Total Synthesis of 6-Deoxyerythronolide B via C–C Bond-Forming Transfer Hydrogenation

Abstract

The 14-membered macrolide 6-deoxyerythronolide B is prepared in 14 steps (longest linear sequence) and 20 total steps. Two different methods for alcohol CH-crotylation via transfer hydrogenation are deployed for the first time in target-oriented synthesis. Enyne metathesis is used to form the 14-membered ring. The present approach represents the most concise construction of any erythronolide reported, to date.

Lessons from the Synthetic Chemist Nature

“…The most recent synthesis by Krische et al elegantly furnished 6-deoxyerythronolide B (1) in only 14 linear steps (20 overall steps) in the longest linear sequence, clearly in fewer steps than nature does it. 10 However, the bioproduction of erythromycin A (2) is efficient because aer about 60 hours Saccharopolyspora erythraea can provide the antibiotic in signicant quantities. Examining the cyclic fed batch fermentation studies of Bushell and Lynch, 11 a Andreas Kirschning studied chemistry at the University of Hamburg and at Southampton University (UK).…”

Toward Ideal Asymmetric Catalysis

“…The most concise man-made total synthesis of 6-deoxyerythronolide B reported to date, consisting of 14 steps from 2-methyl-1,3-propandiol (longest linear sequence) and 20 total steps, was reported in 2013, in which Krische and coworkers applied two elegant protocols of highly enantioselective catalytic asymmetric alcohol CH-crotylation via transfer hydrogenation, developed in their own group, for the synthesis of two important fragments I and II [66] (Scheme 1.10). However, the use of step-by-step purification (18-column chromatography involved), several protection and deprotection manipulations, toxic reagents such as OsO 4 , and large amounts of metal catalysts in key steps suggests the enormous room for human beings to further improve the synthetic efficiency, as compared with the biosynthetic pathway.…”

Total Synthesis of Swinholide A: An Exposition in Hydrogen-Mediated C–C Bond Formation

“…25 The iodo ether 14 is prepared from the pseudo - C 2 -symmetric diol 13 , which, in turn, is obtained directly from 2-methyl-1,3-propane diol 12 via double diastereo- and enantioselective diol C-H anti -crotylation. 26 …”

“…Subsequent O -methylation provides 11 . Cross-metathesis of 11 with iodoether 14 , previously prepared in our laboratory (Scheme 4), 26 was challenging due to competing alkene isomerization of 14 . Using the second-generation Grubbs-Hoveyda catalyst with 1,4-benzoquinone, 31 the desired metathesis product 15 was obtained in 52% yield.…”