A Pd-H/Isothiourea Cooperative Catalysis Approach to anti-Aldol Motifs: Enantioselective α-Alkylation of Esters with Oxyallenes.

The biological and therapeutic significance of natural products is a powerful impetus for the development of efficient methods to facilitate their construction. Accordingly, and reflecting the prevalence of ß-oxy-carbonyl motifs, a sophisticated arsenal of aldol-based strategies has evolved that is contingent on the generation of single enolate isomers. Since this has the potential to compromise efficiency in reagent-based paradigms, direct catalysis-based solutions would be enabling. To complement the array of substrate-based strategies, and regulate enolate geometry at the catalyst level, a direct catalytic alkylation of esters with oxyallenes has been developed. Synergizing metal hydride reactivity with Lewis base catalysis has resulted in a broad reaction scope with useful levels of stereocontrol (up to >99 % ee). Facile derivatization of these ambiphilic linchpins is demonstrated, providing access to high-value vicinal stereocenter-containing motifs, including 1,2-amino alcohols.

Nucleophile-Dependent Z/ E- and Regioselectivity in the Palladium-Catalyzed Asymmetric Allylic C-H Alkylation of 1,4-Dienes.

The asymmetric allylic alkylation (AAA), which features employing active allylic substrates, has historical significance in organic synthesis. The allylic C-H alkylation is principally more atom- and step-economic than the classical allylic functionalizations and thus can be considered a transformative variant. However, asymmetric allylic C-H alkylation reactions are still scarce and yet underdeveloped. Herein, we have found that Z/ E- and regioselectivities in the Pd-catalyzed asymmetric allylic C-H alkylation of 1,4-dienes are highly dependent on the type of nucleophiles. A highly stereoselective allylic C-H alkylation of 1,4-dienes with azlactones has been established by palladium-chiral phosphoramidite catalysis. The protocol proceeds under mild conditions and can accommodate a wide scope of substrates, delivering structurally divergent α,α-disubstituted α-amino acid surrogates in high yields and excellent levels of diastereo-, Z/ E-, regio-, and enantioselectivities. Notably, this method provides key chiral intermediates for an efficient synthesis of lepadiformine marine alkaloids. Experimental and computational studies on the reaction mechanism suggest a novel concerted proton and two-electron transfer process for the allylic C-H cleavage and reveal that the Z/ E- and regioselectivities are governed by the geometry and coordination pattern of nucleophiles.

Access to Chiral Hydropyrimidines through Palladium-Catalyzed Asymmetric Allylic C-H Amination.

A palladium-catalyzed asymmetric intramolecular allylic C-H amination controlled by a chiral phosphoramidite ligand was established for the preparation of various substituted chiral hydropyrimidinones, the precursors of hydropyrimidines, in high yields with high enantioselectivities. In particular, dienyl sodium N-sulfonyl amides bearing an arylethene-1-sulfonyl group underwent a sequential allylic C-H amination and intramolecular Diels-Alder (IMDA) reaction to produce chiral fused tricyclic tetrahydropyrimidinone frameworks in high yields and with high levels of stereoselectivity. Significantly, this method was used as the key step in an asymmetric synthesis of letermovir.

Highly Enantioselective Allylic C-H Alkylation of Terminal Olefins with Pyrazol-5-ones Enabled by Cooperative Catalysis of Palladium Complex and Brønsted Acid.

A highly enantioselective allylic C-H alkylation reaction of allylarenes with pyrazol-5-ones has been established by the cooperative catalysis of a chiral palladium complex and chiral Brønsted acid to afford a wide spectrum of functionalized chiral N-heterocycles with an all-carbon quaternary stereogenic center in high yields and with high levels of enantioselectivity (up to 96% ee), wherein the chiral ligand and phosphoric acid showed synergistic effect on the control of stereoselectivity. In addition, a palladium-catalyzed asymmetric allylic C-H alkylation of 1,4-pentadienes with pyrazol-5-ones has been realized to furnish highly functionalized pyrazol-5-ones in high enantioselectivities. In this case, the chiral ligand controls the stereoselectivity while the achiral Bronsted acid, 2-fluorobenzoic acid, turns out to be a better cocatalyst than the chiral phosphoric acid. The installation of electron-deficient substituents at 3,3'-positions of binaphthyl backbone of chiral phosphoramidites is actually beneficial to the allylic C-H oxidation due to their survival in the presence of quinone derivative oxidants. These allylic C-H alkylation reactions undergo smoothly under mild conditions and tolerate a wide range of substrates. The resultant highly functionalized chiral pyrazol-5-ones have been applied to the preparation of more structurally diverse heterocycles by classical transformations.

Enantioselective 1,2-Difunctionalization of Dienes Enabled by Chiral Palladium Complex-Catalyzed Cascade Arylation/Allylic Alkylation Reaction.

A Pd-catalyzed highly enantioselective three-component coupling of 1,3-dienes with aryl iodines and sodium dialkyl malonates has been successfully established by using a H8-BINOL-based phosphoramidite ligand. This reaction proceeded via a Pd-catalyzed cascade arylation and asymmetric allylic alkylation reaction, providing an efficient strategy for the enantioselective 1,2-difunctionalization of 1,3-dienes.

Asymmetric Allylic C-H Oxidation for the Synthesis of Chromans.

An enantioselective intramolecular allylic C-H oxidation to generate optically active chromans has been accomplished under the cooperative catalysis of a palladium complex of chiral phosphoramidite ligand and 2-fluorobenzoic acid. Mechanistic studies suggest that this reaction commences with a Pd-catalyzed allylic C-H activation event and then undergoes asymmetric allylic alkoxylation. The synthetic significance of the method has been embodied by concisely building up a key chiral intermediate to access (+)-diversonol.

Chiral counteranion strategy for asymmetric oxidative C(sp³)-H/C(sp³)-H coupling: enantioselective α-allylation of aldehydes with terminal alkenes.

The first enantioselective α-allylation of aldehydes with terminal alkenes has been realized by combining asymmetric counteranion catalysis and palladium-catalyzed allylic C-H activation. This method can tolerate a wide scope of α-branched aromatic aldehydes and terminal alkenes, thus affording allylation products in high yields and with good to excellent levels of enantioselectivity. Importantly, the findings suggest a new strategy for the future creation of enantioselective C-H/C-H coupling reactions.

Enantioselective Synthesis of 5-Alkylated Thiazolidinones via Palladium-Catalyzed Asymmetric Allylic C-H Alkylations of 1,4-Pentadienes with 5 H-Thiazol-4-ones.

A palladium-catalyzed, enantioselective allylic C-H alkylation of 1,4-pentadienes with 5 H-thiazol-4-ones has been developed. Under the cooperative catalysis of a palladium complex of chiral phosphoramidite ligand and an achiral Brønsted acid, a broad range of substituted 5 H-thiazol-4-ones bearing sulfur-containing tertiary chiral centers were accessed from the allylic C-H alkylation in high levels of yields and enantioselectivities. Alkyl and aryl 1,4-pentadienes led to linear and branched allylation products, respectively.

Palladium(II)/Lewis acid synergistically catalyzed allylic C-H olefination.

The first allylic C-H olefination with α-diazo esters synergistically catalyzed by a palladium(II) complex and (salen)CrCl has been established to directly generate conjugated polyene derivatives in moderate to high yields and with excellent stereoselectivities.