Enantioselective synthesis of atropisomeric indoles via iron-catalysed oxidative cross-coupling

Abstract

Heterobiaryl compounds that exhibit axial chirality are of increasing value and interest across several fields, but direct oxidative methods for their enantioselective synthesis remain elusive. Here we disclose that an iron catalyst in the presence of a chiral PyBOX ligand and an oxidant enables direct coupling between naphthols and indoles to yield atropisomeric heterobiaryl compounds with high levels of enantioselectivity. The reaction exhibits remarkable chemoselectivity and exclusively yields cross-coupled products without competing homocoupling. Mechanistic investigations enable us to postulate that an indole radical is generated in the reaction but that this is likely an offcycle event, and that the reaction proceeds through formation of a chiral Fe-bound naphthoxy radical which is trapped by a nucleophilic indole. We envision that this simple, cheap, and sustainable catalytic manifold will facilitate access to a range of heterobiaryl compounds and enable their applications across the fields of materials science, medicinal chemistry, and catalysis.Atropisomeric biaryls comprise a privileged class of compounds whose applications span the fields of medicinal chemistry, catalysis and materials science; as such, a panoply of elegant and efficient methods have been developedfor their synthesis 1 . The most convergent route to biaryls is generally the transition metal mediated cross-coupling of two partners 2,3 (although significant advances in metal-free methods have been demonstrated recently) 4 . Whilst this strategy generally results in cross-coupled products in good yields and predictable levels of chemo-and regioselectivity, these advantages may be offset by the requirement to synthesize two specifically functionalized coupling partners (Figure 1a) 5 . In principle, oxidative coupling represents a more direct, atom economic and environmentally benign approach as it creates the desired aryl-aryl linkage from two C-H bonds 6,7 . This realization has led to a significant number of oxidative homo-coupling procedures that can generate C2-symmetric BINOL-like structures in an enantioselective fashion. These include reactions mediated by transition metals including copper 8-10 , iron 11 and vanadium, 12 amongst others. However, in the absence of specific functional groups, controlling the regio-, chemo-and enantioselectivity of the corresponding hetero-couplings remains a formidable challenge, and successful examples have been limited to the synthesis of BINOL or NOBIN type scaffolds [13][14][15][16] . In particular, Katsuki

Organocatalytic Nazarov-type cyclization of 3-alkynyl-2-indolylmethanols: construction of axially chiral cyclopenta[b]indole scaffolds

“…In fact, in recent years, the catalytic asymmetric construction of axially chiral indole-based scaffolds has become an emerging area of study [8,78] due to the importance of such scaffolds in many natural products [90][91][92] , bioactive molecules [93,94] and chiral catalysts or ligands [95][96][97][98][99][100][101] . Although a number of axially chiral indole-based scaffolds, such as N-arylindoles [102][103][104][105][106][107][108][109][110] , 3-arylindoles [111][112][113][114][115][116][117][118][119][120] , 2-arylindoles [121][122][123][124][125][126][127] , 3quinonylindoles [128,129] , isochromenone-indoles [130] , bisindoles [131][132][133][134]…”

Recent advances in iron-catalysed coupling reactions for the construction of the C(sp2)–C(sp2) bond

“…14 In 2023, the Smith group reported an iron-catalysed method for synthesizing atropisomeric heterobiaryl compounds via the direct coupling of indoles and naphthol with high enantioselectivity. 15 As displayed in Scheme 10, atropisomeric heterobiaryl compounds could be obtained in DCE/HFIP (1 : 1) under mild conditions using inexpensive FeCl 3…”

“…14 In 2023, the Smith group reported an iron-catalysed method for synthesizing atropisomeric heterobiaryl compounds via the direct coupling of indoles and naphthol with high enantioselectivity. 15 As displayed in Scheme 10, atropisomeric heterobiaryl compounds could be obtained in DCE/HFIP (1 : 1) under mild conditions using inexpensive FeCl 3 ˙6H 2 O as the catalyst, chiral PyBOX as the ligand, and t -butylhydroperoxide (TBHP) as the oxidant. Notably, the reaction exhibits remarkable chemoselectivity and excellent yields for cross-coupling products without competing homo-coupling.…”

Chiral Phosphoric Acid‐Catalyzed Enantioselective Synthesis of Axially Chiral Compounds Involving Indole Derivatives

“…The reaction occurs through interception of a chiral Fe-bound naphthoxy radical by indole nucleophile. [12] On the other hand, organocatalysis could enable distinctive reaction modes to couple two nucleophilic arene components. In 2017, Shi, Li and co-workers demonstrated the use of CPA to activate 2-indolylmethanols 1 for atroposelective arylation with aromatic alcohols to form 3-aryl-indoles 3 that contain a CÀ C chiral axis (Scheme 1a).…”