Synthesis of N-heterocycles, beta-amino acids, and allyl amines via aza-payne mediated reaction of ylides and hydroxy aziridines

• US 20090012120A1
• Filed: 05/09/2007
• Published: 01/08/2009
• Est. Priority Date: 05/10/2006
• Status: Abandoned Application

• Current Assignee: The Board of Trustees of Michigan State University (Michigan State University)
• Original Assignee: The Board of Trustees of Michigan State University (Michigan State University)
• Inventors: Schomaker, Jennifer M., Borhan, Babak, Korthals, Keith, Bhattacharjee, Somnath
• Application Number:
  US11/801,395
• Publication Number:
  US 20090012120A1
• Time in Patent Office: Days
• US Class Current: 514/315
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 207/12 Oxygen or sulfur atoms
• CPC Class Codes: C07D 209/32 Oxygen atoms
• CPC Class Codes: C07D 209/54 Spiro-condensed

Abstract

An ylide-based aza-Payne rearrangement of 2,3-aziridin-1-ols leads to an efficient process for the preparation of pyrrolidines. The aza-Payne rearrangement under the basic reaction conditions favors the formation of epoxy amines. Subsequent nucleophilic attack of the epoxide by the ylide yields a bis-anion, which upon a 5-exo-tet ring closure yields the desired pyrrolidine, thus completing the relay of the 3-membered the 5-membered nitrogen containing ring system. This process takes place with complete transfer of stereochemical fidelity, and can be applied to sterically hindered aziridinols.

Claims

1. A process for the preparation of a 2,3-di- or tri-substituted pyrrolidine which comprises reacting 1,2-epoxy-3-N protected amine with dimethylsulfoxonium methylide in an aprotic solvent to produce the 2,3-di- or tri-substituted pyrrolidine.

2. The process of claim 1 wherein the 1,2-epoxy-3-protected amine and the 2,3-pyrrolidine are stereoisomers.

3. The process of claim 1 wherein the 1,2-epoxy-3N protected amine has a protected hydroxy methyl group.

4. The process of claim 1 wherein the 1,2-epoxy 3-N-protected amine has an aliphatic or aromatic group containing 1 to 10 carbon atoms, which can be unsaturated, branched or straight chain or cyclic.

5. The process of any one of claims 1, 2, 3 or 4 wherein the reaction is in dimethylsulfoxide as the solvent at 80-85°

C. for at least 24 hours.

6. The process of any one of claims 1, 2, 3 or 4 wherein the amine is pre-formed by a base rearrangement of a 2,3-aziridin-1-ol.

7. The process of any one of claims 1, 2, 3 or 4, wherein the amine is pre-formed by a base rearrangement of a 2,3-aziridin-1-ol and wherein the base is the dimethylsulfoxonium methylide.

8. The process of any one of claims 1, 2, 3 or 4 wherein the amine is pre-formed by a base rearrangement of a 2,3-aziridin-1-ol, wherein the base is the dimethylsulfoxonium methylide and wherein the process is performed sequentially in a single reactor.

9. The process of any one of claims 1, 2, 3 or 4 wherein the amine is subsequently deprotected.

13. The use of any one of compounds produced by the process of claims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 or described in the attached description as an anti-cancer or anti-tumor or other pharmaceutical agent.

10. A process for producing a 1,2-allylic 3- or 4-N protected amine which comprises reacting a 1,2-allylic 3-N protected aziridine with dimethylsulfonium methylide to produce the 1,2-allylic 3- or 4-N-protected amine.

11. The process of claim 10 wherein the allylic 1,2-amine is converted to an amino acid by conversion of the 1,2-allylic group to a carboxylic acid group.

12. The process of claim 10 wherein the 1,2-allylic 4-N-protected amine is converted to a diene and then cyclized to produce a piperidine.