Total syntheses of ustiloxin D, ustiloxin F and analogs via an unprecedented copper-catalyzed ethynyl aziridine ring-opening reaction by phenol derivatives

Ustiloxins A-F and phomopsins A and B are antimitotic heterodetic peptides isolated from distinctly different sources. The two natural product families contain very similar 13-membered cyclic core structures with a synthetically challenging chiral tertiary alkyl-aryl ether linkage. One of the main differences between the two macrocycles is the stereochemical configuration of the beta-hydroxy tyrosine moieties.; Stereoselective tertiary alkyl-aryl ether formation was investigated. The reaction was important because it not only was the key to a short and convergent total synthesis of ustiloxin D, but also because it provided an additional way of forming this moiety. The Pd-catalyzed asymmetric allylic O-alkylation reaction was examined. Although a model study showed that the reaction was applicable with a proper substrate, no satisfactory results were obtained with the desired system. Lewis acid or trialkylphosphine promoted aziridine ring-opening reactions by phenol derivatives were also screened but failed to provide satisfactory results as well.; A copper-catalyzed nucleophilic substitution of a tertiary alkyl methyl carbonate by phenols was successfully applied to a diastereoselective formation of a chiral tertiary alkyl-aryl ether. This reaction represents the first application of this methodology to the synthesis of enantiopure tertiary alkyl-aryl ethers.; An unprecedented copper-catalyzed ethynyl aziridine ring-opening reaction was discovered and optimized. The reaction affords tertiary alkyl-aryl ethers in a stereo- and regioselective fashion. Its mild conditions and broad functionality tolerance enables a convergent synthesis of natural products.; Evans Al-catalyzed asymmetric aldol-type reaction between 5-alkoxyoxazole and aryl aldehydes was successfully utilized to access all four diastereomers of the beta-hydroxy tyrosine moiety. The reaction provided a key intermediate for the total synthesis of ustiloxins, and will also facilitate the synthesis of phomopsin A.; Highly concise and convergent syntheses of ustiloxins D and F were achieved by utilizing the newly discovered ethynyl aziridine ring-opening reaction in a longest linear sequence of 15 steps. The approach was further optimized to achieve a better macrolactamization strategy. Ustiloxins D, F and two analogs, O-Me-ustiloxin D and Ile-ustiloxin, were synthesized via the optimized route in 15 steps as well. The new total synthesis approach is easily modifiable to access other ustiloxin congeners and their analogs.