Chemoenzymatic Total Synthesis of (+)-Galanthamine and (+)-Narwedine from Phenethyl Acetate

The stereoselective total synthesis of unnatural (+)‐galanthamine starting from phenethyl acetate is described. Chirality was introduced via microbial dihydroxylation of phenethyl acetate with the recombinant strain JM109 (pDTG601A) to the corresponding cis‐cyclohexadi–enediol, configuration of which provided the absolute stereochemistry of the ring C of (+)‐galanthamine. Intramolecular Heck cyclization was used to form the quaternary carbon and dibenzofuran functionality. The synthesis of (+)‐galanthamine was completed in a total of ten steps and an overall yield of 5.5 %. Experimental and spectral data are provided for all new compounds. Enzymatic dihydroxylation: The toluene dioxygenase mediated dihydroxylation of phenethyl acetate served to introduce chirality and absolute stereochemistry. An intramolecular Heck cyclization was used to form the quaternary carbon and the dibenzofuran functionality. The synthesis of (+)‐galanthamine was completed in a total of ten steps and an overall yield of 5.5 %.