Synthesis of rocaglamide natural products via photochemical generation of oxidopyrylium species

• US 7,816,544 B2
• Filed: 03/23/2005
• Issued: 10/19/2010
• Est. Priority Date: 03/23/2004
• Status: Active Grant

• Current Assignee: Trustees of Boston University
• Original Assignee: Trustees of Boston University
• Inventors: Porco, John A. Jr., Jones, Guilford II, Gerard, Baudouin
• Primary Examiner(s): Seaman; D. Margaret
• Assistant Examiner(s): Chandrakumar; Nizal S
• Application Number:
  US10/593,502
• Publication Number:
  US 20080177093A1
• Time in Patent Office: 2,036 Days
• Field of Search: 549/355, 549/402, 549/458
• US Class Current: 549/354
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 307/93 condensed with a ring other than six-membered
• CPC Class Codes: C07D 311/30 not hydrogenated in the hetero ring, e.g. flavones
• CPC Class Codes: C07D 313/08 condensed with one six-membered ring
• CPC Class Codes: C07D 493/08 Bridged systems

Abstract

The present invention provides new strategies for the synthesis of compounds of the rocaglamide family and related natural products. In particular, the new biomimetic synthetic approach involves photochemical generation of an oxidopyrylium species from a 3-hydroxychromone derivative followed by 1,3-dipolar cycloaddition of the oxidopyrylium species to a dipolarophile. This approach can be used for the formation of adducts containing an aglain core structure. Methods for 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:

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

performing a cycloaddition reaction between the oxidopyrylium species and a dipolarophile to form a cycloadduct.

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

3. The method of claim 1, wherein the oxidopyrylium species is photochemically generated from a 3-hydroxychromone derivative with the following chemical structure:

4. The method of claim 1, wherein the oxidopyrylium species is photochemically generated from a 3-hydroxychromone derivative with the following chemical structure:

5. The method of claim 4, wherein the 3-hydroxychromone derivative has one of the following chemical structures:

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

7. The method of claim 1, further comprising converting the cycloadduct.

8. The method of claim 7, wherein the cycloadduct is converted into a compound selected from the group consisting of:

9. The method of claim 3 or 4, wherein:

the dipolarophile is of formula (IV);

(R_a)HC═

CH(R_b) 

 

(IV);

and the cycloadduct is of formula (V) or (V′

);

10. The method of claim 9, wherein the 3-hydroxychromone derivative has one of the following chemical structures:

11. The method of claim 9, further comprising converting the compound of formula (V) into a compound of formula (VI):

12. The method of claim 9, further comprising converting the compound of formula (V′

) into a compound of formula (VI'"'"');

13. The method of claim 12, wherein the 3-hydroxychromone derivative has one of the following chemical structures:

14. The method of claim 11 or 12, wherein converting the compound of formula (V) or (V′

) into a compound of (VI) or (VI′

) comprises a reduction.

15. The method of claim 14, wherein the reduction comprises using NaBH₄ or Me₄NBH(OAc)₃.

16. The method of claim 11 or 12, wherein converting the compound of formula (V) or (V′

) into a compound of (VI) or (VI′

) comprises addition of a nucleophile.

17. The method of claim 9, further comprising converting the compound of formula (V) into a compound of formula (VII):

18. The method of claim 9, further comprising converting the compound of formula (V′

) into a compound of formula (VII′

);

19. The method of claim 18, wherein the 3-hydroxychromone derivative has one of the following chemical structures:

20. The method of claim 17 or 18, wherein converting the compound of formula (V) or (V′

) into a compound of formula (VII) or (VII′

) comprises an α

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

21. The method of claim 20, wherein the α

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

22. The method of claim 9, further comprising converting the compound of formula (V) into a compound of formula (VIII):

23. The method of claim 9, further comprising converting the compound of formula (V′

) into a compound of formula (VIII′

);

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

25. The method of claim 22 or 23, wherein converting the compound of formula (V) or (V′

) into a compound of formula (VIII) or (VIII′

) comprises an α

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

26. The method of claim 25, wherein the α

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

27. The method of claim 9, further comprising converting the compound of formula (V) into a compound of formula (IX):

28. The method of claim 9, further comprising converting the compound of formula (V′

) into a compound of formula (IX′

);

29. The method of claim 28, wherein the 3-hydroxychromone derivative has one of the following chemical structures:

30. The method of claim 27 or 28, wherein converting the compound of formula (V) or (V′

) into a compound of formula (IX) or (IX′

) comprises an oxidative cleavage.

31. The method of claim 30, wherein the oxidative cleavage comprises using Pb(OAc)₄.