Methods for the Synthesis of Two or More Dicarba Bridges in Organic Compounds

• US 20090143565A1
• Filed: 09/26/2008
• Published: 06/04/2009
• Est. Priority Date: 02/17/2006
• Status: Active Grant

• Current Assignee: Syngene Limited
• Original Assignee: Syngene Limited
• Inventors: Robinson, Andrea, Elaridi, Jomana, Patel, Jim, Jackson, Roy William
• Granted Patent: US 8,362,204 B2
• Time in Patent Office: Days
• US Class Current: 530/317
• CPC Class Codes: C07B 37/04 Substitution
• CPC Class Codes: C07K 1/006 of peptides containing derivatised side chain amino acids
• CPC Class Codes: C07K 1/061 using protecting groups
• CPC Class Codes: C07K 1/107 by chemical modification of precursor peptides
• CPC Class Codes: C07K 1/1075 by covalent attachment of amino acids or peptide residues
• CPC Class Codes: C07K 1/1077 by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids

Abstract

Described herein are methods for forming two or more dicarba bridges, as well as new compounds containing dicarba bridges.

Claims

1. A method for synthesizing an organic compound with two or more dicarba bridges, the method comprising:

(a) providing one or more reactable organic compounds having, within a single compound or between the one or more compounds (i) a first pair of complementary metathesisable groups that are unblocked, (ii) a second pair of complementary metathesisable groups that are blocked but can be unblocked by an unblocking reaction or series of reactions specific to the second pair, and (iii) optionally, one or more further pairs of complementary methathesisable groups that are blocked but can be unblocked by an unblocking reaction or series of reactions specific to each further pair;

(b) subjecting the reactable organic compound or compounds to cross-metathesis to form an organic compound with an unsaturated dicarba bridge across the first pair of complementary metathesisable groups, without cross-metathesis between the pair or pairs of blocked complementary metathesisable groups;

(c) subjecting the second pair of complementary metathesisable groups to the unblocking reaction or series of reactions specific to the second pair;

(d) subjecting the second pair of complementary metathesisable groups to cross-metathesis to form an organic compound with an unsaturated dicarba bridge across the second pair of complementary metathesisable groups, without cross-methathesis between any pair or pairs of complementary methathesisable groups that remain blocked; and

(e) if any complementary metathesisable groups remain, subjecting those groups to unblocking reactions specific to those pairs, followed by cross metathesis.

2. The method of claim 1, comprising hydrogenation of one or more of the unsaturated dicarba bridges formed by cross-metathesis.

3. The method of claim 1, further comprising subjecting the unsaturated dicarba bridge formed between the first pair of complementary metathesisable groups to hydrogenation and subjecting the unsaturated dicarba bridge formed between the second pair of complementary metathesisable groups to hydrogenation, wherein each hydrogenation is performed separately or at the same time.

4. The method of claim 1, wherein conducting one or each of the cross-metathesis reactions for forming a dicarba bridge is conducted under microwave radiation conditions.

5. The method of claim 1, wherein the complementary metathesisable groups of the first pair of complementary metathesisable groups are each independently selected from the group consisting of olefins comprising the portion ═

CH₂ and monosubstituted olefins comprising the group ═

CHR₅, wherein R₅ is alkyl or an alkyl substituted by a polar functional group.

6. The method of claim 1, wherein the blocking group of the second pair of complementary metathesisable groups is a steric blocking group, and the unblocking reaction comprises removal of the steric blocking group or conversion of the steric blocking group to a group that is cross-metathesisable.

7. The method of claim 6, wherein the steric blocking group comprises a 1,1-dialkylated olefin.

8. The method of claim 1, wherein the unblocking reaction or series of reactions specific to the second pair of complementary metathesisable groups comprises cross-metathesis with a disposable olefin.

9. The method of claim 8, wherein the cross-metathesis with a disposable olefin comprises cross-metathesis with disposable olefin that is a mono-substituted ethylene or a 1,2-disubstituted ethylene.

10. The method of claim 9, wherein the cross-metathesis with a disposable olefin comprises cross-metathesis with a disposable olefin comprising a polar functional group.

11. The method of claim 1, wherein the reactable organic compound comprises a third pair of complementary methathesisable groups that are blocked and can be unblocked by an unblocking reaction or series of reactions specific to the third pair, and the method comprises subjecting the third pair of complementary metathesisable groups to unblocking reactions specific to those pairs, followed by cross metathesis.

12. The method of claim 11, wherein the blocking group of the third pair of complementary metathesisable groups comprises an electronic blocking group, and the unblocking reactions comprise conversion of the electronic steric blocking group to a group that is cross-metathesisable.

13. The method of claim 12, wherein the electronic blocking group comprises a diblocked conjugated diene, and the unblocking reaction comprises subjecting the blocked third pair of complementary metathesisable groups to asymmetric hydrogenation to regioselectively, stereoselectively and chemoselectively hydrogenate one of the diene double bonds to leave a sterically-blocked double bond, followed by cross-metathesis with a disposable olefin to effect removal of the steric blocking groups on the remaining double bond, to yield unblocked complementary metathesisable groups.

14. The method of claim 12, wherein the electronic blocking group comprises

═

CH—

CH═

CR₃R₄, wherein R₃ and R₄ are each alkyl, and the unblocking reaction comprises hydrogenation of this group to ═

CH—

CH₂—

CHR₃R₄, followed by cross-metathesis with a disposable olefin to yield the unblocked group ═

CHR₅, wherein R₅ is alkyl or an alkyl substituted by a polar functional group.

15. The method of claim 1, wherein the reactable organic compound, or one of the reactable organic compounds, is attached to a solid support during the cross-metathesis of the complementary metathesisable groups.

16. The method of claim 15, wherein the loading of the reactable organic compound on the solid support is at least 0.2 mmol/g.

17. The method of claim 15, wherein the loading of the reactable organic compound on the solid support is at least 0.5 mmol/g.

18. The method of claim 15, wherein each cross-metathesis is performed using a cross-metathesis catalyst, and each cross-metathesis is performed in a solvent combination of a resin-swelling solvent, with a coordinating solvent for the catalyst.

19. The method of claim 18, wherein the coordinating solvent is an alcohol.

20. The method of claim 18, wherein the coordinating solvent is used in an amount of about 1-30% by volume, with respect to the total solvent combination.

21. The method of claim 15, wherein the reactable organic compound is a peptide.

22. The method of claim 21, wherein the organic compound with two or more dicarba bridges prepared by the method is a peptidomimetic.

23. The method of claim 21, wherein the organic compound with two or more dicarba bridges prepared by the method is a pseudopeptide.

24-75. -75. (canceled)