CONTROLLED CYCLIZATION OF PEPTOIDS TO FORM CHIRAL DIKETOPIPERAZINES

• US 20200131140A1
• Filed: 10/30/2019
• Published: 04/30/2020
• Est. Priority Date: 10/30/2018
• Status: Active Grant

• Current Assignee: TRIAD National Security, LLC
• Original Assignee: TRIAD National Security, LLC
• Inventors: Williams, Robert F., Peterson, Paul William, Gilbertson, Robert David, Schmidt, Jurgen G., Strauss, Charlie E.
• Granted Patent: US 11,084,794 B2
• Time in Patent Office: Days
• CPC Class Codes: C07D 241/08 with oxygen atoms directly attached to ring carbon atoms

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.

Claims

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.

2. The method of claim 1, wherein the halide is bromine.

3. The method of claim 1, wherein the non-halogenated leaving group is either a mesylate or tosylate leaving group.

4. The method of claim 1, wherein the acetate ester further comprises at least one of an aliphatic group or an aromatic group.

5. The method of claim 4, wherein the at least one of an aliphatic group or an aromatic group comprises at least one of tert-butyl, benzyl, ethyl, or p-tolyl.

6. The method of claim 1, wherein the primary amine is selected from the group consisting of an aliphatic primary amine, an aromatic primary amine, an alkenyl primary amine, an alkynyl primary amine, and an acyl primary amine.

7. The method of claim 1, wherein a functional group, of the primary amine, is protected using at least one of an ester, tert-butoxyl ester (BOC), benzyloxy carbamate (CBz), a silyl ether, or a pivoloyl ester (Piv).

8. The method of claim 1, wherein reacting the acetate ester with the primary amine comprises adding the acetate ester to a solution comprising the primary amine and a tertiary amine.

9. The method of claim 8, wherein the tertiary amine comprises at least one of triethylamine, diisopropylamine, imidazole, diisopropylethylamine, or diazabicyclo[2.2.2]octane (DABCO).

10. The method of claim 8, wherein the solution comprises a solvent comprising at least one of dichloromethane (DCM), acetonitrile, tetrahydrofuran (THF), or N,N′

-dimethylformamide (DMF).

11. The method of claim 1, wherein reacting the acetate ester comprises chilling a reaction mixture to about 0°

C.

12. The method of claim 1, wherein reacting the first product comprises adding the first product to a solution comprising the haloacetyl halide and at least one of pyridine, triethylamine, or diisopropylethylamine.

13. The method of claim 1, wherein the haloacetyal halide is selected from the group consisting of bromoacetyl bromide, chloroacetyl chloride, and chloroacetyal bromide.

14. The method of claim 1, wherein reacting the first product comprises reacting the first product with a N-hydroxysuccinimide (NHS)-ester of the haloacetyl halide.

15. The method of claim 1, wherein reacting the first product comprises adding the first product to a solution comprising the haloacetyl halide and at least one base.

16. The method of claim 15, wherein the at least one base comprises at least one of a tertiary amine or an aromatic amine.

17. The method of claim 1, wherein reacting the first product comprises chilling a solution, comprising the first product and the haloacetyl halide, to about 0°

C.

18. The method of claim 1, further comprising:

producing a charged intermediate that stirs as a colored slurry in dichloromethane, wherein producing the charged intermediate comprises adding at least one of a tertiary amine or an aromatic amine to a solution comprising the haloacetyl halide,

wherein reacting the first product comprises reacting the first product with the charged intermediate to produce the second product.

19. The method of claim 18, wherein reacting the first product with the charged intermediate is performed until the colored slurry has disappeared.

20. The method of claim 1, wherein the amine nucleophile is a primary amine.