The asymmetric Friedel-Crafts reaction is one of the most powerful methods to synthesize optically active aromatic compounds, [1] and chiral Brønsted acids have recently emerged as efficient catalysts.[2] Chiral phosphoric acids, first introduced by Akiyama et al. and Terada and Uraguchi as organocatalysts, [3] were shown to be effective in the FriedelCrafts alkylation reactions of indoles and pyrroles by several groups. However, electrophilic partners that can be activated by chiral phosphoric acids in Friedel-Crafts reactions have, so far, been limited to imines, [4] enamides, [5] a,b-unsaturated carbonyls, [6] and nitroolefins. [7] Developing new, suitable electrophilic partners and novel catalytic models for chiral phosphoric acid catalyzed reactions are extremely desirable. In this regard, vinyl ether [8] and nitroso compounds [9] have recently been developed successfully.[10] Alcohols are among the most abundant chemicals and synthetic intermediates, however, their use in enantioselective FriedelCrafts reactions has only appeared recently.[11] To the best of our knowledge, the only example involving the use of alcohols in the Brønsted acid catalyzed asymmetric FriedelCrafts reaction was carried out by Rueping et al., in which chiral N-triflylphosphoramide was used and a moderate enantiomeric excess (ee) value was obtained.[6a]During our recent study on the chiral Brønsted acid catalyzed Friedel-Crafts reaction, we found that a chiral phosphoric acid could catalyze the Friedel-Crafts reaction of indole with 2-formylbiphenyl derivatives. Interestingly, this reaction proceeded through a double Friedel-Crafts alkylation process, [12] providing the 9-(3-indolyl)fluorene derivatives with high ee values (Scheme 1).[13] To the best of our knowledge, despite their significant applications in organic synthesis, [14] this represents the first asymmetric synthesis of fluorene derivatives. More interestingly, the current reaction proceeds with the activation of both carbonyl and hydroxy groups by a chiral phosphoric acid. The enantiocontrol is likely to be made possible through the close proximity of the chiral phosphate counterion to the 3-benzylidene-3H-indolium ion.[15] Herein, we report a tandem double FriedelCrafts reaction of indoles with 2-formylbiphenyls, leading to 9-(3-indolyl)fluorene derivatives with up to 96 % ee.We first examined the reaction between 3',5'-dimethoxybiphenyl-2-carbaldehyde (2 a) and 2-methyl indole (3 a) catalyzed by different, readily available, chiral phosphoric acids.[16] To our delight, reaction of 2 a and 3 a in the presence of (S)-1 (5 mol %) and 5 molecular sieves (MS), in toluene at room temperature, proceeded smoothly to afford fluorene 4 aa in 70 % yield with 75 % ee (Table 1, entry 1). Optimization of the reaction conditions was carried out and the results are summarized in Table 1. Lowering the temperature to 0 8C resulted in an increase of enantioselectivity (81 % ee; Table 1, entry 2). Several solvents, namely, benzene, dichloromethane, and carbon tetrachloride, were scree...

A highly efficient tandem double Friedel-Crafts reaction between indoles and 2-formylbiphenyl derivatives by chiral N-triflyl phosphoramide was realized. Under mild conditions, various 9-(3-indolyl) fluorene derivatives have been obtained in good yield and up to 94% ee. Comparing to their corresponding chiral phosphoric acids, chiral N-triflyl phosphoramides catalyzed reactions led to products with opposite absolute configuration.

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Through regulation of the epigenome, the bromodomain and extra terminal (BET) family of proteins represent important therapeutic targets for the treatment of human disease. Through mimicking the endogenous N-acetyl-lysine group and disrupting the protein–protein interaction between histone tails and the bromodomain, several small molecule pan-BET inhibitors have progressed to oncology clinical trials. This work describes the medicinal chemistry strategy and execution to deliver an orally bioavailable tetrahydroquinoline (THQ) pan-BET candidate. Critical to the success of this endeavor was a potency agnostic analysis of a data set of 1999 THQ BET inhibitors within the GSK collection which enabled identification of appropriate lipophilicity space to deliver compounds with a higher probability of desired oral candidate quality properties. SAR knowledge was leveraged via Free–Wilson analysis within this design space to identify a small group of targets which ultimately delivered I-BET567 (27), a pan-BET candidate inhibitor that demonstrated efficacy in mouse models of oncology and inflammation.