The Biosynthetic Pathway to TDP-D-Fucofuranose, the Sugar Donor Substrate for the C-Glycosyltranferase Involved in Gilvocarcin V Biosynthesis

D-fucofuranose (5) is the sugar moiety of the anticancer antibiotic gilvocarcin V (GV). It is C-glycosidically linked to the polyketide-derived core of GV and believed to play a key role for its interaction with histone H3. The enzymatic activity catalyzing the ring contraction step remains a mystery, because no gene product of the gil gene cluster possesses sequence homology with Fcf2, a recently discovered mutase in E. coli O52. We hypothesized that either one of the uncharacterized enzymes, GilN and GilL, may adopt a mechanism different from Fcf2, or act after the glycosylation reaction, or that GilGT catalyzes the ring rearrangement along with the C-glycosylation. To solve this intriguing question necessitated the design of enzymatic total syntheses of 4 and 5.