Asymmetric synthesis of rocaglamides via enantioselective photocycloaddition mediated by chiral bronsted acids

• US 8,404,088 B2
• Filed: 03/19/2012
• Issued: 03/26/2013
• Est. Priority Date: 05/22/2006
• Status: Active Grant

• Current Assignee: Trustees of Boston University
• Original Assignee: Trustees of Boston University
• Inventors: Porco, John A. Jr., Gerard, Baudouin
• Primary Examiner(s): DENTZ, BERNARD I
• Application Number:
  US13/423,370
• Publication Number:
  US 20120238766A1
• Time in Patent Office: 372 Days
• Field of Search: 204/157.69, 204/157.71, 548/425, 549/386, 549/458
• US Class Current: 204/157.69
• CPC Class Codes: C07D 307/93 condensed with a ring other than six-membered
• CPC Class Codes: C07D 317/12 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
• CPC Class Codes: C07D 317/72 spiro-condensed with carbocyclic rings
• CPC Class Codes: C07D 493/08 Bridged systems
• CPC Class Codes: C07D 493/10 Spiro-condensed systems

Abstract

The present invention provides a new strategies for the synthesis of compounds of the rocaglamide family and related natural products. The synthetic approach generally involves photochemical generation of an oxidopyrylium species from a 3-hydroxychromone derivative followed by an enantioselective 1,3-dipolar cycloaddition of the oxidopyrylium species to a dipolarophile in the presence of a TADDOL derivative. This approach can be used for the formation of adducts containing an aglain core structure. Methods of the conversion of aglain core structures to aglain, rocaglamide and forbaglin ring systems are also provided. The present invention also relates to the use of rocaglamide/aglain/forbaglin derivatives for the manufacture of medicaments for use in the treatment of cancer or cancerous conditions, disorders associated with cellular hyperproliferation, or NF-κB-dependent conditions.

Claims

1. A method for preparing a compound with an aglain core structure, the method comprising steps of:

producing an oxidopyrylium species (I_T) by photoinduced excited state intramolecular proton transfer of a 3-hydroxychromone derivative (I); and

reacting the oxidopyrylium species with a dipolarophile (IV) to obtain the aglain core-containing compound (V), wherein compounds (I), (I_T), (IV) and (V) have the following chemical structures;

2. The method of claim 1, wherein the 3-hydroxyflavaone derivative has one of the following chemical structures:

3. The method of claim 1, wherein the dipolarophile is a cinnamate derivative.

4. The method of claim 3, wherein the dipolarophile is

5. The method of claim 1, wherein the steps of producing an oxidopyrylium species and reacting the oxidopyrylium species with a dipolarophile are carried out in an aprotic solvent.

6. The method of claim 5, wherein the aprotic solvent is selected from the group consisting of hexane, toluene, pentane, cyclohexane, dioxane, carbon tetrachloride, benzene, carbon disulfide, toluene, diethyl ether, chloroform, ethyl acetate, tetrahydrofuran, methylene chloride, pyridine, dimethylformamide, acetonitrile, dimethylsulfoxide, and combinations thereof.

7. The method of claim 6, wherein the aprotic solvent is toluene.

8. The method of claim 7, wherein the aprotic solvent further comprises methylene chloride.

9. The method of claim 8, wherein the aprotic solvent is a 2:

1 mixture of toluene to methylene chloride.

10. The method of claim 5, wherein the steps of producing an oxidopyrylium species and reacting the oxidopyrylium species with a dipolarophile are carried out at a temperature lower than 0°

C.

11. The method of claim 10, wherein the temperature lower than 0°

C. is comprised in a range selected from the group consisting of between −

20°

C. and −

40°

C., between −

30°

C. and −

50°

C., between −

40°

C. and −

60°

C., between −

50°

C. and −

70°

C., between −

60°

C. and −

80°

C., and between −

70°

C. and −

90°

C.

12. The method of claim 11, wherein the temperature lower than 0°

C. is below about −

70°

C.

13. The method of claim 12, wherein the temperature lower than 0°

C. is about −

70°

C.

14. The method of claim 1, wherein the TADDOL derivative is recovered.

15. The method of claim 14, wherein the TADDOL derivative is recovered by precipitation from methanol.

16. The method of claim 1, wherein the aglain core structure is converted to a ring system selected from the group consisting of an aglain ring system, a rocaglamide ring system, and a forbaglin ring system.

17. The method of claim 16, wherein the ring system is a rocaglamide ring system.

18. The method of claim 17, wherein the ring system is a rocaglamide ring system of formula VII:

19. The method of claim 17, wherein the ring system is a rocaglamide ring system of formula VIII:

20. The method of claim 18, wherein the rocaglamide ring system of formula VII is selected from the group consisting of:

21. The method of claim 19, wherein the rocaglamide ring system of formula VIII is selected from the group consisting of: