Stereocontrolled synthesis of key advanced intermediates toward simplifiedacetogenin Analogues

The stereo- and enantiocontrolled synthesis of substituted beta-hydroxy eth ers based on glycol and catechol bearing an alkyne group and a series of su bstituents is reported. These substrates were designed to mimic the bis-THF array of annonaceous acetogenins and to provide an access to simplified an d modified analogues. The key seeps of the synthesis involve the condensati on of the nonracemic mesylate of solketal with ethylene glycol and catechol , followed by an alkylation with a glycidyl derivative. Under appropriate c onditions, the reaction is completely stereoselective and allows the synthe sis of all the diastereomers. After the epoxide was opened with triethylsil ylacetylene, the second epoxide was unmasked and reacted with a series of a lkyl, aryl, amine, and alcohol reagents. A series of 28 analogues was prepa red having a glycol or a catechol core, a stereodefined configuration of th e flanking hydroxyl groups,and an acetylenic appendage suitable for a coupl ing to a lactone-bearing fragment.