The First Synthesis of Herbicidin B. Stereoselective Construction of the Tricyclic Undecose Moiety by a Conformational Restriction Strategy Using Steric Repulsion between Adjacent Bulky Silyl Protecting Groups on a Pyranose Ring

Abstract

The first total synthesis of the nucleoside antibiotic herbicidin B (1b) was achieved, where a novel aldol-type C-glycosidation reaction promoted by samarium diiodide (SmI2) was used as a key step. Treatment of methyl 3,4-O-(1,1,3,3-tetraisopropyl-1,3-disiloxanediyl)-1-phenylthio-2-ulos-β-d-glucuronate (13) with SmI2 in THF regioselectively gave the corresponding 1-enolate, which was readily trapped with 1-β-d-xylosyladenine 5'-aldehyde derivative 7 to afford the product 19a,b as an anomeric mixture. Dehydration of the 5'-hydroxyl in 19a,b with using Burgess's inner salt gave the enone 20, which was subsequently hydrogenated to give undeculofuranuronyl adenine derivative 21. Deprotection of 21 gave a tricyclic sugar nucleoside, 23. However, it was an epimer of herbicidin B at the 6'-position. Construction of the desired 6'-α-configuration was achieved by using a conformational restriction strategy based on repulsion between adjacent bulky protecting groups on the pyranose ring. Thus, when methyl 3-O-tert-butyldimethylsilyl-4-O-tert-butyldiphenylsilyl-1-phenylthio-2-ulos-d-glucuronate (29c), the conformation of which was restricted in an unusual 1C4-like conformation, was used as a precursor for ulose 1-enolate in the SmI2-promoted aldol reaction with 7, the desired 6'-α-aldol product 30c was predominantly obtained. Compound 30c was dehydrated, followed by hydrogenation of the alkenyl bond and then deprotection to form an internal ketal linkage between the 3'- and 7'-positions, which spontaneously gave herbicidin B.