(--)-sparteine mediated asymmetric synthesis through conjugate addition of allylic and benzylic organolithium species: Development of a methodology and its application toward a total synthesis

Organolithium/(−)-sparteine complexes derived from N-Boc- N-(p-Methoxyphenyl)benzyl- and cinnamylamines have been shown to be powerful nucleophiles for conjugate addition reactions. Reactions between configurationally stable benzylic and allylic organolithium/(−)-sparteine complexes and doubly activated olefins proceed with high regio-, diastereo-, and enantioselectivity to provide exclusively 1,4-addition products. Ketone, ester, cyano, and nitro functional groups all activate alkenes for conjugate addition of the benzylic and allylic organolithium species without requiring a copper transmetalation step. In addition, the methodology is general to both trisubstituted and tetra substituted activated olefins; thus, products with either contiguous tertiary-tertiary or tertiary-quaternary carbon centers may be accessed with high stereocontrol. A rationale for the regioselection of the organolithium species in conjugate addition reactions is based on known structural and electronic properties of the organolithium/(−)-sparteine complexes.; The synthetic utility of the methodology is demonstrated with the synthesis of diastereo-, and enantiomerically pure 2,3,4-trisubstituted γ-lactams in high yield. In addition, conjugate addition of the allylic organolithium species with N-protected 4-pyridones provides high yields of the corresponding 1,4-addition adduct with high enantiomeric ratios (ers). The reaction is believed to proceed through an N-acyl pyridinium salt formed on reaction of N-protected pyridone with TMSCl. An organolithium species derived from N-Boc-N-( p-Methoxyphenyl)dimethylphenylsilyl-allylamine, stabilized with a silyl group rather than a phenyl, has been successfully employed in this lithiation-conjugate addition sequence. The enantioenriched products that arise on electrophilic substitution with N-protected pyridones are precursors to piperidine alkaloids. Moreover, this reaction has been applied as the key step in the total synthesis of an immediate precursor to the indolizidine alkaloid castanospermine.