Synthesis of hydroxylated pyrrolidine and pyrrolizidine compounds from isoxazolidine diols

Hydroxylated pyrrolidine and pyrrolizidine compounds are a common structural motive amongst the wide range of natural products that exhibit interesting inhibition activities and are considered as possible drug candidates in the treatment of various kinds of illnesses. Our main synthetic target, a pyrrolizidine alkaloid (+)-hyacinthacine C_3, was isolated from Scilla socialis and shows a good inhibition activity against C. saccharolyticum ß-glycosidase (IC₅₀ = 25μM) and bovine liver ß-galactosidase (IC₅₀ = 52 μM). [1,2]

This work builds on the ongoing interest of our research group in the synthesis and utilisation of isoxazolidine-4,5-diols. [3] Owing to the hemiacetal character of the anomeric isoxazolidine diols, we were already able to synthesize (-)-hyacinthacine B₂, starting from sugar derived nitrone and with 1,3-dipolar cycloaddition and Horner-Wadsworth-Emmons olefination as the key steps. [4]

This report deals with the synthesis of polyhydroxylated pyrrolizidine alkaloid (-)-hyacinthacine C₃ and its C-5 isomer starting from a sugar derived five-membered cyclic nitrone that undergoes a syn-stereoselective 1,3-dipolar cycloaddition with vinylene carbonate. The essential step of this synthesis is Wittig olefination of the prepared bicyclic isoxazolidine-2,3-diol with stable P-ylide, which is followed by reduction of the ethyl ester group to build up the primary hydroxymethyl substituent. Next, the reductive cleavage of the weak N-O bond offers a pyrrolidine derivative with an alkenol sidechain that undergoes intramolecular iodocyclisation, leading to a mixture of pyrrolizidines with the configuration of the natural hyacinthacine C₃ and its C-5 isomer. The desired products can be obtained by final dehalogenation and deprotection.