Synthesis of chiral heterocycles by ligand-controlled regiodivergent and enantiospecific Suzuki Miyaura cross-coupling.
Non-aromatic nitrogen- and oxygen-containing heterocycles such as piperidines and pyrans are prevalent components of natural products and pharmaceutical drugs. Although it has been a workhorse as a synthetic method for assembling unsaturated sp(2)-hybridized substrates, transition metal-catalysed cross-coupling chemistry is traditionally not a suitable approach to prepare chiral non-aromatic heterocycles. Several mechanistic issues hamper the coupling of stereogenic secondary sp(3)-hybridized carbon-metal centres. Moreover, use of unsymmetrical allylic boronates in the Suzuki Miyaura cross-coupling is further complicated by the possibility of forming two regioisomeric products. Here we address this two-pronged problem and demonstrate that chiral enantiomerically enriched heterocyclic allylic boronates can be coupled with high stereochemical retention with a wide variety of aryl and alkenyl halides to independently afford both regioisomeric 2- and 4-substituted dihydropyrans and dehydropiperidines in high selectivity. A divergent mechanism is proposed where regiochemistry is governed by the nature of the ligands on the palladium catalyst. This scalable method is applied to the efficient preparation of the neuroactive alkaloid anabasine and the antidepressant drug paroxetine.
Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2.
Jinyue
J
Ding
Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2.
Taras
T
Rybak
Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2.
Dennis G
DG
Hall
D000691:Anabasine / Q000138:chemical synthesis* / Q000737:chemistry; D002384:Catalysis; D008024:Ligands; D015394:Molecular Structure; D010165:Palladium / Q000737:chemistry*; D017374:Paroxetine / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
D008024:Ligands; D017374:Paroxetine; D010165:Palladium; D000691:Anabasine