Atroposelective Phosphoric Acid Catalyzed Three‐Component Cascade Reaction: Enantioselective Synthesis of Axially Chiral N‐Arylindoles

Abstract

An efficient organocatalytic atroposelective threecomponent cascade reaction of 2,3-diketoesters,a romatic amines,a nd 1,3-cyclohexanediones has been developed for the highly enantioselective synthesis of axially chiral Narylindoles.T he success of this method derives from the use of an ewly developed second-generation chiral spirocyclic phosphoric acid as the catalyst. In addition, this protocol was extended to the synthesis of an axially chiral monophosphorus ligand.

A Thioxanthone Sensitizer with a Chiral Phosphoric Acid Binding Site: Properties and Applications in Visible Light‐Mediated Cycloadditions

“…In this communication, we describe the synthesis of a C 2 -symmetric chiral phosphoric acid with two thioxanthone units and report on preliminary studies as to its mode of action in photochemical [2+ +2] cycloaddition reactions.Since their initial use in organocatalysis, [8] chiral phosphoric acids have emerged as ah ighly efficient class of compounds for ap lethora of applications. [9] Most phosphoric acids display aryl groups in positionsC 3a nd C3' of the 2,2'-binaphthol core and we envisaged that these positions would serve as suitable pointso fattachment for at hioxanthone unit. However,t he direct linkage of a9 -oxo-9H-thioxanthen-3-yl group to posi-Figure 1.…”

“…Since their initial use in organocatalysis, [8] chiral phosphoric acids have emerged as ah ighly efficient class of compounds for ap lethora of applications. [9] Most phosphoric acids display aryl groups in positionsC 3a nd C3' of the 2,2'-binaphthol core and we envisaged that these positions would serve as suitable pointso fattachment for at hioxanthone unit. However,t he direct linkage of a9 -oxo-9H-thioxanthen-3-yl group to posi- tions C3 and C3' led to ap hosphoric acid which did not induce any enantioselectivity in photochemical test reactions (see Supporting Information for furtherd etails).…”

Organocatalytic Asymmetric Methodologies towards the Synthesis of Atropisomeric N-Heterocycles

“…A CPA-catalyzed three-component cascade reaction was reported by Lin and co-workers for the preparation of enantioenriched atropisomeric N-arylindoles 48 (Scheme 11). 34 ortho-Substituted anilines 39 condense with cyclohexane-1,3-diones 47 to produce reactive enamines. These enamines undergo a cyclocondensation-elimination-double tautomerization sequence with compounds 46 towards the formation of the desired products.…”

Atroposelective Phosphoric Acid Catalyzed Three‐Component Cascade Reaction: Enantioselective Synthesis of Axially Chiral N‐Arylindoles

“…Finally,t he absolute configurations of 4gfa and 4gsa were determined by X-ray crystallographic analysis. [14] We also evaluated the scope with respect to the 1,3cyclohexanedione substrates 3.Asshown in Table 4, amethyl and phenyl group were well tolerated, and the N-arylindoles (4gab, 4gac, 4gfb and 4gfc)were isolated in good yields with high enantioselective control (up to 94 % ee). Interestingly, the cyclohexanone 3d also worked well to afford the desired axially chiral N-aryl-4,5-dihydroinole 4gad in 64 %yield with 87 % ee under the optimal reaction conditions (Scheme 3).…”

“…Subsequently,t he Pd-catalyzed reduction with formic acid afforded (R)-8a in 92 %yield, or the Pd-catalyzed Suzuki coupling reaction between (R)-7 and arylboron reagents gave the corresponding (R)-8b and (R)-8c in high yields.Then, the desired TM-SPINOL derivatives (R)-9 were obtained in 91-92 %y ield by the Baeyer-Villiger oxidation rearrangement and subsequent hydrolysis.F inally,p hosphorylation of (R)-9 afforded the corresponding chiral phosphoric acids (R)-5a-c.T he structure and absolute configuration of (R)-5c was determined by X-ray diffraction analysis. [14] We next set out to examine the asymmetric threecomponent cascade reaction of the 2,3-diketoester 1a,2 -(tert-butyl)aniline (2a), and 1,3-cyclohexanedione (3a)i n dichloroethane in the presence of 10 mol %o f( R)-5a (Table 1, entry 1). Encouragingly,d espite its high steric hindrance,t he reaction gave the axially chiral N-arylindole 4aaa in 25 %y ield with 66 % ee.…”