A novel linking-protecting group strategy for solid-phase organic chemistry with configurationally stable α-[N-(phenylfluorenyl)]amino carbonyl compounds:: Synthesis of enantiopure norephedrines on solid support

A novel linking strategy has been developed for synthesizing configurationally stable alpha-amino aldehyde on polymeric supports. Alkylation of L-alanine methyl ester with 9-bromo-9-p-bromophenylfluorenene, followed by ester hydrolysis and coupling to isoxazolidine, provided N-(9-p-bromophenylfluoren-9-yl)alanine isoxazolidide (5), which was transformed into its corresponding boronate 2 by a palladium-catalyzed cross-coupling reaction with diboron pinacol ester. Boronate 2 was anchored to four different polymeric aryl halides 6-9 in 70-99% yields. Polymer-bound alaninal Ib was then synthesized on non-cross-linked polystyrene by hydride reduction of isoxazolidide 10b. Treatment of alaninal Ib with phenylmagnesium bromide, cleavage of the resulting amino alcohol in a 1:2:2 TFA/CH2Cl2/anisole cocktail, and acylation with di-tert-butyl dicarbonate furnished N-(BOC)norephedrines 14 that were demonstrated to be enantiopure by conversion to diastereomeric thioureas 15 and analysis by HPLC. In summary, we have developed a process by which the 9-phenylfluoren-9-yl protecting group has been converted into a new linker for the solid-phase synthesis and manipulation of alpha-amino carbonyl compounds.