Total Synthesis of Unsymmetrically Oxidized Nuphar Thioalkaloids via Copper-Catalyzed Thiolane Assembly

An asymmetric total synthesis of (+)-6-hydroxy­thio­binupharidine (1b) and (−)-6-hydroxy­thio­nuphlutine (2b), a set of hemiaminal containing dimeric sesquiterpenes isolated from yellow water lilies of the Nuphar genus, is described. The central bis-spirocyclic tetrahydro­thiophene ring was forged through the Stevens rearrangement of a sulfonium ylide, generated in situ from the coupling of a copper-carbene with a spirocyclic thietane. This strategy diverges both from the proposed biosynthesis and previous syntheses of this family of alkaloids, , all of which employ dimerization of symmetric monomers to form the aforementioned thiaspirane. The coupling of unsymmetrical monomers allowed access to the unsymmetrically oxidized product 2b for the first time.