and other targets.
Figure 9: Evolving synthetic techniques and concepts.

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Acknowledgements

We acknowledge the contributions and commitment of all the members of the Polymer-Supported Reagents Group at the University of Cambridge and thank the Pfizer Postdoctoral Fellowship (to IRB), the BP endowment and the Novartis Research Fellowship (to SVL) for their financial support.

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  1. Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK

    Steven V. Ley & Ian R. Baxendale

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Correspondence to Steven V. Ley.

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DATABASES

Analtech Technical Data Sheet — Rotors and Accessories

CombiChem.net

Glossary

COMBINATORIAL CHEMISTRY

The generation of large collections, or 'libraries', of compounds by synthesizing all possible combinations of a set of smaller chemical structures.

PARALLEL SYNTHESIS

Creation of a series of individual compounds through reactions performed simultaneously, rather than one at a time.

CONVERGENT SYNTHESIS

Yields of synthetic organic reactions are usually less than 100%. So, for example, a three-step reaction linking the components A, B, C and D to give the linear sequence A–B–C–D, with each step having a 90% yield, would have an overall yield of 73%. But if A was linked to B and C linked to D separately, each with 90% yield, and then A–B and C–D linked with a 90% yield — a convergent synthetic strategy — then the overall yield is improved to 81%.

WORK-UP

Work-up is the phase of synthesis directed at product isolation. On completion of the synthetic transformation, the reaction may be quenched, neutralized or diluted to prevent further reaction(s). This phase of synthesis also incorporates any washing, extraction, separation, drying and, ultimately, solvent-removal steps.

FUNCTIONALIZED DIVINYLBENZENE-CROSSLINKED POLYSTYRENE

2–4% cross-linking produces a swelling resin, referred to as a microporous resin. 30–50% cross-linking produces a non-swelling structure, referred to as a macroporous resin.

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Ley, S., Baxendale, I. New tools and concepts for modern organic synthesis. Nat Rev Drug Discov 1, 573–586 (2002). https://doi.org/10.1038/nrd871

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