SYNTHESIS OF CONDURAMINES FROM N-TERT-BUTOXYCARBONYLPYRROLE

Two related synthetic strategies were devised to convert the Diels-Ald er adduct 3c of Boc-pyrrole and p-toluenesulfonylacetylene into variou s racemic and optically pure conduramines. One process consists of the regio-and stereoselective hydroxylation of 3c to the tri-and dihydrox ylated azabicyclo[2.2.1]heptane derivatives 10b (Scheme 2) and the exo -endo mixture 13-14 (Scheme 3). Anionic fragmentation of 10b (methylma gnesium bromide) and of the 13-14 sulfone mixture (lithium bis(trimeth ylsilyl)amide) generated the corresponding tri-and dihydroxylated amin ocyclohexenes 17 and 16 (Scheme 3). Compound 17 is an aminocyclitol wi th a stereochemistry and partial aminotriol sequence identical to that found in neoinosamine. Compound 16 served as a source of the protecte d and fi ee aminodiols 35b, and 35a (Scheme 6), which were stereospeci fically epoxidized to 36 (Scheme 6) and 40 (Scheme 7). Phenylselenide cleavage of these epoxides provided 37 (Scheme 6) and 41a (Scheme 7), which after selenoxide cycloelimination and protecting group manipulat ion were converted into (+/-)-conduramine C-l (39a, Scheme 6) and the previously unreported, all-cis-conduramine D-l (43a, Scheme 7). In a s econd process, anionic fragmentaion of the bicyclic system is effected prior to introduction of the hydroxyl groups, as exemplified by the h igh-yielding conversion of the exo-endo mixture of azabicycloheptenes 11 and 12 into the aminocyclohexadiene 15 (Scheme 3). Osmate catalyzed cis-dihydroxylation of the derived bis-Boc derivative 20 (Scheme 4) Z ed stereospecifically to the alpha-cis-diol 21 which was transformed i nto (+/-)-conduramine A-1 (27a) and its tetraacetyl derivative 27b via the epoxy compound 24. On the other hand, peracid oxidation of the di ene 15 gave the beta-epoxide 28 (Scheme 5) which was cleaved to the tr ans-diol 29 with aqueous sulfuric acid. This diol was converted into ( +/-)-conduramine F-1(34a) and its tetraacetyl derivative (34b) by a re action sequence similar to that used for the other conduramine synthes es. Fractional crystallization of the diastereomeric mixture of Michae l adducts obtained from (+/-)-3c and (-)methyl lactate gave (-)-44a an d (-)-45a both in greater than or equal to 47% yield (Scheme 8). Both the carboxylic acid (+)-44b and the primary alcohol (+)-46 derived fro m (-)-44a were converted into (-)-3c with excess methylmagnesium bromi de (ca. 40% overall yield). In the same way (-)-45a was transformed in to optically pure (+)-3c. (-)-3c and (+)-3c were then converted into ( -)-conduramine C-l [(-)-39a] and (+)-conduramine D-l [(+)-43a] by proc edures identical to those used for the racemic compounds.