Transition metal initiators for controlled poly (beta-peptide) synthesis from beta-lactam monomers

• US 6,818,732 B2
• Filed: 08/30/2002
• Issued: 11/16/2004
• Est. Priority Date: 08/30/2001
• Status: Active Grant

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Cheng, Jianjun, Deming, Timothy J.
• Primary Examiner(s): HAMPTON HIGHTOWER, PATRICIA
• Application Number:
  US10/232,049
• Publication Number:
  US 20030083460A1
• Time in Patent Office: 809 Days
• Field of Search: 528/310, 528/312, 528/323, 528/324, 528/329.1, 528/328, 528/342, 528/363, 525/420
• US Class Current: 528/328
• CPC Class Codes: C08G 69/22 Beta-lactams

Abstract

A series of initiators based on transition metal complexes for the polymerization of optically active beta-lactams into poly-beta-peptides and block copolymers have been developed. These initiators are unique in being able to eliminate chain transfer and chain termination side reactions from these polymerizations resulting in narrow molecular weight distributions, molecular weight control, and the ability to prepare copolymers of defined block sequence and composition.

Claims

1. A method of making a poly(β

-peptide) comprising, combining a beta lactam monomer and a transition metal complex, said complex comprising a transition metal and a nucleophilic ligand, for a time and under conditions effective to polymerize the beta lactam monomer and to form the poly(β

-peptide).

2. The method of claim 1, said poly(β

-peptide) having the formula;

wherein R is hydrogen or an alkyl, aryl, oligo-ethylene glycol monomethyl, or side-chain protecting group and n is about 5 to about 200.

3. The method of claim 2 wherein R is an oligo-ethylene glycol monomethyl moiety having the formula —

(CH₂CH₂O)_nCH₃, wherein n is one to twenty.

4. The method of claim 2 wherein R is isobutyl.

5. The method of claim 1, wherein the transition, metal is selected from the group consisting of Ni, Co, Cu, Fe, Sc, and Mg.

6. The method of claim 1 wherein the ligand is N(TMS)₂, wherein TMS is trimethyl silyl, or an amido amidate (AA), wherein AA is (NHCH(CH(CH₃)₂)C(O)NH₂C(CH₃)₃).

7. The method of claim 1 wherein the transition metal complex is a transition metal amido complex.

8. The method of claim 1 wherein the transition metal complex is selected from the group consisting of Sc(N(TMS)₂)₃, Zn(N(TMS)₂)₂, Cr(N(TMS)₂)₃, Co(N(TMS)₂)₂, Cu(N(TMS)₂)₂, Mg(N(TMS)₂)₂, and Fe(N(TMS)₂)₃, wherein TMS is trimethyl silyl.

9. The method of claim 1 wherein the transition metal complex is BDIMgN(TMS)₂, or BDIZnN(TMS)₂, wherein BDI is 2-((2,6-diisopropylphenyl)amido)-4-((2,6-diidopropylphenyl)imino)-2-pentene) and TMS is trimethyl silyl.

10. The method of claim 1 wherein the transition metal complex is DEPENiAA, wherein DEPE is 1,2-bis(dimethylphosphino)ethane and M is an amido amidate having the formula NHCH(CH(CH₃)₂)C(O)NH₂C(CH₃)₃.

11. The method of claim 1 wherein the transition metal complex is Co(PMe₃)₄, wherein Me is methyl.

12. The method of claim 1, wherein the transition metal complex is a Ru-amido complex having the formula (para-cymene)Ru(NHCH₂CH₂NS(O)₂C₆H₅CH₃).

13. The method of claim 1, wherein said beta lactam monomer is selected from the group-consisting of (S)-4-(benzyloxycarbonyl)-2-azetidinone, (S)-4-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)carbonyl-2-azetidinone, and (S)-4-(2-(2-(2(2-methoxyethoxy)ethoxy)ethoxy)ethoxy)carbonyl-2-azetidinone.

14. The method of claim 1, wherein the polymerization of beta lactam monomer is a living polymerization controlled by monomer to initiator stoichiometry.

15. The method of claim 1 wherein the poly(β

-peptide) is a homopolymer.

18. A composition comprising a poly(β

-peptide) made according to claim 1 and another beta-lactam monomer.

16. A composition of matter comprising a beta lactam monomer and a transition metal complex, said complex comprising a transition metal and a nucleophilic ligand.

