Concise Enantioselective Synthesis of Oxygenated Steroids via Sequential Copper(II)-Catalyzed Michael Addition/Intramolecular Aldol Cyclization Reactions.
A new scalable enantioselective approach to functionalized oxygenated steroids is described. This strategy is based on chiral bis(oxazoline) copper(II) complex-catalyzed enantioselective and diastereoselective Michael reactions of cyclic ketoesters and enones to install vicinal quaternary and tertiary stereocenters. In addition, the utility of copper(II) salts as highly active catalysts for the Michael reactions of traditionally unreactive β,β'-enones and substituted β,β'-ketoesters that results in unprecedented Michael adducts containing vicinal all-carbon quaternary centers is also demonstrated. The Michael adducts subsequently undergo base-promoted diastereoselective aldol cascade reactions resulting in the natural or unnatural steroid skeletons. The experimental and computational studies suggest that the torsional strain effects arising from the presence of the Δ(5)-unsaturation are key controlling elements for the formation of the natural cardenolide scaffold. The described method enables expedient generation of polycyclic molecules including modified steroidal scaffolds as well as challenging-to-synthesize Hajos-Parrish and Wieland-Miescher ketones.
Department of Chemistry, University of Michigan , 930 North University Avenue, Ann Arbor, Michigan 48109, United States.
Nathan R
NR
Cichowicz
Department of Chemistry, University of Michigan , 930 North University Avenue, Ann Arbor, Michigan 48109, United States.
Will
W
Kaplan
Department of Chemistry, University of Michigan , 930 North University Avenue, Ann Arbor, Michigan 48109, United States.
Yaroslav
Y
Khomutnyk
Department of Chemistry, University of Michigan , 930 North University Avenue, Ann Arbor, Michigan 48109, United States.
Bijay
B
Bhattarai
Department of Chemistry, University of Michigan , 930 North University Avenue, Ann Arbor, Michigan 48109, United States.
Zhankui
Z
Sun
Department of Chemistry, University of Michigan , 930 North University Avenue, Ann Arbor, Michigan 48109, United States.
Pavel
P
Nagorny
D002384:Catalysis; D003300:Copper / Q000737:chemistry*; D003500:Cyclization; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry*; D010100:Oxygen / Q000737:chemistry*; D013237:Stereoisomerism; D013256:Steroids / Q000138:chemical synthesis* / Q000737:chemistry
D009942:Organometallic Compounds; D013256:Steroids; D003300:Copper; D010100:Oxygen