DIAZENE DIRECTED MODULAR SYNTHESIS OF COMPOUNDS WITH QUATERNARY CARBON CENTERS

• US 20170342077A1
• Filed: 05/24/2017
• Published: 11/30/2017
• Est. Priority Date: 05/24/2016
• Status: Abandoned Application

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Mohammad Movassaghi
• Inventors: MOVASSAGHI, Mohammad, LINDOVSKA, Petra
• Application Number:
  US15/604,508
• Publication Number:
  US 20170342077A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

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 compounds of Formula (I), or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, comprising reacting a compound of Formula (II), and thereby extruding dinitrogen to provide a compound of Formula (I):

2. The method of claim 1, wherein the compound of Formula (I) is:

3. The method of claim 2, wherein R¹ is comprised of

4. The method of claim 2, wherein the compound of Formula (I) is:

5. The method of claim 1, wherein the compound of Formula (II) is:

6. The method of claim 5, wherein R¹ is,

7. The method of claim 1, wherein the compound of Formula (II) is prepared by reacting a compound of Formula (III), and a compound of Formula (IV):

8. The method of claim 7, wherein the compound of Formula (III) is:

9. The method of claim 7, wherein the compound of Formula (III) is:

10. The method of claim 7, wherein the compound of Formula (III) is:

11. The method of claim 7, wherein R¹⁵ is —

S(═

O)_pR¹³, wherein p is 2, and R¹³ is C₁-C₁₂ alkyl.

12. The method of claim 11, wherein the compound of Formula (II) is formed in one synthetic step.

13. The method of claim 7, wherein the compound of Formula (IV) is:

14. The method of claim 10, wherein the compound of Formula (IV) is:

15. The method of claim 1, wherein the compound of Formula (II) is prepared by the extrusion of sulfur dioxide from a compound of Formula (V):

16. The method of claim 15, wherein the compound of Formula (V) is:

17. The method of claim 15, wherein the compound of Formula (V) is prepared by the following steps:

a. reacting a compound of Formula (VI), and a compound of Formula (IV) to give a compound of Formula (VII);

18. The method of claim 17, wherein the compound of Formula (VII) is:

19. The method of claim 17, wherein the compound of Formula (VIII) is:

20. The method of claim 18, wherein the compound of Formula (VIII) is:

21. The method of claim 1, wherein the reaction is a radical recombination reaction.

22. The method of claim 21, wherein the reaction is carried out by irradiation.

23. The method of claim 22, wherein the irradiation occurs in a photoreactor.

24. The method of claim 23, wherein the photoreactor is equipped with 1 to about 20 lamps operating at a wavelength λ

from about 250 nm to about 400 nm.

25. The method of claim 24 wherein the wavelength λ

is 300 nm or 380 nm.

26. The method of claim 21, wherein the radical recombination reaction results in the formation of a Csp3-Csp3 bond or a Csp3-Csp2 bond.

27. The method of claim 1, wherein the stereochemical configuration of the compound of Formula (II) is retained in the compound of Formula (I) following the reaction.

28. The method of claim 7, wherein the reaction comprises an electrophilic activation of a compound of Formula (IV).

29. The method of claim 28, wherein the electrophilic activation comprises reaction of the compound of Formula (IV) with a silver (I) salt, and a base.

30. The method of claim 29, wherein the silver (I) salt is AgOSO₂CF₃ or AgSF₆.

31. The method of claim 29, wherein the compound of Formula (III) is resistant to oxidation by the silver (I) salt.

32. The method of claim 15, wherein the sulfur dioxide extrusion is carried out in the presence of an oxidizing agent.

33. The method of claim 32, wherein the oxidizing agent is an electrophilic halogenating reagent.

34. The method of claim 1, wherein the compounds of Formula (I) are: