Enantioselective Desymmetrization of 2-Aryl-1,3-propanediols by Direct O-Alkylation with a Rationally Designed Chiral Hemiboronic Acid Catalyst That Mitigates Substrate Conformational Poisoning

Abstract

Enantioselective desymmetrization by direct monofunctionalization of prochiral diols is a powerful strategy to prepare valuable synthetic intermediates in high optical purity. Boron acids can activate diols toward nucleophilic additions; however, the design of stable chiral catalysts remains a challenge and highlights the need to identify new chemotypes for this purpose. Herein, the discovery and optimization of a bench-stable chiral 9-hydroxy-9,10-boroxaro­phenanthrene catalyst is described and applied in the highly enantioselective desymmetrization of 2-aryl-1,3-diols using benzylic electrophiles under operationally simple, ambient conditions. Nucleophilic activation and discrimination of the enantiotopic hydroxy groups on the diol substrate occurs via a defined chairlike six-membered anionic complex with the hemiboronic heterocycle. The optimal binaphthyl-based catalyst 1g features a large aryloxytrityl group to effectively shield one of the two prochiral hydroxy groups on the diol complex, whereas a strategically placed “methyl blocker” on the boroxarophenanthrene unit mitigates the deleterious effect of a competing conformation of the complexed diol that compromised the overall efficiency of the desymmetrization process. This methodology affords monoalkylated products in enantiomeric ratios equal or over 95:5 for a wide range of 1,3-propanediols with various 2-aryl/heteroaryl groups.

Unraveling the Silent Hydrolysis of Cyclic B–X/C═C Isosteres: The Striking Impact of a Single Heteroatom on the Aromatic, Acidic, and Dynamic Properties of Hemiboronic Phenanthroids

“…The lower pK a of 4 and its more facile complexation of nucleophiles such as diols is attractive in nucleophilic catalysis for the monofunctionalization of polyols, as demonstrated recently. 7 However, the dynamic behavior of boroxarophenanthrenes in water makes them potentially less suitable as phenanthroid drug scaffolds or isosteres, owing to the facile ring opening to a boronic acid that could lead to the promiscuous binding of biological polyols and off-target interactions. On the other hand, the ability of boroxarophenanthrenes to undergo such a unique and dynamic hydrolytic process could enable the design of new covalent reversible systems for molecular switching, receptors, sensors, and selfhealing materials.…”

“…The larger phenanthroid isosteres 4 and 5 , 10-hydroxy-10,9-boroxarophenanthrene and 10-hydroxy-10,9-borazaphenanthrene, respectively, differ considerably from naphthoids 1 – 3 ; specifically, they lack the additional nitrogen atom, which provides an opportunity to study an isolated B–X bond as a CC isostere and compare the effect of the heteroatom on their properties, especially their aqueous behavior. Borophenanthroids 4 and 5 , which have been employed as catalysts , and synthetic intermediates, − have drawn conflicting reports regarding the aromatic character of their central boroheterocyclic ring and the acidic nature (Lewis versus Brønsted) of their boranol unit. Moreover, although they exist preferentially in the cyclic hemiboronic form, their potential to undergo a rapid and reversible (“silent”) hydrolysis to the open boronic acid form is unknown.…”

Recent advances towards organocatalytic enantioselective desymmetrizing reactions

“…Notably, the presence of H 2 O here could not only promote the generation of gem-diols but also stabilize the hemiketal products (46) from further degradation. Recently, Hall and coworkers designed a novel hemiboronic acid catalyst and used it in a straightforward O-alkylation of 1,3-diols (47) using benzylic chlorides under ambient conditions (Figure 4E) [65]. Presumably, the formed activated anionic species (47-A) favored chair-like conformation and underwent enantiodetermining substitution, where the catalyst created the steric interaction to form the final monoalkylated products (48).…”

“…This approach converted diverse oxetanes (63) to yield chiral 1,4-benzodioxepines (64) in 85-99% yields with 87-98% enantioselectivities (Figure 5C). During the same year, Jacobsen presented an elegant squaramide-catalyzed enantioselective addition of TMSBr to oxetanes (65) for the expedient preparation of 1,3-bromohydrins (66) (Figure 5D) [82]. In the proposed transition state (65-A), the catalyst interacted with the bromide via hydrogen bonds and with the oxetane via Lewis basic functionality to induce the enantioselectivity.…”

Desymmetrization of Diols by Phosphorylation with a Titanium-BINOLate Catalyst

“…This study highlighted that 1,3-propane diols substituted at C-2 resulted in very high yields of monophosphate product, with little to no diphosphorylation. The desymmetrization of 2-substituted-1,3-propane diols via alkylation, acylation, oxidation, and benzoylation has recently been highlighted in the literature. We thus turned our attention to studying the phosphorylation of 2-substituted-1,3-diols with chiral Ti-catalysts (see Figure c).…”