Triad National Security, LLC

Paul William Peterson

Jurgen G Schmidt

Robert F Williams

Robert David Gilbertson

Charlie E Strauss

The present disclosure provides improved methods for controlled cyclization of peptoid dimers to form N,N'-2,5-diketopiperazines (N,N&#x2032;-2,5-DKPs) with significant selectivity. In at least some examples, selectivity is based on a serendipitous conglomeration of slow exchange of amide rotamers, steric repulsion from the degree of &#x3b1;-substitution, and the geometric bulk of an amine nucleophile. By varying reaction conditions, the selectivity of the reaction and formation of a particular N,N&#x2032;-2,5-DKP can be switched. The cyclization works in the presence of a variety of protection groups and diverse functionalities. The teachings herein provide techniques for synthesizing N,N&#x2032;-2,5-DKPs that can be readily docked with drug candidates for shuttling across the blood brain barrier. This method provides a facile way to produce substituted DKPs containing groups ready for post-modification to include docking drug candidates.

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Los Alamos, NM, United States of America

Paul William Peterson