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 SN2′‐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

“…An alkylating agent bearing ac hiral phosphate as al eaving group can be generated in situ from achiral phosphoric acid and an appropriate trichloroacetimidate.T he generated alkylating agent undergoes asymmetric substitution under the control of the chiral leaving group and enantioselectively gives Nu* À Ra st he product, with regeneration of the catalyst. [7] Although this strategy for asymmetric transformations (nucleophilic catalysis) is common for reactions at unsaturated sp 2 -hybridized carbon atoms,such as acylation [8] or allylic substitution, [9] thec orresponding reaction at saturated sp 3 -hybridized carbon atoms is unexplored.…”

Organocatalytic Activation of the Leaving Group in the Intramolecular Asymmetric SN2′ Reaction

“…[9] Theg eometries of the transition state (TS) model were calculated at the B3LYP/6-31G** level of theory ( Figure 2). Although this catalyst converted imidate 1da into 2a (Scheme 1), no reaction occurred with phosphonate 1ff,w hich was quantitatively recovered.…”

“…[7] We also reported the kinetic resolution of chiral secondary alcohols by ac hiral phosphoric acid-catalyzed acylation with acid anhydride. [9][10][11][12] Herein, we describe the enantioselective intramolecular S N 2' reaction catalyzed by ac hiral phosphoric acid providing chiral pyrrolidines. To the best of our knowledge, catalytic activation of al eaving group in ac atalytic asymmetric S N 2' reaction has rarely been reported.…”

Organocatalytic Activation of the Leaving Group in the Intramolecular Asymmetric SN2′ Reaction

“…To the best of our knowledge, catalytic activation of al eaving group in ac atalytic asymmetric S N 2' reaction has rarely been reported. [9][10][11][12] Herein, we describe the enantioselective intramolecular S N 2' reaction catalyzed by ac hiral phosphoric acid providing chiral pyrrolidines.…”

“…This result clearly indicates that the developed asymmetric reaction is not anucleophilic catalysis in which phosphonates are generated as intermediates from allylic imidates 1d and phosphoric acids 3. [9] Theg eometries of the transition state (TS) model were calculated at the B3LYP/6-31G** level of theory ( Figure 2). In the major TS (Figure 2A), the bond lengths of the forming CÀNa nd the breaking CÀOw ere 2.29 and 2.44 , respectively.The distances of > N···H···OÀPand =N···H···O=Pwere 1.06 and 1.63, and 1.03 and 1.79 , respectively.These atomic distances indicate that this substitution synchronously proceeds with spontaneous activation of the leaving group and the sulfonamide by hydrogen bonding,asexpected.…”