Organocatalytic [3+3] cycloaddition

Ξ August 26th, 2008 | → 0 Comments | ∇ Organocatalytic Cycloaddition |

 

 Organocatalytic Asymmetric Formal [3+3] Cycloaddition Reactions of α,β-Unsutered Aldehydes with Nazarov Reagents

 


Tetrahydropyran and dihydropyran derivates are very important frameworks in organic chemistry as this structures form the core unit of many natural substances; they also are important building blocks with widesperad applications in organic synthesis.

There are lots of methodology to access 2,3-dihydropyran derivates, such as for example hetero-Diels-Alder reactions, but there aren’t protocols for the synthesis of 1 (figure below); the presence of a C=C bond conjugated to an enol increases the possybility of further structure modifications.

 

 

Very recently Jorgensen and co-workers have reported that α,β-unsutered aldehydes 2 underwent a tandem Michela/Morita-Baylis-Hillman reaction with Nazarov reagent 3, with prolinol derivates as catalyst, to afford cycloexanone derivates with high stereoselectivity.

However, the Nazarov reagent 4 in presence of prolinol as catalyst didn’t undergo the tandem Micheal/MBH reaction, but underwent a formal [3+3] cycloaddition, which after oxidation, furnished a chiral pyranone in good yield and ee.

 

 

The optimized procedure was tyhen extended to formal [3+3] cycloaddition reactions  between varius unsatured aldehydes and Nazarov reagents.

Gong e co-workers have also proposed a mechanism for the cycloaddition.

 

The unsutered aldehydes 5 first condensed with chiral catalyst to afford imminium salt 6. Enantioselective Micheal addition of Nazarov reagents 7 afforded intermediates 8 which can be isomerized to 9 that occur from an intramolecular oxo-addition to form intermediates 10. Then hydrolysis generates the product 11 and the catalyst.