| Novel N-(alkoxycarbony1)-4-exo-8- anti-disubstituted-6-azabicyclo[3.2.1]octanes have been stereoselectively synthesized by addition-rearrangement of 2-azabicyclo[2.2.2]oct-5-enes, using IX (X = CI, OH, F) and BrX (X = Br, OH). The rearrangement was possible with neighboring group participation from adjacent nitrogen. Substitution reactions at C4 and C8 were carried out with nucleofuges like SelectfluorRTM and mercury fluoride. It was found that the substitutions were a function of the bridge size, position and the type of substituent involved. Substituents in the larger bridge were more reactive, were displaced with SelectfluorRTM, whereas substituents in the smaller bridge were less reactive and required a stronger nucleofuge like mercury fluoride. En route, a mild procedure to oxidize secondary alcohols and carbon-bromine bonds to ketones using SelectfluorRTM coupled with sodium bromide was discovered.; N-(tert-butoxycarbonyl)-5- syn-(tert-butyldimethylsilyloxymethyl)-2-azabicyclo[2.1.1]hexanes with various substituents at C1 have been prepared. These compounds can be considered as precursors of rigid beta-amino acids. Some of these precursors were oxidized into their corresponding amino acids. In the future these building blocks would be used in the construction of oligomers with definite conformational preferences. The bridgehead substituent could play a role in controlling the amide conformation and could also be used as a source of biologically active functional groups that can play a role in folding.; A variety of N-(benzy1)-5-anti-substituted-2-azabicyclo[2.1.1]hexanes were prepared by substituting the bromine at C5 with nucleophiles like azide, acetate and cyanide. These substitution reactions proceeded with retention of configuration at C5 owing to the double inversion reaction caused by the neighboring group participation from the nitrogen. A fluoro substituent was also successfully introduced at C5.; Amide conformational preferences were determined for 5-fluoro- and 5,6-ditluoro- N-acetyl-2-azabicyclo[2.1.1]hexane-3-carboxylic acid methyl esters which did not exhibit sterically demanding 1,3-F/COOMe interactions. The results were consistent with the calculated dipole moments and with a calculated preference for higher trans/cis amide ratios for (2S,4R)-4-fluoroproline (Flp) residues in their minor endo pucker. |
