CONTROLLED CYCLIZATION OF PEPTOIDS TO FORM CHIRAL DIKETOPIPERAZINES
First Claim
1. A method for controlling cyclization of peptoids to form chiral diketopiperazines, comprising:
- reacting an acetate ester, comprising a halide or non-halogenated leaving group, with a primary amine to produce a first product having two electrophiles;
reacting the first product with a haloacetyl halide to produce a second product; and
reacting the second product with an amine nucleophile to produce an N,N′
-2,5-diketopiperazine.
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Accused Products
Abstract
The present disclosure provides improved methods for controlled cyclization of peptoid dimers to form N,N′-2,5-diketopiperazines (N,N′-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 α-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′-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′-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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Citations
20 Claims
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1. A method for controlling cyclization of peptoids to form chiral diketopiperazines, comprising:
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reacting an acetate ester, comprising a halide or non-halogenated leaving group, with a primary amine to produce a first product having two electrophiles; reacting the first product with a haloacetyl halide to produce a second product; and reacting the second product with an amine nucleophile to produce an N,N′
-2,5-diketopiperazine. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20)
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Specification