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Solution-phase high throughput synthesis has emerged as a powerful method for the rapid generation of chemical libraries. The success of this approach is largely due to the development of novel synthetic methodologies that expedite the preparation of compounds. Several isolation/purification techniques have also been developed to eliminate the time-consuming purification procedures often associated with solution-phase chemistry. These methods are amenable to parallel synthesis and combinatorial strategies and can be fully automated. In addition, the compound libraries generated using solution-phase high throughput synthesis have been used to accelerate both lead identification and lead optimization programs at various companies. © 1998 John Wiley & Sons, Inc. Biotechnol Bioeng (Comb Chem) 61:95–106, 1998.

As part of our efforts in the area of combinatorial chemistry, we have been exploring new methods for the construction of combinatorial libraries in a bidirectional fashion. Herein, we describe a new one-pot procedure for the simultaneous protection/activation of amino and thiol carboxylic acids using pentafluorophenyl trifluoroacetate (TFAPfp) and related pentafluorophenyl reagents (FmocPfp and AcPfp).

Described are various techniques that employ ion-exchange resins for the solution-phase synthesis of chemical libraries. We have found these resins to be useful as reagents and/or scavengers in a variety of reactions. Nine basic ion-exchange resins were evaluated for the catalysis and purification of an amide synthesized from an acid chloride. A number of the resins examined provided products in >95% purity. Acidic ion-exchange resins were also useful as scavengers in the synthesis of ureas. A demonstration of the utility of these resins for the preparation of amide, ester and urea libraries is also described.

The construction of small heterocycles using solid-phase chemistry is usually done through the use of a polar group to attach the compounds to the resin. These polar functionalities invariably become part of the structure and eventually limit the structure-activity relationships derived from these compounds. We have identified a method for overcoming some of these limitations. A sulfur-based linker has been identified that can serve not only as a point of attachment for a small heterocycle, but also as a means to introduce further diversity into the molecule. The linker remains inert until “activated” by oxidation. A limiting amount of a nucleophile can then be used to cleave the molecule from the resin and introduce additional diversity into the molecule.