Enantioselective
Enantiomeric bicyclic lactone compounds as can be prepared via an N-heterocyclic carbene-catalyzed annulation reaction.
1. A method of preparing a bicyclic lactone compound, said method
comprising: providing a mixture of a heterocyclic alkylidene imidazolidinone, a triazolium N-heterocyclic carbene catalyst precursor compound and a base component, said alkylidene imidazolidinone of a formula
wherein Ar is selected from aryl and substituted aryl moieties, said Ar substituents selected from alkyl, alkoxy, halo and haloalkyl substituents and combinations thereof, and R 1 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl and cycloalkyl moieties, said R 1 substituents selected from alkyl, alkoxy, halo and haloalkyl substituents and combinations thereof; and
introducing to said mixture an α,β-unsaturated aldehyde in the presence of an acid component, said aldehyde of a formula
wherein R 2 is selected from H, alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl moieties, said R 2 substituents selected from alkyl, alkoxy and halo substituents and combinations thereof, to provide a bicyclic lactone compound of a formula or a salt thereof
2. The method of claim 1 wherein said acid component is acetic acid.
3. The method of claim 2 wherein said base component is an acetate.
4. The method of claim 3 wherein said base component is an ammonium acetate.
5. The method of claim 1 wherein Ar is substituted aryl and a said Ar substituent is selected from fluoro- and chloro-substituents.
6. The method of claim 5 wherein a said substituent is at an ortho-position on said aryl moiety.
7. A method of using a heterocyclic conjugate acceptor component to prepare a bicyclic lactone compound of a formula
said method comprising:
providing a mixture of a heterocyclic alkylidene imidazolidinone, a triazolium N-heterocyclic carbene catalyst precursor compound and a base component, said alkylidene imidazolidinone of a formula
wherein Ar is selected from aryl and substituted aryl moieties, said Ar substituents selected from alkyl, alkoxy, halo and haloalkyl substituents and combinations thereof, and R 1 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl and cycloalkyl moieties, said R 1 substituents selected from alkyl, alkoxy, halo and haloalkyl substituents and combinations thereof;
introducing to said mixture an α,β-unsaturated aldehyde in the presence of an acid component, said aldehyde of a formula
wherein R 2 is selected from H, alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl moieties, said R 2 substituents selected from alkyl, alkoxy and halo substituents and combinations thereof, to couple said components; and
intramolecular O-acylation of said imidazolidinone to provide said bicyclic lactone compound or a salt thereof.
8. The method of claim 7 wherein said acid component is acetic acid.
9. The method of claim 8 wherein said base component is an acetate.
10. The method of claim 9 wherein said base component is an ammonium acetate.
11. The method of claim 7 wherein Ar is substituted aryl and a said Ar substituent is selected from fluoro- and chloro-substituents.
12. The method of claim 11 wherein a said substituent is at an ortho-position on said aryl moiety.
13. A compound selected from compounds of a formula
wherein Ar is selected from aryl and substituted aryl moieties, said Ar substituents selected from alkyl, alkoxy, halo and haloalkyl substituents and combinations thereof; R 1 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl and cycloalkyl moieties, said R 1 substituents selected from alkyl, alkoxy, halo and haloalkyl substituents and combinations thereof; and R 2 is selected from H, alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl moieties, said R 2 substituents selected from alkyl, alkoxy and halo substituents and combinations thereof, and salts thereof.
14. The compound of claim 13 wherein Ar is substituted aryl and a said Ar substituent is selected from fluoro- and chloro-substituents.
15. The compound of claim 14 wherein a said substituent is at an ortho-position on said aryl moiety.
16. The compound of claim 13 enantioenriched with a cis-diastereomer.
17. A compound selected from compounds of a formula
wherein Ar is selected from aryl and substituted aryl moieties, said Ar substituents selected from alkyl, alkoxy, halo and haloalkyl substituents and combinations thereof; R 1 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl and cycloalkyl moieties, said R 1 substituents selected from alkyl, alkoxy, halo and haloalkyl substituents and combinations thereof; and R 2 is selected from H, alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl moieties, said R 2 substituents selected from alkyl, alkoxy and halo substituents and combinations thereof, and salts thereof.
18. The compound of claim 17 wherein Ar is substituted aryl and a said Ar substituent is selected from fluoro- and chloro-substituents.
19. The compound of claim 18 wherein a said substituent is at an ortho-position on said aryl moiety.
20. The compound of claim 19 enantioenriched with a cis-diastereomer.