Disparate Catalytic Scaffolds for Atroposelective Cyclodehydration

Abstract

Catalysts that control stereochemistry are prized tools in chemical synthesis. When an effective catalyst is found, it is often explored for other types of reactions, frequently under the auspices of different mechanisms. As successes mount, a unique catalyst scaffold may become viewed as "privileged". However, the mechanistic hallmarks of privileged catalysts are not easily enumerated, nor readily generalized to genuinely different classes of reactions or substrates. We explored the concept of scaffold uniqueness with two catalyst types for an unusual atropisomerselective cyclodehydration: (a) C 2-symmetric chiral phosphoric acids, and (b) phosphothreonineembedded, peptidic phosphoric acids. Pragmatically, both catalyst scaffolds proved fertile for enantioselective/atroposelective cyclodehydrations. Mechanistic studies revealed that the determinants of often equivalent and high atroposelectivity are different for the two catalyst classes. A data-descriptive classification of these asymmetric catalysts reveals an increasingly broad set of catalyst chemotypes, operating with different mechanistic features, that creates new opportunities for broad and complementary application of catalyst scaffolds in diverse substrate space.

Palladium‐Catalyzed Enantioselective Cacchi Reaction: Asymmetric Synthesis of Axially Chiral 2,3‐Disubstituted Indoles

“…[3] In sharp contrast to the longstanding interest in asymmetric synthesis of axially chiral six-membered arylaryl and aryl-heteroaryl compounds, [4,5] catalytic enantioselective synthesis of atropisomers bearing af ive-membered heterocycle in general, and an indole unit in particular, attracted the attention of synthetic chemists only very recently. [6][7][8][9][10][11] Due to the reduced rotational energy barrier around the 5-6 and 5-5 biaryl axis,t he atropenantioselective synthesis of this two types of biaryls is known to be ac hallenging endeavor.…”

Peptide‐Catalyzed Fragment Couplings that Form Axially Chiral Non‐C2‐Symmetric Biaryls

“…Atroposelective biaryl construction through the coupling of one arene to a second partner, which then aromatizes to reveal a newly formed axis of chirality has also been reported . Recently, our group has contributed to this category with a peptide‐catalyzed cyclodehydration that transforms a pre‐existing C−N bond into an axis of chirality . Also within this third category is the innovative work of Tan and co‐workers, who demonstrated that BINOL‐derived chiral phosphoric acids (BINOL‐CPAs), such as ( R )‐TRIP, can catalyze the addition of naphthols to quinones to afford enantioenriched non‐ C 2 ‐symmetric biaryls in good yields and selectivity (Scheme A) .…”

Organocatalytic Asymmetric Methodologies towards the Synthesis of Atropisomeric N-Heterocycles

“…Indeed, an excellent example can be found in the strategy developed by Sigman, Toste, Miller, and co-workers, who assessed the performances of the C 2 -symmetric chiral phosphoric acid D (for structure see Scheme 2) or the phosphothreonine-embedded peptidic phosphoric acid O in a catalytic atroposelective cyclodehydration to obtain products 50 from specifically designed ortho-substituted aniline derivatives 49 (Scheme 12a). 35 Indeed, it is possible to rely on alternative catalytic systems, even though the mode of action is intrinsically different, to promote the same enantioselective reaction. Thorough experimental data and computational investigations were collected to evaluate which are the most influential factors affecting the stereoselectivity of the reaction.…”