H₃PO₂-Catalyzed Intramolecular Stereospecific Substitution of the Hydroxyl Group in Enantioenriched Secondary Alcohols by N-, O-, and S-Centered Nucleophiles to Generate Heterocycles

Abstract

The direct intramolecular stereospecific substitution of the hydroxyl group in enantiomerically enriched secondary benzylic, allylic, propargylic, and alkyl alcohols was successfully accomplished by phosphinic acid catalysis. The hydroxyl group was displaced by O-, S-, and N-centered nucleophiles to provide enantioenriched five-membered tetrahydrofuran, pyrrolidine, and tetrahydrothiophene as well as six-membered tetrahydroquinolines and chromanes in up to a 99% yield and 100% enantiospecificity with water as the only byproduct. Mechanistic studies using both experiments and calculations have been performed for substrates generating 5-membered heterocycles. Rate studies show dependences in a catalyst, an internal nucleophile, and an electrophile, however, independence in an external nucleophile, an electrophile, or water. Kinetic isotope effect studies show an inverse KIE of k H/k D = 0.79. Furthermore, phosphinic acid does not promote SN1 reactivity. Computational studies support a bifunctional role of the phosphinic acid in which activation of both nucleofuge and nucleophile occurs in a bridging SN2-type transition state. In this transition state, the acidic hydrogen of phosphinic acid protonates the leaving hydroxyl group simultaneously as the oxo group partially deprotonates the nucleophile. Thereby, phosphinic acid promotes the substitution of the nonderivatized hydroxyl group in enantioenriched secondary alcohols by uncharged nucleophiles with conservation of the chirality from the alcohol to the heterocycle.

Hydrogen-bond donor and acceptor cooperative catalysis strategy for cyclic dehydration of diols to access O-heterocycles

“…As shown in fig. S14A, >99% of ( S )-2-methyltetrahydrofuran ( 3b′ , ee > 90%) was obtained via the dehydrative cyclization of ( R )-pentane-1,4-diol ( 3a′ , ee = 97%), which suggests that the [HO-EtMIm][OTf] catalyst mainly promotes an S N 2 pathway to yield 3b′ and little 3b may be obtained via an S N 1 pathway under these reaction conditions ( 7 , 8 , 38 ). Because of the steric effects, the primary alcohol and secondary carbon acted as the nucleophile and the electrophile, respectively, which resulted in the inversion of configuration for 3a′ to 3b′ .…”

“…Moreover, an inverse deuterium kinetic isotope effect ( k H / k D = 0.89) was observed by comparing the rate of dehydrative etherification of 1c with that of CD 3 OH ( 1c′ ), which supports the idea that the reaction mainly follows an S N 2-like pathway (fig. S14, B and C) ( 7 , 9 , 39 ). In addition, tertiary alcohol (e.g., 5a ) was also tolerant to this IL catalyst but showed a low reactivity with a 36% yield of 5b under the similar reaction conditions.…”

“…1) (1)(2)(3)(4)(5)(6). Homogeneously catalytic systems including Brønsted acids (e.g., H 2 SO 4 , H 3 PO 4 , and H 3 PO 2 ), Lewis acids [e.g., BuSnCl 3 , CuBr 2 , and Fe(OTf) 3 ], and metalbased complex catalysts (e.g., Ru/P/Al) have been widely applied in catalyzing dehydrative cyclization of diols to access cyclic ethers (5,(7)(8)(9). However, they generally suffer from corrosion, pollution, and difficulty in separation, thus limiting their practical applications (10)(11)(12)(13)(14)(15).…”

Asymmetric β-arylation of cyclopropanols enabled by photoredox and nickel dual catalysis

“…21 Subsequently, Brønsted acid catalyzed stereospecific benzylic substitution occurred, furnishing the concise synthesis of a marine natural product ent -calyxolane B analog 6 in 80% yield ( Scheme 2C ). 22 Moreover, subjecting 3a to the Wittig reaction, followed by deprotection of TIPS could generate γ-hydroxy ene 8 in 75% overall yield with 88% ee ( Scheme 2D ). With product 8 in hand, the indomethacin ester 9 was easily obtained in 95% yield.…”

Restoration of catalytic activity by the preservation of ligand structure: Cu-catalysed asymmetric conjugate addition with 1,1-diborylmethane

“…A two-step sequence involving Jones oxidation and Fisher esterification furnished the corresponding methyl ester in 51% overall yield ( 3ad ). Alternatively, an enantioselective reduction of the carbonyl group in the presence of the ( R )-oxazaborolidine catalyst, 20 followed by stereospecific benzylic displacement 21 afforded marine natural product calyxolane B in its enantiomeric form ( 3ae ). 22 …”