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PMC:7571312 / 10217-14244 JSONTXT 8 Projects

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Id Subject Object Predicate Lexical cue
T50 0-9 Sentence denotes Chemistry
T51 10-183 Sentence denotes Central to our strategy of examining ketone-based thiophiles was the preparation of an array of intermediates containing diverse methylketone moieties and protecting groups.
T52 184-402 Sentence denotes The preparation of halomethylketone intermediates was accomplished in a two-step procedure by the generation of a diazoketone intermediate31 or directly by a modified Kowalski–Haque reaction,32 as depicted in Scheme 1.
T53 403-454 Sentence denotes Scheme 1 Preparation of P1 Synthetic Intermediates
T54 455-809 Sentence denotes (i) 3 M NaOH, MeOH (95%), (ii) isobutylchloroformate (IBCF), triethylamine (TEA), tetrahydrofuran (THF), (iii) CH2N2/ether (92%), (iv) 4 M HCl/dioxane (83%), (v) 1.0 equiv 48% HBr (83%), (vi) HNCH3(OCH3), EDC, HOBt, NMM, dichloromethane (DCM) (79%), (vii) Mg, HgCl2, BOM-Cl, THF, −78°C (50%), and (viii) lithium diisopropylamide (LDA), ClCH2I, THF (54%).
T55 810-915 Sentence denotes Saponification of amino ester 5(33) afforded the corresponding amino acid 6 in nearly quantitative yield.
T56 916-1084 Sentence denotes Acid 6 was treated with isobutylchloroformate and triethylamine, and the resulting mixed anhydride was reacted with diazomethane34 to provide high isolated yields of 7.
T57 1085-1236 Sentence denotes Diazoketone 7 was treated with hydrochloric acid for simultaneous nitrogen deprotection and conversion to the chloromethylketone (CMK) intermediate 10.
T58 1237-1396 Sentence denotes Alternatively, the N-Boc-protected bromomethylketone was prepared by treatment of 7 with stoichiometric quantities of 48% HBr in dichloromethane to provide 11.
T59 1397-1581 Sentence denotes Another preparation of CMK intermediates that avoids the use of diazomethane was accomplished by the reaction of 5 with excess LDA and chloroiodomethane to afford 8 in moderate yields.
T60 1582-1789 Sentence denotes A direct approach to oxymethylketone intermediate 9 was achieved by conversion of acid 6 to the corresponding Weinreb amide followed by treatment with the Grignard generated from benzyl chloromethyl ether.35
T61 1790-1922 Sentence denotes A key element for rapid access to substituted methylketone derivatives was the generation of the fully elaborated CMK 12 (Scheme 2).
T62 1923-2031 Sentence denotes The utility of the CMK moiety to prepare acyloxy- and hydroxy-substituted methylketones is well established.
T63 2032-2284 Sentence denotes Elaboration of 10 in a sequence of deprotection/1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU)-mediated peptide couplings provided CMK derivative 12 in moderate yield with no epimerization observed.
T64 2285-2410 Sentence denotes Reaction of 12 with various carboxylic acids in the presence of cesium fluoride at 60 °C provided acyloxymethylketones 13–28.
T65 2411-2535 Sentence denotes Using this synthetic approach with substitution of P2 and amine capping structural elements provided inhibitors 3 and 29–31.
T66 2536-2616 Sentence denotes Scheme 2 Preparation of Substituted Acyloxymethylketones and Aminomethylketones
T67 2617-2823 Sentence denotes (i) Boc-Leu-OH, HATU, NMM, N,N-dimethylformamide (DMF), 0 °C (64%), (ii) 4 M HCl/dioxane, (iii) HATU, 4-MeO-2-indolecarboxylic acid, NMM, DMF, 0 °C (61%), and (iv) CsF, DMF, carboxylic acid, 60 °C (43–91%).
T68 2824-2932 Sentence denotes Hydroxymethylketone (HMK) derivatives were accessed by two complimentary approaches illustrated in Scheme 3.
T69 2933-3152 Sentence denotes Elaboration of the P1′-protected oxygen intermediate 9 by sequential amide bond coupling reactions provided benzylether derivatives such as 34 in moderate yields with a low propensity for epimerization at the P1 center.
T70 3153-3242 Sentence denotes Hydrogenolytic debenzylation readily afforded the final HMK inhibitors exemplified by 36.
T71 3243-3592 Sentence denotes Alternatively, fully elaborated CMK derivatives such as 35 were reacted with benzoylformic acid followed by methanolysis to generate HMK final products such as 36.36 Alkylation of the terminal hydroxyl was achieved under microwave-assisted conditions in the presence of silver (I) oxide to afford alkoxymethylketone inhibitors, as illustrated by 37.
T72 3593-3724 Sentence denotes Using these two synthetic approaches with substitution of P2 and amine capping structural elements provided inhibitors 4 and 38–50.
T73 3725-3781 Sentence denotes Scheme 3 Preparation of Hydroxymethylketone Derivatives
T74 3782-3983 Sentence denotes (i) 4 M HCl/dioxane, (ii) Boc-Leu-OH, HATU, NMM, DMF, 0 °C, (iii) HATU, 4-MeO-2-indolecarboxylic acid, NMM, 0 °C, (iv) Pd/C, H2, EtOH (77%), (v) CsF, DMF, benzoylformic acid, 60 °C, and then MeOH, cat.
T75 3984-4027 Sentence denotes K2CO3 (53%), and (vi) CH3I, Ag2O, DCE (9%).