Enantioselective Catalytic Transannular Ketone–Ene Reactions

Highly enantio- and diastereoselective transannular ketone–ene reactions are catalyzed by a new chromium(III) triflate tridentate Schiff base complex. Electronically unactivated keto-olefins undergo heteroene reactions at ambient temperature to afford enantioenriched bicyclic alcohols, common structural motifs in natural products. The kinetic resolution of a configurationally stable planar-chiral cyclodecenone is also described

Evidence for Oxonium Ions in Ethereal “Hydrogen Chloride”

Although solutions of hydrogen chloride in ethereal solvents like diethyl ether or dioxane are commonly employed in the laboratory, the solution structure of these reagents has yet to be firmly established. Here, we analyze solutions of ethereal hydrogen chloride or deuterium chloride in toluene, in dichloromethane, or in the absence of a co-solvent by in situ infrared spectroscopy. The resulting spectra are inconsistent with free HCl or often-proposed 1:1 HCl–ether complexes but closely match the predicted spectra of oxonium ions generated via protonation of diethyl ether. Molecular dynamics simulation of the oxonium chloride complexes provides evidence for an outer-sphere contact ion pair. These results suggest new approaches for tuning the acidity of strong Brønsted acids in organic solvents and demonstrate the importance of conducting spectroscopic measurements under reaction-relevant conditions

A Simple Primary Amine Catalyst for Enantioselective α‑Hydroxylations and α‑Fluorinations of Branched Aldehydes

A new primary amine catalyst for the asymmetric α-hydroxylation and α-fluorination of α-branched aldehydes is described. The products of the title transformations are generated in excellent yields with high enantioselectivities. Both processes can be performed within short reaction times and on gram scale. The similarity in results obtained in both reactions, combined with computational evidence, implies a common basis for stereoinduction and the possibility of a general catalytic mechanism for α-functionalizations. Promising initial results in α-amination and α-chlorination reactions support this hypothesis

A Practical Method for the Synthesis of Highly Enantioenriched <i>trans</i>-1,2-Amino Alcohols

A highly enantioselective addition of phenyl carbamate to <i>meso</i>-epoxides has been developed to efficiently generate protected <i>trans</i>-1,2-amino alcohols. This transformation is promoted by an oligomeric (salen)Co–OTf catalyst and has been used to prepare two useful 2-aminocycloalkanol hydrochlorides in enantiopure form on a multigram scale from commercially available starting materials

Enantioselective, Catalytic Fluorolactonization Reactions with a Nucleophilic Fluoride Source

The enantioselective synthesis of 4-fluoroisochromanones via chiral aryl iodide-catalyzed fluorolactonization is reported. This methodology uses HF-pyridine as a nucleophilic fluoride source with a peracid stoichiometric oxidant and provides access to lactones containing fluorine-bearing stereogenic centers in high enantio- and diastereoselectivity. The regioselectivity observed in these lactonization reactions is complementary to that obtained with established asymmetric electrophilic fluorination protocols

Enantioselective Aza-Sakurai Cyclizations: Dual Role of Thiourea as H‑Bond Donor and Lewis Base

An enantioselective, catalytic aza-Sakurai cyclization of chlorolactams has been developed as an efficient entry into indolizidine and quinolizidine frameworks. Structure–enantioselectivity relationship studies and mechanistic analysis point to a dual role of the catalyst wherein the thiourea moiety of the catalyst is engaged in both anion binding and Lewis base activation of a substrate

Catalytic 1,3-Difunctionalization via Oxidative C–C Bond Activation

Electronegative substituents arrayed in 1,3-relationships along saturated carbon frameworks can exert strong influence over molecular conformation due to dipole minimization effects. Simple and general methods for incorporation of such functional group relationships could thus provide a valuable tool for modulating molecular shape. Here, we describe a general strategy for the 1,3-oxidation of cyclopropanes using aryl iodine­(I–III) catalysis, with emphasis on 1,3-difluorination reactions. These reactions make use of practical, commercially available reagents and can engage a variety of substituted cyclopropane substrates. Analysis of crystal and solution structures of several of the products reveal the consistent effect of 1,3-difluorides in dictating molecular conformation. The generality of the 1,3-oxidation strategy is demonstrated through the catalytic oxidative ring-opening of cyclopropanes for the synthesis of 1,3-fluoroacetoxylated products, 1,3-diols, 1,3-amino alcohols, and 1,3-diamines

Catalytic, Diastereoselective 1,2-Difluorination of Alkenes

We describe a direct, catalytic approach to the 1,2-difluorination of alkenes. The method utilizes a nucleophilic fluoride source and an oxidant in conjunction with an aryl iodide catalyst and is applicable to alkenes with all types of substitution patterns. In general, the vicinal difluoride products are produced with high diastereoselectivities. The observed sense of stereoinduction implicates anchimeric assistance pathways in reactions of alkenes bearing neighboring Lewis basic functionality

Enantioselective Total Synthesis of (+)-Reserpine

A catalytic, enantioselective synthesis of (+)-reserpine is reported. The route features a highly diastereoselective, chiral catalyst-controlled formal aza-Diels–Alder reaction between a 6-methoxytryptamine-derived dihydro-β-carboline and an enantioenriched α-substituted enone to form a key tetracyclic intermediate. This approach addresses the challenge of setting the C3 stereogenic center by using catalyst control. Elaboration of the tetracycle to (+)-reserpine includes an intramolecular aldol cyclization and a highly diastereoselective hydrogenation of a sterically hindered enoate

Asymmetric Mannich Synthesis of α‑Amino Esters by Anion-Binding Catalysis

We report a scalable, one-pot Mannich route to enantioenriched α-amino esters by direct reaction of α-chloroglycine ester as a practical imino ester surrogate. The reaction is promoted by a chiral aminothiourea, which is proposed to operate cooperatively by generating an iminium ion by chloride abstraction and an enolate by deprotonation, followed by highly stereoselective C–C bond formation between both reactive intermediates associated non-covalently within the catalyst framework