A TANDEM HORNER-EMMONS OLEFINATION-CONJUGATE ADDITION APPROACH TO THESYNTHESIS OF 1,5-DISUBSTITUTED-6-AZABICYCLO[3.2.1]OCTANES BASED ON THE AE RING STRUCTURE OF THE NORDITERPENOID ALKALOID METHYLLYCACONITINE

A novel Horner-Emmons olefination conjugate addition reaction of N-ace tylamides to form 1,5-disubstituted-6-azabicyclo[3.2.1]octane with two bridgehead quarternary carbon centers is reported. This reaction is a key step in an approach to the synthesis of small ring analogues base d on the AE ring structure of the Delphinium norditerpenoid, methyllyc aconitine (MLA) (1). Initially, 3-(hydroxymethyl)cyclohex-2-en-1-one ( 10) was selected as the starting material to these structures, but its generation proved inefficient. In contrast, the synthesis of 3-[(phen ylthio)methyl]cyclohex-2-en-1-one (6) and 3-(1,3-dithian-2-yl)cyclohex -2-en-1-one (11) proceeded in good yield. Subsequent hydrocyanation, k etalization, reduction, acetylation, deprotection of the acetal, and H orner-Emmons olefination-conjugate addition reaction to form onyl)meth yl]-6-acetamido-6-azabicyclo[3.2.1]octane (28), arbonyl)methyl]-6-acet yl-6-azabicyclo[3.2.1]octane (29), respectively, are reported, as well as for readily available 3-methylcyclohex-2-en-1-one (12). Studies on the Pummerer rearrangement of 28 and subsequent desulfurization and r eduction to form an hydroxymethyl-substituted azabicyclo[3.2.1.]octane (40) and then selective protection to form a protected hydroxyethyl N -ethyl (hydroxymethyl)azabicyclo[3.2.1]octane (3) are also described.