Isothiourea‐Catalyzed Atropselective Acylation of Biaryl Phenols via Sequential Desymmetrization/Kinetic Resolution

Abstract

Axially chiral phenols are attractive targets in organic synthesis.T his motif is central to many natural products and widely used as precursors to,ordirectly,aschiral ligands and catalysts.D espite their utility few simple catalytic methods are available for their synthesis in high enantiopurity.Herein the atropselective acylation of ar ange of symmetric biaryl diols is investigated using isothiourea catalysis.S tudies on amodel biaryl diol substrate shows that the high product er observed in the process is ar esult of two successive enantioselective reactions consisting of an initial enantioselective desymmetrization coupled with as econd chiroablative kinetic resolution. Extension of this process to ar ange of substrates, including achallenging tetraorthosubstituted biaryl diol, led to highly enantioenriched products (14 examples,u pt o9 8:2e r), with either HyperBTM or BTM identified as the optimal catalyst depending upon the substitution pattern within the substrate.Computation has been used to understand the factors that lead to high enantiocontrol in this process,w ith maintenance of planarity to maximizea1,5-S···O interaction within the key acyl ammonium intermediate identified as the major feature that determines atropselective acylation and thus product enantioselectivity.

Isothiourea‐Catalyzed Atropselective Acylation of Biaryl Phenols via Sequential Desymmetrization/Kinetic Resolution

“…On apreparative scale,and using i-Pr 2 NEt as the organic base,( S)-6 was isolated in 32 %y ield and 94:6 er (entry 11), with the absolute configuration of 6 confirmed by X-ray analysis. [27] Thea lternative isothiourea HyperBTM 9 gave asimilar product ratio but provided (S)-6 in reduced er (85:15 er, entry 12). In-situ reaction monitoring of the enantioselective acylationo fd iol 1 indicated that the er of product (S)-6 increased with reaction conversion (see SI for further information).…”

“…Notably,f or the series of C(2')heteroatom derivatives,( S)-BTM 8 proved the optimal catalyst, giving (S)-monoesters 32-34 in excellent (92:8-95:5) er in each case.T he absolute configuration of 32 was confirmed by X-ray crystallographic analysis. [39] Theu se of (2R,3S)-HyperBTM 9 gave the opposite (R)-enantiomer of C(2')-halogen-substituted monoesters 32 and 33,h owever 32 and 33 were obtained in both reduced yield and er.…”

“…Theabsolute configuration within (R)-19 was unambiguously confirmed by X-ray crystal structure analysis. [38] Pleasingly incorporation of both electron-donat- in the kinetic resolution step.T he lack of selectivity in the atropselective acylation of (AE)-15 when using BTM as the catalyst indicates that the monoester product enantioselectivity derives entirely from the initial desymmetrization event, as the rate constants for acylation of each enantiomer of monoester are equal. Taken together, these observations imply that the initial enantioselective acylation event leading to desymmetrization will have opposite enantioselectivities for each catalyst, with (S)-BTM 8 being (S)-selective and (2R,3S)-HyperBTM 9 being (R)-selective despite both catalysts being in the same enantiomeric series.…”

“…Thea bsolute configuration of (S)-47 was confirmed by X-ray crystallography. [40] Investigation of the KR of (AE)-47 was indicative of the operation of ac ompli- It is clear from the changes in product configuration obtained upon variation of both the substrate and catalyst that subtle and complex differences in the interactions between acylated catalyst and substrate markedly affect the enantiorecognition events involved in both the desymmetrization and kinetic resolution steps.This makes the proposal of ag lobal stereochemical model to explain the observed differences in selectivity challenging.Despite the complexity of this process,qualitative conclusions (excluding atropselective acylation of the naphthyl substituted examples 1 and 46)…”

Atroposelective transformation of axially chiral (hetero)biaryls. From desymmetrization to modern resolution strategies

“…A seminal contribution by Hayashi and co-workers 7 is based on this strategy: starting from achiral biaryl bistriflates, an enantioselective Kumada coupling was developed by using PdCl 2 [(S)-Phephos] [Phephos = 2-(dimethylamino)-1-(diphenylphosphino)-3-phenylpropane] as the catalyst (Scheme 4A). More recently, Cheong, Smith and co-workers 8 have exploited chiral bases BTM and HyperBTM as acyl transfer catalysts for the acylative desymmetrization of biaryl diols (Scheme 4B). Remarkably, a divergent stereoselectivity was observed depending on the substitution pattern of the substrate and the catalyst used.…”