Ynamides are among the most powerful building blocks in organic synthesis and have become invaluable starting materials for the construction of multifunctional compounds and challenging architectures that would be difficult to prepare otherwise. The rapidly growing popularity originates from the unique reactivity and ease of manipulation of the polarized ynamide triple bond, the advance of practical methods for making them, and the simplicity of storage and handling. These attractive features and the demonstration of numerous synthetic applications have spurred the development of intriguing asymmetric reaction strategies during the last decade. An impressive variety of chemo-, regio- and stereoselective carbon–carbon and carbon–heteroatom bond forming reactions with ynamides have been developed and now significantly enrich the toolbox of synthetic chemists. This review provides a comprehensive overview of asymmetric ynamide chemistry since 2010 with a focus on the general scope, current limitations, stereochemical reaction control and mechanistic aspects.

Asymmetric synthesis with ynamides: unique reaction control, chemical diversity and applications.

Photocatalysis opens up a new window for carbonyl chemistry. Despite a multitude of photochemical reactions of carbonyl compounds, visible light-induced catalytic asymmetric transformations remain elusive and pose a formidable challenge. Accordingly, the development of simple, efficient, and economic catalytic systems is the ideal pursuit for chemists. Herein, we report an enantioselective radical photoaddition to ketones through a Lewis acid-enabled photoredox catalysis wherein the in situ formed chiral N,N'-dioxide/Sc(III)-ketone complex serves as a temporary photocatalyst to trigger single-electron transfer oxidation of silanes for the generation of nucleophilic radical species, including primary, secondary, and tertiary alkyl radicals, giving various enantioenriched aza-heterocycle-based tertiary alcohols in good to excellent yields and enantioselectivities. The results of electron paramagnetic resonance (EPR) and high-resolution mass spectrum (HRMS) measurements provided favorable evidence for the stereocontrolled radical addition process involved in this reaction.

Enantioselective Radical Addition to Ketones through Lewis Acid-Enabled Photoredox Catalysis.

This article presents a comprehensive overview of multicomponent reactions (MCRs) that proceed via ortho‐quinone methide intermediates (o‐QM) generated in the reaction medium. Examples of applications involving these highly reactive intermediates in organic synthesis and biological processes (e. g., biosynthetic pathways, prodrug cleavage and electrophilic capture of biological nucleophiles) are also described. QMs are often generated by eliminative processes of phenol derivatives or by photochemical reactions, including reversible generation in photochromic substances. This class of compounds can undergo various reaction types, including nucleophilic attack at the methide carbon, with subsequent rearomatization, and react with electron‐rich dienophiles in inverse‐electron demand hetero‐Diels‐Alder reactions. Its versatile reactivity has been explored in the context of cascade reactions for the construction of several classes of substances, including complex natural products.

Multicomponent Reactions (MCRs) with o‐Quinone Methides

Enantioselective Radical Hydroacylation of α,β-Unsaturated Carbonyl Compounds with Aldehydes by Triplet Excited Anthraquinone

Catalytic Asymmetric Hydroacyloxylation/Ring-Opening Reaction of Ynamides, Acids, and Aziridines.

Visible-Light-Activated Asymmetric Addition of Hydrocarbons to Pyridine-Based Ketones

Chiral Lewis Acid-Catalyzed Norrish Type II Cyclization to Synthesize
 α
 -Oxazolidinones via Enantioselective Protonation

A highly enantioselective three-component hydroacyloxylation/1,4-conjugate addition of ortho-hydroxybenzyl alcohols, ynamides and carboxylic acids was developed under mild reaction conditions in the presence of a chiral N,N'-dioxide/Sc(OTf)3 complex, which went through in situ generated ortho-quinone methides with α-acyloxyenamides, delivering a range of corresponding chiral α-acyloxyenamides derivatives containing gem(1,1)-diaryl skeletons in moderate to good yields with excellent ee values. The scale-up experiment and further derivation showed the practicality of this catalytic system. In addition, a possible catalytic cycle and transition state model was proposed to elucidate the origin of the stereoselectivity based on X-ray crystal structure of the α-acyloxyenamide intermediate and product.

Catalytic Asymmetric Three-component Hydroacyloxylation/ 1,4-Conjugate Addition of Ynamides.

A diastereo- and enantioselective photoenolization/Mannich (PEM) reaction of ortho-alkyl aromatic ketones with benzosulfonimides was established by utilizing a chiral N,N′-dioxide/Ni(OTf)2 complex as the Lewis acid catalyst. It afforded a series of benzosulfonamides and the corresponding ring-closure products, and a reversal of diastereoselectivity was observed through epimerization of the benzosulfonamide products under continuous irradiation. On the basis of the control experiments, the role of the additive LiNTf2 in achieving high stereoselectivity was elucidated. This PEM reaction was proposed to undergo a direct nucleophilic addition mechanism rather than a hetero-Diels–Alder/ring-opening sequence. A possible transition state model with a photoenolization process was proposed to explain the origin of the high level of stereoinduction.

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Tangyu Zhan

Papers

Enantioselective Radical Addition to Ketones through Lewis Acid-Enabled Photoredox Catalysis.

Visible-Light-Activated Asymmetric Addition of Hydrocarbons to Pyridine-Based Ketones

Chiral Lewis Acid-Catalyzed Norrish Type II Cyclization to Synthesize α -Oxazolidinones via Enantioselective Protonation

Catalytic Asymmetric Three-component Hydroacyloxylation/ 1,4-Conjugate Addition of Ynamides.

NickelII-catalyzed asymmetric photoenolization/Mannich reaction of (2-alkylphenyl) ketones