17. A composition of matter made by combining a beta lactam monomer and a transition metal complex, said complex comprising a transition metal and a nucleophilic ligand.

19. A poly(β

-peptide) having the formula;

wherein R is an alkyl, aryl, oligo-ethylene glycol monomethyl, or side-chain protecting group and n is about 5 to about 200.

20. The poly(β

-peptide) of claim 19 having a polydispersity index of about 1 to about 1.3.

21. The poly(β

-peptide) of claim 19 having a molecular weight of about 10,000 to about 250,000.

22. A method of making a metalated lactam comprising, combining a beta lactam monomer and a transition metal complex, said complex comprising a transition metal and a reactive nucleophilic ligand, for a time and under conditions effective liberate a reactive ligand and to form the metalated lactam.

23. The method of claim 22, wherein the transition metal is selected from the group consisting of Ni, Co, Cu, Fe, Sc, and Mg.

24. The method of claim 22 wherein the ligand is N(TMS)₂, wherein TMS is trimethyl silyl, or an amido amidate (AA), wherein AA is (NHCH(CH(CH₃)₂)C(O)NH₂C(CH₃)₃).

25. The method of claim 22 wherein the transition metal complex is a transition metal amido complex.

26. The method of claim 22 wherein the transition metal complex is selected from the group consisting of Sc(N(TMS)₂)₃, Zn(N(TMS)₂)₂, Cr(N(TMS)₂)₃, Co(N(TMS)₂)₂, Cu(N(TMS)₂)₂, Mg(N(TMS)₂)₂, and Fe(N(TMS)₂)₃, wherein TMS is trimethyl silyl.

27. The method of claim 22 wherein the transition metal complex is BDIMgN(TMS)₂, or BDIZnN(TMS)₂, wherein BDI is 2-((2,6-diisopropylphenyl)amido)-4-((2,6-diidopropylphenyl)imino)-2-pentene) and TMS is trimethyl silyl.

28. The method of claim 22 wherein the transition metal complex is DEPENiAA, wherein DEPE is 1,2-bis(dimethylphosphino)ethane and M is an amido amidate having the formula NHCH(CH(CH₃)₂)C(O)NH₂C(CH₃)₃.

29. The method of claim 22 wherein the transition metal complex is Co(PMe₃)₄, wherein Me is methyl.

30. The method of claim 22, wherein the transition metal complex is a Ru-amido complex having the formula (para-cymene)Ru(NHCH₂CH₂NS(O)₂C₆H₅CH₃).

31. The method of claim 22, said metalated lactam having the formula:

wherein R is an alkyl, aryl, oligo-ethylene glycol monomethyl moiety or side chain protecting group;

M is a transition metal, L is a ligand and n is 1, 2 or 3.

32. A composition of matter comprising a beta lactam monomer and a metalated lactam made according to claim 22.

33. A method of making a block copoly (β

-peptide) comprising;

combining a first beta lactam monomer and a transition metal complex, said complex comprising a transition metal and a nucleophilic ligand, in a reaction mixture, for a time and under conditions effective to polymerize the first beta lactam monomer and to form a first block of the block copoly (β

-peptide); and

adding a second beta lactam monomer to the reaction mixture, wherein the second monomer is different from the first monomer, for a time and under conditions effective to polymerize the second beta lactam monomer and to form a second block of the block copoly (β

-peptide).

34. The method of claim 33 wherein the block copoly (β

-peptide) is an amphiphilic block copoly (β

-peptide), the first block having one or more hydrophilic side chains and the second block having one or more hydrophobic side chains.

35. The method of claim 33 wherein the hydrophilic side chains of the first block are charged or oligo-ethylene glycol functionalized side chains.

36. The method of claim 33, wherein the hydrophobic side chains of the second block are alkyl or aryl esters.

40. A composition comprising a block copoly (β

-peptide) made according to claim 33.

37. A block copoly (β

-peptide) comprising a first block and a second block attached to the first block, the first block having ten or more identical first beta amino acid residues and the second block having ten or more identical second beta amino acid residues, wherein the second beta amino acid residues are different than the first beta amino acid residues.

38. The block copoly (β

-peptide) of claim 37, which is an amphiphilic block copoly (β

-peptide), said first beta amino acid residue having a hydrophilic side group and said second beta amino acid residue having a hydrophobic side group.

39. The block copoly (β

-peptide) of claim 37, having a polydispersity index of about 1 to about 1.3.