Ning the diaryl moiety are isoform selective ligands for RAR and
Ning the diaryl moiety are isoform selective ligands for RAR and . 1,1-Diarylethane two and BMS 184394, which is the saponified ester 50, are RAR agonists.38 RAR is known to become sensitive to stereochemistry at the benzylic position. The (S)-enantiomer of BMS 184394 is 10-fold far more potent than the (R)-enantiomer.7c Even though racemic 1,1-diarylethane 2 has comparable activity to (S)-BMS184394, activities from the two enantiomers of 2 haven’t been reported. We envisioned making use of our cross-coupling tactic as a important step inside the synthesis of enantioenriched acid 2. We started our synthesis with bromide 46, which was converted to boronic acid 47 from the corresponding Grignard reagent by quenching with trimethoxyborane followed by hydrolysis.39 Enantioselective arylation of aldehyde 48 as outlined by the Bolm technique furnished the preferred enantioenriched alcohol (R)-50 in 94 yield and 94 ee.27b The traceless directing group was then installed by DCC coupling23 and also the substrate was subjected to standard cross-coupling conditions. Diarylethane 53 was obtained in 92 yield with outstanding transfer of stereochemical info (97 es). We confirmed that the cross-coupling reaction proceeded with inversion in the benzylic center by preparation of a crystalline derivative that was subjected to X-ray crystallographic evaluation (see Supporting Information for particulars).40 Saponification with 1 N NaOH provided the desired retinoic acid receptor ligand (S)-2 in higher yield.7c We subsequent applied our methodology towards the synthesis of fatty acid amide hydrolase (FAAH) inhibitor 3. FAAH is a membrane bound serine hydrolase, which has recently gained interest for discomfort remedy as an option target to cannabinoid receptor 1 (CB1). Inactivation of FAAH produces analgesic and anti-inflammatory effects in rodents without the weight gain that commonly accompanies CB1 agonists.7d The first reported synthesis of 3 featured a sodium borohydride reduction followed by chiral chromatography to separate the enantiomers. When the authors demonstrated that the two enantiomers exhibited a 20-fold distinction in activity, they did not report the MAP3K5/ASK1 Storage & Stability absolute configuration in the extra active stereoisomer.7d Considering the fact that our cross-coupling proceeds with net inversion, the configuration from the product can be readily assigned when the configuration of your enantioenriched alcohol isJ Am Chem Soc. Author manuscript; obtainable in PMC 2014 June 19.Wisniewska et al.Pageknown.29,41 We started our synthesis with addition of aryl lithiate 54 to 1-Boc-piperidine-4carboxaldehyde to afford racemic 56, followed by oxidation to ketone 55.42 Subsequent CBS reduction afforded the requisite enantioenriched alcohol intermediate in 93 ee.25b,c We assigned the absolute configuration of alcohol 56 as R depending on the accepted model for selectivity in CBS reductions,28a which was then confirmed by the Competing Enantioselective Conversion (CEC) approach.29 The directing group was installed by a DCC coupling without loss of ee.23 Cross-coupling of 57 beneath our optimized reaction Mcl-1 list conditions afforded the methyl-bearing benzylic stereocenter in 87 yield with 99 es. Subsequent elaboration of key intermediate 58 to FAAH inhibitor three was accomplished in four steps. To introduce the requisite methyl substituent on the benzothiophene ring, we chose to employ a second cross-coupling reaction. Bromination in the 3-position of your benzothiophene supplied 59,43 which was then subjected to cross-coupling circumstances. A Suzuki cross-coupli.