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

Abstract

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.

Use of a Catalytic Chiral Leaving Group for Asymmetric Substitutions at sp3‐Hybridized Carbon Atoms: Kinetic Resolution of β‐Amino Alcohols by p‐Methoxybenzylation

“…The first kinetic resolution of amino alcohols through p ‐methoxybenzylation was achieved with this strategy by using the novel chiral phosphoric acid 1 d . NMR studies and a stoichiometric reaction verified a mechanism based on a catalytic leaving group, which had previously been proposed based on MS observations and DFT calculations …”

Experimental and Computational Studies on Regiodivergent Chiral Phosphoric Acid Catalyzed Cycloisomerization of Mupirocin Methyl Ester

“…In particular, Zimmerman group's reaction exploration tools were used to facilitate the accurate and fast search of relevant reactions paths and transition states . These tools have previously been used in the elucidation of fine mechanistic details of phosphoric acid‐catalyzed spiroketalizations, glycosylations, and intramolecular aza‐Michael reactions . Here, the single‐ended growing string method (GSM) was employed to detail the mechanism of phosphoric acid‐catalyzed intramolecular ERO.…”

“…The endo pathway was preferred minutely by 0.16 kcal mol −1 , a number that, although within the error of the computational methods, agrees with the small intrinsic endo selectivity that is observed with achiral phosphoric acids experimentally (Figure , TS endo vs. TS exo and Table , entry 7). An alternative mechanism through epoxide opening and involving a phosphate intermediate was ruled out because the barrier was substantially higher (≈8.3 kcal mol −1 , TS P ) than the concerted pathways.…”

Metal‐Free Enantioselective Electrophilic Activation of Allenamides: Stereoselective Dearomatization of Indoles

“…Differently, a covalent interaction between the catalyst and the π system, resulting from the hydrophosphorylation of the activated allenamide (i.e., an S N 2′‐type mechanism, Scheme ) cannot be ruled out at the present 2b. 20…”