Brønsted Acid-Catalyzed Intramolecular Nucleophilic Substitution of the Hydroxyl Group in Stereogenic Alcohols with Chirality Transfer

Abstract

The hydroxyl group of enantioenriched benzyl, propargyl, allyl, and alkyl alcohols has been intramolecularly displaced by uncharged O-, N-, and S-centered nucleophiles to yield enantioenriched tetrahydrofuran, pyrrolidine, and tetrahydrothiophene derivatives with phosphinic acid catalysis. The five-membered heterocyclic products are generated in good to excellent yields, with high degree of chirality transfer, and water as the only side-product. Racemization experiments show that phosphinic acid does not promote SN1 reactivity. Density functional theory calculations corroborate a reaction pathway where the phosphinic acid operates as a bifunctional catalyst in the intramolecular substitution reaction. In this mechanism, the acidic proton of the phosphinic acid protonates the hydroxyl group, enhancing the leaving group ability. Simultaneously, the oxo group of phosphinic acid operates as a base abstracting the nucleophilic proton and thus enhancing the nucleophilicity. This reaction will open up new atom efficient techniques that enable alcohols to be used as nucleofuges in substitution reactions in the future.

A General Catalytic Method for Highly Cost‐ and Atom‐Efficient Nucleophilic Substitutions

“…In an ideal S N ‐type reaction that employs alcohols as starting components, water would be formed as the sole byproduct. This type of transformation has been realized in (1) Brønsted and Lewis acid catalyzed unimolecular nucleophilic substitutions (S N 1) and (2) transition metal catalyzed allylic alkylations . However, these appealing strategies are not generally applicable, because the substrate scope is limited to S N 1‐reactive or allylic and propargylic alcohols.…”

Catalytic mechanism of human glyoxalase I studied by quantum-mechanical cluster calculations

“…In this paper, we investigate all proposed mechanisms for both the S and R substrates on an equal footing. We have used the quantum mechanical (QM) cluster approach, which has extensively been used to study catalytic mechanisms and structures of enzymes [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] . In this approach, the most important residues are cut out from the active site of the enzyme.…”

Synthesis of Enantiopure γ‐Lactones via a RuPHOX‐Ru Catalyzed Asymmetric Hydrogenation of γ‐Keto Acids

“…[17] After aminolysis with aniline, the ring-opening product 4 of 2 a, a valuable N-aryl amide scaffold, was obtained in good yield and ee. For example, 2 a could be reduced to diol 3 in 90% yield and 88% ee, which is an important building block in organic synthesis.…”

“…The Synthesis of (R)-1-Phenylbutane-1,4-Diol (3) [17] To a solution of 2 a (162.2 mg, 1.0 mmol) in THF was added LiAlH 4 in portions. The reaction was monitored by TLC for the disapperance of starting material and was quenched by water.…”