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

• US 8,137,509 B2
• Filed: 05/21/2007
• Issued: 03/20/2012
• Est. Priority Date: 05/22/2006
• Status: Active Grant

• Current Assignee: Trustees of Boston University
• Original Assignee: Trustees of Boston University
• Inventors: Gerard, Baudouin, Porco, John A. Jr.
• Primary Examiner(s): DENTZ, BERNARD I
• Application Number:
  US12/301,727
• Publication Number:
  US 20090299081A1
• Time in Patent Office: 1,765 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 comprising steps of:

photochemically generating an oxidopyrylium species from a 3-hydroxychromone derivative; and

reacting the oxidopyrylium species with a dipolarophile, wherein the steps of photochemically generating the oxidopyrylium species and of reacting the oxidopyrylium species with a dipolarophile are carried out in the presence of a TADDOL derivative.

2. The method of claim 1, wherein the oxidopyrylium species is photochemically generated via a process comprising an excited state intramolecular proton transfer.

3. The method of claim 2, wherein the step of reacting the oxidopyrylium species and the dipolarophile comprises a cycloaddition leading to the formation of an adduct.

4. The method of claim 3, wherein the cycloaddition comprises a 1,3-dipolar cycloaddition.

5. The method of claim 4, wherein the 1,3-dipolar cycloaddition is enantioselective.

6. The method of claim 2, wherein the oxidopyrylium species is photochemically generated from a 3-hydroxychromone derivative with the following chemical structure:

7. The method of claim 2, wherein the oxidopyrylium species is photochemically generated from a 3-hydroxyflavone derivative with the following chemical structure:

8. The method of claim 7, wherein the 3-hydroxyflavone derivative has one of the following chemical structures:

9. The method of claim 2, wherein the dipolarophile is a cinnamate derivative.

10. The method of claim 2, wherein the TADDOL derivative is a L-tartrate derivative.

11. The method of claim 2, wherein the TADDOL derivative has the following structure:

12. The method of claim 2, wherein the TADDOL derivative has the following structure:

13. The method of claim 2, wherein the steps of photochemically generating the oxidopyrylium species and of reacting the oxidopyrylium species with a dipolarophile are carried out in an aprotic solvent.

14. The method of claim 13, 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.

15. The method of claim 2, wherein the steps of photochemically generating the oxidopyrylium species and of reacting the oxidopyrylium species with a dipolarophile are carried out at a temperature lower than 0°

C.

16. The method of claim 15, 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.

17. The method of claim 3 further comprising a step of converting the adduct formed.

18. The method of claim 17, wherein the adduct formed comprises an aglain core structure and wherein converting the adduct formed results in formation of a ring system selected from the group consisting of an aglain ring system, a rocaglamide ring system, and a forbaglin ring system.

19. 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;

21. The method of claim 19 or 20, wherein the step of reacting the oxidopyrylium species with the dipolarophile comprises a 1,3-dipolar cycloaddition.

22. The method of claim 21, wherein the 1,3-dipolar cycloaddition is enantioselective.

24. The method of claim 19 or 20, wherein the dipolarophile (IV) is a cinnamate derivative with the following chemical structure:

25. The method of claim 19 or 20, wherein the TADDOL derivative is a L-tartrate derivative.

26. The method of claim 19 or 20, wherein the TADDOL derivative has the following structure:

27. The method of claim 19 or 20, wherein the TADDOL derivative has the following structure:

28. The method of claim 19 or 20, wherein the steps of producing the oxidopyrylium species and of reacting the oxidopyrylium species with a dipolarophile are carried out in an aprotic solvent.

29. The method of claim 28, 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.

30. The method of claim 19 or 20, wherein the steps of producing the oxidopyrylium species and of reacting the oxidopyrylium species with a dipolarophile are carried out at a temperature lower than 0°

C.

31. The method of claim 30, 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.

32. The method of claim 19 further comprising a step of converting the compound with an aglain core structure into a rocaglamide (VII) with the following chemical structure:

34. The method of claim 32 or 33, wherein converting the compound with an aglain core structure into a rocaglamide derivative comprises an α

-ketol (acyloin) rearrangement.

35. The method of claim 34, wherein the α

-ketol (acyloin) rearrangement comprises a base-mediated reaction.

36. The method of claim 19 further comprising a step of converting the compound with an aglain core structure into a rocaglamide derivative (VIII) with the following chemical structure:

38. The method of claim 36 or 37, wherein converting the compound with an aglain core structure into a rocaglamide derivative comprises an α

-ketol (acyloin) rearrangement and a hydroxyl-directed reduction.

39. The method of claim 38, wherein the α

-ketol (acyloin) rearrangement comprises a base-mediated reaction.

40. The method of claim 36 or 37, wherein said method produces a mixture of endo and exo isomers of the rocaglamide derivative such that the mixture comprises more endo isomer than exo isomer.

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

producing an oxidopyrylium species (II_T) by photoinduced excited state intramolecular proton transfer of a 3-hydroxyflavone derivative (II); and

reacting the oxidopyrylium species with a dipolarophile (IV) to obtain the aglain core-containing compound (V′

), wherein compounds (II), (II_T), (IV) and (V′

) have the following chemical structures;

23. The method of claim 20, wherein the 3-hydroxyflavone derivative has one of the following chemical structures:

33. The method of claim 20 further comprising a step of converting the compound with an aglain core structure into a rocaglamide derivative (VII′

) with the following chemical structure;

37. The method of claim 20 further comprising a step of converting the compound with an aglain core structure into a rocaglamide derivative (VIII′

) with the following chemical structure;