Chiral Phosphoric Acid-Catalyzed Stereoselective Transformations of Vinyl Ethers and Acetals.

Few methods exist for asymmetric nucleophilic addition to reactive oxocarbenia-like systems. A direct, chiral-catalyst controlled method to perform such transformations would simplify the task of synthesizing moieties such as nonthermodynamic spiroketals and chiral piperidines. We have developed a chiral phosphoric acid-mediated spiroketalization reaction yielding spiroketals with 54-96%ee. Lower enantioselectivities were observed when nucleophile sterics were decreased. Hammett analysis is consistent with a concerted mechanism that does not involve a significant amount of charge development in the transition state of the reaction (ro = -1.3). In addition, a deuterium labeling study suggests the acidic proton from the catalyst and the hydroxy nucleophile add to the enol ether from the same face of the molecule. This syn addition was observed in a range of solvents as well as with a variety of achiral, strong Bronsted acids. These findings raise the possibility that even achiral acids can provide stereocontrol in an underappreciated manner. Computational analysis found agreement with a concerted pathway being the lowest in energy. Direct dynamics assist us in concluding that oxocarbenia are not stable intermediates in this reaction, nor are they long-lived transition states, with collapse of the transition state to spiroketal occurring in an average of 519 fs in model systems. Finally, the mechanism of an aza-Michael reaction yielding chiral piperidines was investigated computationally. A new transacetilization/SN2’-like pathway involving a chiral phosphate acetal intermediate was identified as the lowest energy pathway. The validity of this pathway was reinforced upon investigation of the formation of the minor enantiomer of the product, the pathway for which was 3.2 kcal/mol higher than that of the major stereoisomer. This difference in energy is in agreement with the propensity of the reaction to favor the observed major product, and stems from the ability of the major isomer to form an H-bond between the N-H and a phosphate oxygen present in the catalyst. These findings call for a recategorization of the mechanism of strong Bronsted acid-catalyzed spiroketalization reactions and chiral pipieridine formations from operating through an oxocarbenium ion intermediate to a concerted, asynchronous reaction mechanism, and a transacetilization/SN2’-like mechanism, respectively.PHDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/113427/1/gwinsche_1.pd

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

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. A rich seam : An enantioselective 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. A new computational method was utilized to elucidate the mechanism and stereoselectivity of this transformation. Cbz=benzyloxycarbonyl; S =resolution.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109355/1/anie_201405128_sm_miscellaneous_information.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/109355/2/11194_ftp.pd

Chiral Phosphoric Acid-Catalyzed Enantioselective and Diastereoselective Spiroketalizations

Catalytic enantioselective and diastereoselective spiroketalizations with BINOL-derived chiral phosphoric acids are reported. The chiral catalyst can override the inherent preference for the formation of thermodynamic spiroketals, and highly selective formation of nonthermodynamic spiroketals could be achieved under the reaction conditions

Studies of the Mechanism and Origins of Enantioselectivity for the Chiral Phosphoric Acid-Catalyzed Stereoselective Spiroketalization Reactions

Mechanistic and computational studies were conducted to elucidate the mechanism and the origins of enantiocontrol for asymmetric chiral phosphoric acid-catalyzed spiroketalization reactions. These studies were designed to differentiate between the S_N1-like, S_N2-like, and covalent phosphate intermediate-based mechanisms. The chiral phosphoric acid-catalyzed spiroketalization of deuterium-labeled cyclic enol ethers revealed a highly diastereoselective syn-selective protonation/nucleophile addition, thus ruling out long-lived oxocarbenium intermediates. Hammett analysis of the reaction kinetics revealed positive charge accumulation in the transition state (ρ = −2.9). A new computational reaction exploration method along with dynamics simulations supported an asynchronous concerted mechanism with a relatively short-lived polar transition state (average lifetime = 519 ± 240 fs), which is consistent with the observed inverse secondary kinetic isotope effect of 0.85. On the basis of these studies, a transition state model explaining the observed stereochemical outcome has been proposed. This model predicts the enantioselective formation of the observed enantiomer of the product with 92% ee, which matches the experimentally observed value