Diastereoselective Synthesis of Highly Substituted Tetrahydrofurans by Pd-Catalyzed Tandem Oxidative Cyclization–Redox Relay Reactions Controlled by Intramolecular Hydrogen Bonding

Abstract

Palladium-catalyzed oxidative cyclization of alkenols provides a convenient entry into cyclic ethers but typically proceeds with little or no diastereoselectivity for cyclization of trisubstituted olefins to form tetrahydrofurans due to the similar energies of competing 5-membered transition-state conformations. Herein, a new variant of this reaction has been developed in which a PdCl2/1,4-benzoquinone catalyst system coupled with introduction of a hydrogen-bond acceptor in the substrate enhances both diastereoselectivity and reactivity. Cyclization occurs with 5-exo Markovnikov regioselectivity. Mechanistic and computational studies support an anti-oxypalladation pathway in which intramolecular hydrogen bonding increases the nucleophilicity of the alcohol and enforces conformational constraints that enhance diastereoselectivity. The cyclization is followed by a tandem redox-relay process that provides versatile side-chain functionalities for further derivatization.

1- and 2-Azetines via Visible Light-Mediated [2 + 2]-Cycloadditions of Alkynes and Oximes

“…In subsequent investigations, we developed a one-pot method to access highly functionalized tetrahydrofuran products incorporating desirable amino-ester functionalities upon in situ hydrolysis of initially formed intermediate 1-azetines (Table ). We anticipate that these products are desirable for pharmaceutical and drug discovery applications, as amino esters and tetrahydrofurans both represent valuable synthetic scaffolds. , While numerous methods exist to access tetrahydrofurans, the formation of densely substituted analogs is less established often resulting in either 1,4- or 1,2- substitution patterns. In comparison, the method established herein relies on a single step, is diastereoselective, and provides access to tetrahydrofuran products incorporating distinct 1,2,4-substitution.…”

Recent Development in Palladium-Catalyzed Domino Reactions: Access to Materials and Biologically Important Carbo- and Heterocycles

“…Introduction of a hydrogen bond acceptor in the substrate enhances the reactivity and stereoselectivity. The cyclization occurred with 5- exo - trig -Markovnikov regioselectivity using an alkene relay system …”

“…The cyclization occurred with 5-exo-trig-Markovnikov regioselectivity using an alkene relay system. 149 Scheme 97. Synthesis of substituted tetrahydrofurans.…”

“…The cyclization occurred with 5-exo-trig-Markovnikov regioselectivity using an alkene relay system. 149 Tsvelikhovsky et al developed a cascade etherification− Heck reaction to synthesize substituted tricyclic spiranoid ethers from dienealcoholic precursors taking advantage of an alkene relay system. These tricyclic spiroether structures can frequently be observed as scaffold segments of various biochemical compounds and drugs of natural origins.…”

Hydrogen‐Bonding as a Factor to Determine the Regioselectivity for Pd‐mediated C−H Activation of Pyridine

“…Our interest in this study is to expand upon this theoretical understanding ways how non‐covalent interactions, such as hydrogen bonds, could supplement or mitigate the inherent regiochemical bias of the substrate. This approach (i. e. using hydrogen‐bonding interactions to control selectivity in transition metal catalysis) has been very successful in other contexts [47–53] . Therefore, here we use density functional theory (DFT) calculations to study the regioselectivity of C−H activation of the pyridinium cation (i. e., protonated pyridine), which can act as a hydrogen bond donor, and further demonstrate the potential for hydrogen bonding as a key design feature for C−H functionalization catalyst design.…”