Chiral Phosphoric Acid Catalyzed Kinetic Resolution of 2‐Amido Benzyl Alcohols: Asymmetric Synthesis of 4H‐3,1‐Benzoxazines

Abstract

An efficient method for the asymmetric synthesis of 4H‐3,1‐benzoxazines was developed by kinetic resolution of 2‐amido benzyl alcohols using chiral phosphoric acid catalyzed intramolecular cyclizations. A broad range of benzyl alcohols (both secondary and tertiary alcohols) were kinetically resolved with high selectivities, with an s factor of up to 94. Mechanistic studies were performed to elucidate the mechanism of these reactions, wherein the amide moieties reacted as the electrophiles. Gram‐scale reaction and facile transformations of the chiral products demonstrate the potential of this method in asymmetric synthesis of biologically active chiral heterocycles.

Kinetic Resolution of 2‐N‐Acylamido Tertiary Allylic Alcohols: Asymmetric Synthesis of Oxazolines

“…The sterically bulky CPA catalyst A10 was also investigated in this reaction, however, which generated significant amount of byproduct in this reaction, albeit still giving the recovered SM and product with high enantioselectivities (entry 10). Next, a range of solvents were examined in this reaction, which indicated toluene still as the optimal solvent (entries [11][12][13][14]. Further decreasing the reaction temperature to 10°C provided the optimal kinetic resolution conditions, under which an improved s-factor of 126 was obtained (entry 15).…”

“…Treatment of the (S)-3 a with racemic phosphoric acid catalysts PA1 (1 mol%) readily provided the oxazoline (S)-4 a in 98% yield with retained enantiomeric excess, providing important insight on the reaction mechanism, in which the hydroxy group played as the nucleophile and the amide moiety as the electrophile under the promotion of CPA catalyst (Scheme 2, c). [11] Hydro-genation (1 atm) of (R)-4 a using Raney Ni as catalyst gave the oxazoline product 7 a in 73% yield, with > 25:1 dr, which underwent the hydrolysis in the presence of TFA to afford the β-amino tertiary alcohol 8 a in 80% yield with 94% ee (Scheme 2, d). Additionally, direct hydrolysis of oxazoline (R)-4 a in the presence of TFA and H 2 O readily afforded the αhydroxy ketone 9 a, without diminishment of enantioselectivity.…”

“…List group developed ingenious kinetic resolution of tertiary alcohols via asymmetric acetalizations. [9] Our group realized the kinetic resolution of tertiary 2-alkoxycarboxamido allylic alcohols [10] and 2-amido benzyl alcohols [11] enabled by chiral phosphoric acid catalyzed intramolecular cyclizations, generating chiral oxazolones and 4H-3,1benzoxazines ( Figure 1, b).…”

Isothiourea‐Catalyzed Acylative Kinetic Resolution of Tertiary α‐Hydroxy Esters

“…To date, only nine methods have been reported for the non‐enzymatic catalytic KR of tertiary alcohols in which an enantioenriched chiral product is obtained (Figure ) . Chiral phosphoric acid catalysis has been exploited by the List and Yang groups in intra‐ and intermolecular approaches for the KR of tertiary alcohols, amino alcohols, and diols; whilst the KR of tertiary propargylic alcohols has been reported by the Oestreich and Ma using Cu and co‐operative Pd/phosphoric acid catalysis, respectively. The acylative KR of alcohols is a particularly attractive option as simple separation of products, coupled with facile ester hydrolysis, provides straightforward access to both enantiomers of the alcohol.…”

Kinetic Resolution of Tertiary Benzyl Alcohols via Palladium/Chiral Norbornene Cooperative Catalysis

“…List and Yang successively developed efficient KR strategies based on chiral phosphoric acid-catalyzed (trans)acetalization, [7] transesterification [8] or condensation. [9] Additionally, efficient KR strategies based on transition metal catalysis were also developed by Hayashi, [10] Ma, [11] Oestreich [12] and Zhou. [13] Despite these stunning progresses, there is still room for improvement with regard to KR efficiency, substrate generality and so on.…”