Enantioselective Synthesis of Piperidines through the Formation of Chiral Mixed Phosphoric Acid Acetals: Experimental and Theoretical Studies

An enantioselective intramolecular chiral phosphoric acid‐catalyzed cyclization of unsaturated acetals has been utilized for the synthesis of functionalized chiral piperidines. The chiral enol ether products of these cyclizations undergo subsequent in situ enantioenrichment through acetalization of the minor enantiomer. A new computational reaction exploration method was utilized to elucidate the mechanism and stereoselectivity of this transformation. Rather than confirming the originally postulated cyclization proceeding directly through a vinyl oxocarbenium ion, simulations identified an alternative two‐step mechanism involving the formation of a mixed chiral phosphate acetal, which undergoes a concerted, asynchronous S N 2′‐like displacement to yield the product with stereoselectivity in agreement with experimental observations. Eine enantioselektive Cyclisierung ungesättigter Acetale mit einem chiralen Phosphorsäurekatalysator führt zu funktionalisierten Piperidinen. Die dabei erhaltenen chiralen Enolether durchlaufen anschließend in situ eine Enantiomerenanreicherung. Eine neue Rechenmethode wurde genutzt, um den Mechanismus und die Stereoselektivität dieser Transformation zu beleuchten. Cbz=Benzyloxycarbonyl; S =Anreicherungsfaktor.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109322/1/ange_201405128_sm_miscellaneous_information.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/109322/2/11376_ftp.pd