Lewis acid-assisted ene cyclization of 2-azetidinone-tethered enals: synthesis of enantiopure carbacepham derivatives.

Diastereocontrolled Lewis acid-catalyzed preparation of enantiopure carbacepham derivatives have been developed starting from 2-azetidinone-tethered enals. The BF3.Et2O-promoted reaction of alkenylaldehydes 1 and 16 is effective as carbocyclization protocol to afford 4-substituted 5-hydroxycarbacephams or 3-substituted 4,5-dihydroxycarbacephams, respectively, by a type I carbonyl-ene reaction, while the BF3.Et2O or SnCl4-mediated type II carbonyl-ene cyclization of alkenylaldehydes 2 furnishes 3-methylene 5-hydroxycarbacephams along with the corresponding 3-halo 5-hydroxycarbacepham. The stereochemical outcome of these carbonyl-ene cyclizations leading to carbacepham derivatives can be explained in terms of six-membered, cyclic chair-like transition-state models. The formation of halocarbacepham derivatives is proposed to proceed by a stepwise mechanism.

Lewis acid-promoted intermolecular carbonyl-ene reaction of enantiopure 4-oxoazetidine-2-carbaldehydes. Rapid entry to novel fused polycyclic beta-lactams.

Lewis acid-promoted carbonyl-ene reaction of enantiomerically pure 4-oxoazetidine-2-carbaldehydes with various activated alkenes gives 4-[(1'-hydroxy)homoallyl]-beta-lactams with a very high level of syn diastereofacial selectivity. The above homoallylic alcohols are used for the diastereoselective preparation of fused bicyclic, tricyclic, and tetracyclic beta-lactams of nonconventional structure using tandem one-pot radical addition/cyclization or elimination-intramolecular Diels-Alder sequences. In addition, a novel domino process was discovered, the C4-N1 beta-lactam bond breakage/intramolecular Diels-Alder reaction.

Stereoselective Synthesis of Fused Bicyclic beta-Lactams through Radical Cyclization of Enyne-2-azetidinones(1).

A convenient, stereoselective entry to racemic and enantiomerically pure fused bicyclic beta-lactams has been developed that involves the radical-mediated cycloisomerization of easily available monocyclic enyne-beta-lactams as the key synthetic step. These compounds are obtained provided that an activated double bond is present as a radical acceptor. In the absence of this condition, new forms of reactivity were observed, including C3-C4 bond cleavage of the beta-lactam ring to yield tetrahydropyridine derivatives and 1,5-radical translocation to yield new bicyclic derivatives. Some simple transformations were tested on representative examples of the different types of bicyclic systems prepared to demonstrate their potential as intermediates in the preparation of other differently functionalized systems.