Total syntheses of (+)-australine and (-)-7-epialexine

Three approaches were examined for the synthesis of 3-(hydroxymethyl)pyrrol izidines, a class of compounds that includes the polyhydroxylated pyrrolizi dine alkaloids alexine (1), australine (2), and various stereoisomers of th ereof. In the first approach, the intramolecular cycloaddition of an azide onto an electron-rich 1,3-diene bearing a terminal alkoxymethyl substituent (i.e., 21) afforded the dehydropyrrolizidines 22a and 22b, with 22a predom inating. A rationale for this stereoselectivity was proposed. Transformatio n of the major diastereomer 22a into a natural 3-(hydroxymethyl)pyrrolizidi ne was not possible due to difficulties encountered in transforming the phe nyl vinyl sulfide functionality into other useful functional groups. A seco nd approach was examined, wherein the intramolecular cycloaddition of an az ide with an optically pure S-t-Bu-substituted diene (i.e., 30) was found to produce the pyrrolizidine 31. In this case, the alkoxymethyl substituent w as incorporated into the tether between the azide and the diene, rather tha n on the diene itself. A key transformation in the synthesis of the diene 3 0 was the use of the allylic borane R2BCH2CH=C(TMS)(StBu) for the stereosel ective conversion of the D-arabinose-derived azido aldehyde 28 to the E-iso mer of 30. The cyclization of 30 to 31 also produced the bicyclic triazene 32, the result of 1,3-dipolar cycloaddition of the azide onto the distal do uble bond of the diene. Again, difficulties in transformation of the vinyl sulfide functionality of 31 into useful oxygen functionality limited this a pproach to naturally occurring 3-(hydroxymethyl)pyrrolizidines. A third app roach to these compounds was successful. The transformation of L-xylose int o the azido epoxy tosylate 46 was accomplished using two Wittig reactions a nd an epoxidation, in addition to other standard functional group manipulat ions. Reductive double-cyclization of 46 afforded the pyrrolizidines 47a an d 47b, which were debenzylated to afford (+)-australine 2 and (-)-7-epialex ine 4, respectively. In the preliminary report of this work, erroneous spec troscopic data in the original literature on the structural assignment of a ustraline led to the conclusion that the synthetic material obtained herein was actually (+)-7-epiaustraline. Recently corrected spectroscopic data ha ve appeared which verify that (+)-australine 2 was indeed synthesized for t he first time.