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

Abstract

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(N)1-like, S(N)2-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.

Activation of olefins via asymmetric Brønsted acid catalysis

“…Mechanistically, we initially envisioned the reaction to proceed via a stepwise protonation, cyclization pathway. However, a concerted mechanism in which protonation and C−O bond formation occur more synchronously is also plausible (18,31). Toward gaining more insight into the reaction mechanism and the origin of enantioselectivity, we performed density functional theory (DFT) studies (see the supplementary materials for a description of the methods and a detailed discussion).…”

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

“…The quadrant‐based analysis, developed by the groups of Himo and Terada to explain the selectivity of BINOL‐based CPAs, has been previously used to describe the steric profile imposed by these acids (Figure A) . Herein, we use a similar analysis to explain the observed selectivity pattern.…”

“…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.…”

“…Our group has a long‐standing interest in the application of chiral phosphoric acids (CPAs) to control the regio‐ and stereoselective functionalization of natural products . In our recent efforts, we demonstrated that CPAs could mimic enzymatic processes and control the regioselectivity and/or stereoselectivity of acetalization, spiroketalization, and glycosylation reactions. Inspired by the endo regiocontrol exhibited by the epoxide hydrolase Lsd19, which catalyzes the selective formation of lasalocid A rather than its kinetically favored regioisomer isolacid A (Figure B), we sought to investigate the possibility of controlling the formation of the exo and endo products through CPA catalysis.…”

Bimetallic Catalytic Asymmetric Tandem Reaction of β‐Alkynyl Ketones to Synthesize 6,6‐Spiroketals

“…[5,6] Among the family of spiroketals,6 ,6-spiroketal behaves as ac rucial pharmacophore in many natural products, [7] and also as an important skeleton in chiral ligands applied in various transition-metal-catalyzed asymmetric reactions (Scheme 1b). [8] In previous works,t he common strategy was to deliver chiral 6,6-spiroketal through intramolecular nucleophilic addition of alcohol to oxocarbenium ion intermediate or carbonyl group catalyzed by chiral Brønsted acids [9] or chiral iridium complexes. [10] Despite these significant advances,d eveloping intermolecular diastereo-and enantioselective synthesis would be highly beneficial to extend the diversity of chiral multi-functionalized 6,6-spiroketals.…”