Design, synthesis and resolution of a chiral, non-racemic organometallic chiron: Asymmetric total syntheses of tetrahydropyridine based alkaloids

An enantiopure 5-oxo-(eta-2,3,4)-dihydropyridinyl molybdenum complex has been designed as a versatile organometallic chiron for the synthesis of piperidine based alkaloid natural products and biologically active pharmaceuticals. A scalable synthetic route starting from benzyl glycine ether ester has been developed. After installation of a chiral non-racemic (S)-1-phenylbutoxycarbonyl protecting group, the key scaffold was successfully resolved in large quantity and in high enantiomeric excess.; A series of 2,3,6-trisubstituted tetrahydropyridinyl molybdenum complexes were prepared in five steps from the platform complex. Organocerium addition of the key scaffold followed by dehydration afforded an ene-allyl complex. The key intermediate exocyclic olefin complex was synthesized efficiently through a one-pot regioseletive methoxy abstraction/nucleophilic addition/deprotonation sequence from the ene-allyl complex. A cascade protonation/organocuprate addition of the exocyclic olefin complex furnished the synthesis of 2,3,6-trisubstituted tetrahydropyridinyl molybdenum complex. The exocyclic olefin complex also underwent a novel Prins reaction initiated cascade reaction to give perhydroquinolinyl molybdenum complex. Further studies should lead to a general approach to perhydroquinoline alkaloids.; The 2,3,6-trisubstituted tetrahydropyridinyl molybdenum complexes underwent reductive or proto demetallation to afford 2,6-cis-3- trans-tetrahydropyridines and 2,3,6-cis tetrahydropyridines respectively. The generality, versatility and synthetic utility of this methodology have been demonstrated by the concise total syntheses of indolizidine (+/-)209I, indolizidine (+/-)-3-epi-219F, indolizidine (-)-251N, dehydroindolizidine (-)-233E and quinolizidine (-)-251AA.