Diazene directed modular synthesis of compounds with quaternary carbon centers

• US 10,640,508 B2
• Filed: 10/15/2018
• Issued: 05/05/2020
• Est. Priority Date: 10/13/2017
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Movassaghi, Mohammad, Lindovska, Petra
• Primary Examiner(s): Shameem, Golam M
• Application Number:
  US16/161,036
• Publication Number:
  US 20190119286A1
• Time in Patent Office: 568 Days
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 519/00 Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

Diazene-directed modular synthesis is described for the preparation Csp2-Csp3 and Csp3-Csp3 linkages where one or more stereogenic quaternary carbon centers are formed. The disclosed methods are directed to the preparation of compounds of Formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, from compounds of Formula (II):

wherein R¹-R⁵ and q are as defined independently for each occurrence herein. A wide variety of compounds can be accessed in this manner, including oligocyclotryptamines, where the stereochemistry of each subunit is beneficially secured before fragment coupling.

Claims

1. A method of preparing a compound of Formula (II′

);

2. The method of claim 1, wherein a compound of Formula (II′

), or a salt, tautomer, or stereoisomer thereof, is of the formula;

3. The method of claim 2, wherein a compound of Formula (IV′

-A), or a salt, tautomer, or stereoisomer thereof, is of the formula;

4. The method of claim 1, wherein the compound of Formula (III′

), or a salt, tautomer, or stereoisomer thereof, is of the formula;

5. The method of claim 4, wherein the compound of Formula (III′

), or a salt, tautomer, or stereoisomer thereof, is of the formula;

6. The method of claim 1, wherein the compound of Formula (III′

), or a salt, tautomer, or stereoisomer thereof, is of the formula;

7. The method of claim 1 further comprising reacting a compound of Formula (II′

);

8. The method of claim 7, wherein the product of reacting a compound of Formula (II′

), or a salt, tautomer, or stereoisomer thereof, is a compound of Formula (I′

);

9. The method of claim 8, wherein the compound of Formula (I′

), or a salt, tautomer, or stereoisomer thereof, is of the formula;

10. The method of claim 9, wherein the compound of Formula (I′

), or a salt, tautomer, or stereoisomer thereof, is;

11. The method of claim 7, wherein the product of reacting a compound of Formula (II′

), or a salt, tautomer, or stereoisomer thereof, is of the formula;

12. The method of claim 2, wherein:

Ring A is a substituted or unsubstituted, 5-14 membered ring, saturated, unsaturated, or aromatic, carbocyclic ring or a substituted or unsubstituted, 5-14 membered, saturated, unsaturated, or aromatic, heterocyclic ring;

R³ is absent, alkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, or R³ is fused to Ring A to additionally form a substituted or unsubstituted, 5-14 membered, saturated, unsaturated, or aromatic, carbocyclic ring or a substituted or unsubstituted, 5-14 membered, saturated, unsaturated, or aromatic, heterocyclic ring.

13. The method of claim 3, wherein:

R22

14. The method of claim 4, wherein the compound of Formula (III'"'"') or a salt, tautomer, or stereoisomer thereof, is of the formula:

15. The method of claim 4, wherein the compound of Formula (III'"'"'), or a salt, tautomer, or stereoisomer thereof, is of the formula:

16. The method of claims 7, wherein the reaction by extruding one or more equivalents of dinitrogen is a radical recombination reaction.

17. The method of claim 16, wherein the reaction by extruding one or more equivalents of dinitrogen is carried out by irradiation.

18. The method of claim 1, wherein the reaction of a compound of Formula (III'"'"'), or a salt, tautomer, or stereoisomer thereof, and a compound of Formula (IV'"'"'), or a salt, tautomer, or stereoisomer thereof, comprises an electrophilic activation of a compound of Formula (IV'"'"'), or a salt, tautomer, or stereoisomer thereof.

19. The method of claim 18, wherein the electrophilic activation comprises reaction of the compound of Formula (IV'"'"'), or a salt, tautomer, or stereoisomer thereof, with a silver (I) salt, and a base.

20. The method of claim 19, wherein the compound of Formula (III'"'"'), or a salt, tautomer, or stereoisomer thereof, is resistant to oxidation by the silver (I) salt.