Enantioselective Synthesis of Paraconic Acids

The development of a new method for the enantioselective synthesis of disubstituted γ‐butyrolactones is reported. Based on this strategy, the total synthesis of three paraconic acids, that is (−)‐roccellaric acid, (−)‐nephrosteranic acid and (−)‐protopraesorediosic acid, and the formal total synthesis of (−)‐methylenolactocin and (−)‐protolichesterinic acid is described, which are important because of their antibiotic and antitumor properties. Key steps of the synthesis are copper(I)‐catalyzed asymmetric cyclopropanations of furans, highly diastereoselective Sakurai allylations, Lewis acid or Lewis base catalyzed retroaldol/lactonization cascades, and ruthenium(II)‐catalyzed, intermolecular cross metathesis reactions. Aufbauend auf einer neuen, allgemein anwendbaren Strategie zur Synthese von disubstituierten γ‐Butyrolactonen gelang die enantioselektive Totalsynthese von drei verschiedenen Paraconsäuren, (−)‐Roccellarinsäure, (−)‐Nephrosteraninsäure und (−)‐Protopraesoridiosinsäure, sowie die formale Totalsynthese von (−)‐Methylenolactocin und (−)‐Protolichesterinsäure, die aufgrund ihrer antibiotischen und Antitumoreigenschaften von Bedeutung sind. Schlüsselschritte der Synthesen sind Kupfer‐katalysierte, asymmetrische Cyclopropanierungen von Furanen, hoch diastereoselektive Sakurai Allylierungen, Lewissäure‐ oder basenkatalysierte Retroaldol‐Lactonisierungskaskaden sowie Ruthenium‐katalysierte, intermolekulare Metathese Reaktionen. The enantioselective synthesis of anti‐2,3‐substituted γ‐butyrolactone derivatives starting from inexpensive furan‐2‐carboxylic esters is described. Key steps are copper(I)‐catalyzed asymmetric cyclopropanations of furans, highly diastereoselective Sakurai allylations and Lewis‐acid or base catalyzed retroaldol/lactonization cascades. Further transformations of the γ‐butyrolactones after ruthenium‐catalyzed intermolecular cross‐metathesis reactions lead to generation of various paraconic acids of medicinal importance.