Catalytic Z-selective olefin cross-metathesis for natural product synthesis

Abstract

Alkenes are found in many biologically active molecules, and there are a large number of chemical transformations in which alkenes act as the reactants or products (or both) of the reaction. Many alkenes exist as either the E or the higher-energy Z stereoisomer. Catalytic procedures for the stereoselective formation of alkenes are valuable, yet methods enabling the synthesis of 1,2-disubstituted Z alkenes are scarce. Here we report catalytic Z-selective cross-metathesis reactions of terminal enol ethers, which have not been reported previously, and of allylic amides, used until now only in E-selective processes. The corresponding disubstituted alkenes are formed in up to >98% Z selectivity and 97% yield. These transformations, promoted by catalysts that contain the highly abundant and inexpensive metal molybdenum, are amenable to gram-scale operations. Use of reduced pressure is introduced as a simple and effective strategy for achieving high stereoselectivity. The utility of this method is demonstrated by its use in syntheses of an anti-oxidant plasmalogen phospholipid, found in electrically active tissues and implicated in Alzheimer’s disease, and the potent immunostimulant KRN7000. The Z-alkene bond is one of the most important chemical bonds in nature. Many natural products contain one or several Z alkenes, consisting of a double bond with two substituents at each end pointing in the same direction. The potency or function of these natural products disappears or changes significantly if the two substituents point in opposite directions — a structure called an E alkene. Convenient methods for the stereoselective synthesis of 1,2-disubstituted Z alkenes are scarce. Amir Hoveyda and colleagues now describe catalytic Z-selective cross-metathesis reactions of terminal enol ethers and allylic amides, previously used only in E-selective processes. The potential of this reaction is demonstrated by its use in syntheses of antioxidant plasmalogen phospholipids found in electronically active tissues and implicated in Alzheimer's disease, and the potent immunostimulant and antitumour agent KRN7000. There are a large number of chemical transformations in which alkenes act as the reactants and/or the products of the reaction, but methods enabling the facile synthesis of 1,2-disubstituted Z alkenes are scarce. This paper describes catalytic Z-selective cross-metathesis reactions of terminal enol ethers, which have not been reported previously,and allylic amides, used thus far only in E-selective processes. The utility of this methodology is demonstrated by its use in syntheses of anti oxidant C18 (plasm)-16:0 (PC), found in electrically active tissues and implicated in Alzheimer's disease, and the potent immunostimulant KRN7000.