Abstract:

In recent years, combinatorial library synthesis has rapidly emerged as a powerful methodology for the preparation of a variety of molecular diversity. A solid-phase approach to combinatorial library generation may be advantageous due to the greater ability to automate a synthetic protocol while enabling the rapid escalation of number of possible compounds employing split and mix strategies of intermediate functionalized supports. Accordingly, facile manipulation of reactive functionality is imperative for synthetic method development in combinatorial library synthesis.

By virtue of their clean addition reactions with a wide variety of protic nucleophiles such as amines and alcohols, we have illustrated the use of diisocyanates as bis-functional scaffolds for library synthesis. This solid-phase method for terminii differentiation was demonstrated employing Kaiser oxime resin through the heat-labile, oxime-derived carbamate linkage. This linking functionality can also be generated by primary amine addition to phosgenated oxime or Phoxime resin. Oxime carbamates of this resin serve as latent isocyanates upon thermolysis and have been utilized to effect acyclic and heterocyclic urea formation as well as resin-to-resin aminoacyl transfer. Similarly, resin-to-resin acyl transfer of oxime resin-derived esters was developed and offers a convergent route to libraries of enhanced diversity. Applications of library diversity applied to peptide presentation on symmetric core scaffolds and conformation in template-constrained systems will also be discussed.