Full details of the total synthesis of (+)-
caprazol are described. The key elements of our approach includethe early stage introduction of the aminoribose in a highly -selective manner, using the steric hindrancein the transition state
and the construction of the diazepanone by a modified intramolecular reductiveamination. The 5'-
C-glycyluridine derivative
9, which was prepared stereoselectively via Sharplessasymmetric aminohydroxylation, was ribosylated with 2,3-
O-alkylidene ribofuranosyl donors. It wasrevealed that increasing the size of the alkyl substituents of the acetal unit resulted in improving thestereoselectivity of the anomeric position,
and the desired ribosides
21b (1' '-)
and 22b (1' '-) wereobtained in 80% yield (
21b/
22b = 24.0/1) when the ribosyl fluoride
16 possessing a more stericallyhindered 3-pentylidene group was used. The origin of the stereoselectivity of the ribosylation was alsodiscussed. Construction of the diazepanone system was optimized with the model aldehyde
37,
and thedesired diazepanone
38 was obtained in 88% yield via two-step reaction sequence including catalytichydrogenation followed by hydride reduction. Application of this method to the aldehyde
44 successfullyafforded the diazepanone derivatives
45 and 46, functional group manipulation of which completed thetotal synthesis of (+)-
caprazol.
