Desymmetrizing Asymmetric Ring Expansion of Cyclohexanones

Significance

The authors report on the Lewis acid mediated reaction of chiral α-diazocarbonyl compound (+)-1 with cyclohexanones providing cyclic β-keto carbonyls bearing a kinetically stabilized α-hydrogen. This method reliably provides high selectivity and good yields for a range of different substrates. Furthermore, desymmetrization of meso-substrates allows for multiple stereocenters to be set in a single operation.

Comment

The authors rationalize the observed selectivity by proposing that cyclohexanones will undergo equatorial attack from the less sterically hindered prochiral face of (+)-1. The bulky carbonyl group will then orient itself in an anti fashion. Collapse of the intermediate then causes bond migration to occur from the backside of the leaving group, leading to inversion at this chiral center. Support for this proposal comes from the regio­selective reactions of chiral cyclohexanones, whereby switching the enantiomer of camphor­sultam one can select for either regioisomer. ­Cyclopentanones are not suitable substrates and attempted reaction led only to recovered starting materials. Cyclobutanones can be used; however, the resulting cyclopentanones exhibited epimeri­zation of the α-hydrogen upon purification. This ­instability could be avoided by reaction of the ­ketone functionality before isolation.