Modular Assembly of beta-Amino Acids via Donor-Acceptor Cyclopropanes
Final Report Abstract
A new strategy to prepare β-amino acid derivatives from readily available olefins and alkyl amines was developed. β-Amino carbonyls are interesting chemical motifs present in a wide range of bioactive molecules, e.g. the antiarrhythmic moracizine. The most common routes to access these compounds are the aza-Michael and Mannich additions. Except for simple acrylates, the aza-Michael addition proceeds sluggishly in low yields under non-hyperbaric conditions. The Mannich addition offers a more generable approach, but the required iminium ion intermediates are sensitive to base-mediated enolisation. Mukaiyama’s pioneering approach tackles this using softer silyl ketene acetals, but strong bases are required for the deprotonation of carbonyl derivatives (e.g. LDA), excluding the presence of weakly acidic functional groups. Intramolecular Mannich additions cannot be used to synthesize cyclic β-aminocarbonyl derivatives, while cyclic Michael acceptors are not widely available and expensive compared to cycloalkenes. I developed a visible-lightmediated atom-transfer radical addition-ring closure sequence using bromomalononitrile for the preparation of 1,1-dicyanocyclopropanes from olefins, and investigated their nucleophilic ring-opening with amines. The resulting aminomalononitriles were converted to β- aminocarbonyl derivatives in one pot under aerobic conditions.
