Total Syntheses Of Aetheramide A And B

Natural products,because of their outstanding biological activities and structural diversities,are commonly used as lead compounds for drug discovery and have been a focus in organic chemistry for decades.Many marketed antibiotics are derived from natural macrolides,and interest in natural product based researches continues.Aetheramide A and B are two novel depsipeptides isolated from the myxobacterial genus Aetherobacter by Muller and co-workers in 2012.Both aetheramide A and B are 22/21 membered macrolactones containing a unique polyketide moiety and a dipeptide residue.Aetheramide A and B possess potent anti-HIV activity at nano-molar concentrations with unique structures differring from any other reported anti-HIV drugs,and may have a novel anti-HIV mechanism.A concise total synthesis of aetheramide A in an overall yield of 4.7% with a longest linear sequence of 15 steps is described in this thesis.The synthetic strategy features macrocyclization via an intramolecular trapping of acylketene generated from dioxinone precursor,and late-stage stereoselective methylation of β-ketoamide.In addition,the key steps involved a number of named reactions,such as Sharpless Asymmetric Dihydroxylation,Vinylogous Mukaiyama Aldol Reaction,Stille Cross-coupling Reaction,Horner-Wadsworth-Emmons Olifination etc..In order to synthesize aetheramide A and B efficiently,environmental-friendly and economically,we have conducted a series of optimizations on the several key transformations during our synthesis,such as the selective reduction of α,β-unsaturated esters containing iodoalkene structures,and Vinylogous Mukaiyama Aldol Reaction catalyzed by the adducts,which are formed from boric acids and chiral amino acids,to construct key chiral centres.The efficient and concise syntheses of aetheramide A and B laid a firm foundation for further studies on their structure-activity relationships and mechanism of actions.