RESUMO
Stereoselective, intramolecular, formal hydroamination of dienamines via directed hydroboration is reported. Four stereocenters are set in the process. Natural and unnatural indolizidine alkaloids can be synthesized from simple unsaturated amines using the title process.
Assuntos
Indolizidinas/síntese química , Polímeros/síntese química , Aminação , Cristalografia por Raios X , Indolizidinas/química , Modelos Moleculares , Conformação Molecular , Polímeros/química , EstereoisomerismoRESUMO
ß-Lactam antibiotics, one of the most important class of human therapeutics, act via the inhibition of penicillin-binding proteins (PBPs). The unparalleled success in their development has inspired efforts to develop them as inhibitors of other targets. Bacterial type I signal peptidase is evolutionarily related to the PBPs, but the stereochemistry of its substrates and its catalytic mechanism suggest that ß-lactams with the 5S stereochemistry, as opposed to the 5R stereochemistry of the traditional ß-lactams, would be required for inhibition. We report the synthesis and evaluation of a variety of 5S penem derivatives and identify several with promising activity against both a Gram-positive and a Gram-negative bacterial pathogen. To our knowledge these are the first 5S ß-lactams to possess significant antibacterial activity and the first ß-lactams imparted with antibacterial activity via optimization of the inhibition of a target other than a PBP. Along with the privileged status of their scaffold and the promise of bacterial signal peptidase I (SPase) as a target, this activity makes these compounds promising leads for development as novel therapeutics.
RESUMO
Dissection of lepadiformine by a double hydroamination transform affords a simple achiral amino diene. This reaction is accomplished in the forward sense by amine-directed hydroboration and an oxidative alkyl shift to nitrogen, both of which occur with high stereoselectivity to generate three stereogenic centers and the lepadiformine skeleton.