Entropy‐Controlled Catalytic Asymmetric 1,4‐Type Friedel–Crafts Reaction of Phenols Using Conformationally Flexible Guanidine/Bisthiourea Organocatalyst

Abstract

One of the most important aspects of protein function is the motion that occurs in response to substrate binding. [1] In the dynamics of enzyme catalysis, multiple weak hydrogenbonding interactions [2] in the polypeptide that are controlled by interrelated enthalpy and entropy changes play a significant role in governing the conformational changes that take place. [3] In contrast, the development of asymmetric organocatalysts has rarely focused on hydrogen-bond donors [4][5][6][7][8] that have conformationally flexible scaffolds [9][10][11] as a likely consequence of difficulties in controlling the conformation of acyclic skeletons.[12] However, recently our research group has successfully demonstrated the utility of conformationally flexible guanidine/bisthiourea organocatalysts 1 for organocatalytic carbon-carbon bond-forming reactions.[9] Herein, we describe studies that have led to the development of new acyclic C 3 -linked guanidine/bisthiourea organocatalysts 2. Analysis of these processes shows that the catalytic effect resides in a trade off between enthalpies and entropies of activation and reveals the existence of dramatic concentration effects. This investigation has uncovered a unique catalytic stereodiscrimination process controlled only by differences in the activation entropies.The primary aim of this study was to extend our newly developed organocatalytic system to asymmetric 1,4-additions reactions of nitroolefins.[13] A plausible interaction mode for the catalytic reactions of nitroolefins with nucleophilic anions is shown in Scheme 1. In the reactive complex involving an acyclic guanidine/bisthiourea organocatalyst, the thiourea moiety can interact with the nitro group in the acceptor and ionic interactions with the guanidinium cation can orient a nucleophilic anion. [14] We envisaged that a long chiral spacer between the two centers in the catalyst would be required for the promotion of the 1,4-addition reactions that take advantage of these synergistic proximity effects.In the current study, we initially selected catalytic asymmetric Friedel-Crafts (FC) reactions [15,16] of phenol derivatives. [17][18][19] Although a variety of electron-rich aromatic compounds such as indoles, pyrroles, and furans have been successfully utilized as nucleophiles in 1,4-addition processes, [15,16] asymmetric reactions of phenol derivatives have been rarely studied. The difficulty in employing phenol derivatives in these processes could be a result of two intrinsic factors that are related to the fact that phenoxide anions generated in situ 1) often promote ligand exchange with metal catalysts, [17] and 2) can participate in reactions that take place with low levels of chemo-and regioselectivity. In 2007, Chen and co-workers developed the first 1,4-type of FC reaction of naphthols with nitroolefins that utilize cinchona-based thiourea catalysts. These processes give ortho-selective FC products with 85-95 % ee.[18a] However, the undesired dimeric furans that are formed in these reactions cannot be easily separat...

Dianhydrohexitols: new tools for organocatalysis. Application in enantioselective Friedel-Crafts alkylation of indoles with nitroalkenes

“…[31][32][33][34][35][36][37][38][39][40][41] The indole skeleton is considered to be one of the most useful moieties in pharmaceutical chemistry. [42][43] …”

Organocatalytic Asymmetric Friedel–Crafts Reaction of Sesamol with Isatins: Access to Biologically Relevant 3‐Aryl‐3‐hydroxy‐2‐oxindoles

“…Initially, the Friedel-Crafts-type addition of sesamol (5) to N-benzylisatin (6 a) was performed by using quinidine (1 a, 10 mol %) in the presence of 4 molecular sieves in tetrahydrofuran as a solvent at ambient temperature. Product 7 a was obtained in a good 76 % yield, albeit with a poor enantiomeric excess (ee) of 3 % (Table 1, entry 1).…”

“…Keywords: alkaloids · alkylation · click chemistry · organocatalysis · sesamol tries 2-4), quinine (2 a) was found to yield 7 a in a good 75 % yield with enhanced 30 % ee (Table 1, entry 3). Encouraged by this result, we studied the catalytic ability of modified Cinchona alkaloids on the same reaction (Table 1, entries [5][6][7][8][9][10][11][12][13][14]. Cupreine (2 c) provided 7 a in good yield (77 %), but with low enantioselectivity (21 % ee; Table 1, entry 6), whereas its pseudoenantiomeric partner cupreidine (1 c) offered moderate enantioselectivity (50 % ee; Table 1, entry 5).…”

“…[4] However, the organocatalytic enantioselective Friedel-Crafts reaction of phenols as C nucleophiles has been less studied. [5] Given that the phenol unit is widely distributed in biologically active natural products and pharmaceutically useful molecules, [6] expansion of the scope of phenols in the Friedel-Crafts reaction is of high interest. Chen and co-workers [7] reported the first enantioselective Friedel-Crafts alkylations of phenols by using Cinchona alkaloids as organocatalysts.…”

Organocatalytic Enantioselective Regiodivergent C−H Bond Functionalization of 1‐Naphthols with 1‐Azadienes

“…[6] Furthermore, the catalytic enantioselective Friedel-Crafts alkylation of naphthols has emerged as a powerful tool to construct benzylic stereocenters, a structural motif widely distributed in naturally occurring products and bioactive compounds. [7] In this context, organocatalytic enantioselective o-selective carbonÀ hydrogen bond functionalization of 1-naphthols has been established via catalytic asymmetric Friedel-Crafts alkylation in the presence of chiral secondary amine, [8] thiourea, [9] tertiary amine, [10] primary amine, [11] and squaramide, [12] respectively. In sharp contrast, organocatalytic enantioselective p-selective CÀ H bond functionalization of 1naphthols remains rare.…”