Target and diversity-oriented synthesis using epoxyquinoid scaffolds
The first enantioselective total synthesis of the ubiquitin-activating enzyme inhibitor (+)-panepophenanthrin has been achieved employing tartrate-mediated asymmetric nucleophilic epoxidation and stereoselective Diels-Alder dimerization of an epoxyquinol dienol monomer. Modification of the epoxyquinol monomer leading to panepophenanthrin by substitution of a tertiary hydroxyl for a methyl group led to mechanistic insight for the critical [4+2] dimerization. A complex, stereochemically well-defined chemical library with distinct skeletal frameworks has been achieved via elaboration of angular epoxyquinol scaffolds. The key strategy involved highly stereocontrolled [4+2] Diels-Alder cycloaddition of chiral, nonracemic epoxyquinol dienes to generate the scaffolds. Further scaffold diversification involved hydrogenation, epimerization, dehydration, and condensation of the carbonyl functionality with alkoxyamine and carbazate building blocks. The overall process afforded 244 highly complex and functionalized compounds. Preliminary biological screening of the library revealed six compounds which showed significant inhibition of Hsp 72 induction. The first enantioselective total synthesis of the complex diazobenzofluorene natural product (-)-kinamycin C has been accomplished. The synthesis relies on a hydroxyl-directed, asymmetric nucleophilic epoxidation process to establish the desired stereochemistry of the complex and highly functionalized D-ring subunit. Additional key reactions include Stille cross coupling, intramolecular Friedel-Crafts annulation, and late stage diazo formation.