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  • The only reported synthesis of the aminobicyclic core of is

    2020-10-22

    The only reported synthesis of the aminobicyclic core of is based on bis-alkylation of a 4-amino-5,6-dihydroxypyrmidine with dibromoethane. The likelihood of poor regiocontrol/reactivity in utilizing such a transformation for the synthesis of compounds with a substituent on the dioxinyl ring led us to develop a stepwise approach to targets represented by (). Two key hallmarks of the retro-synthetic strategy utilized in the development of an asymmetric synthetic route were: (1) construction of the pyrimidine ring from a functionalized sidechain precursor as a means of controlling regiochemistry and (2) application of Sharpless dihydroxylation technology to generate homochiral products via a readily available vinyl sidechain intermediate. Palladium catalyzed coupling of the previously reported triflate with potassium trifluoro(vinyl)borate provided the corresponding styrene intermediate. Asymmetric dihydroxylation, followed by selective protection of the primary alcohol afforded in 66% overall yield and >95% ee. Incorporation of a symmetrically-functionalized pyrimidine ring was accomplished via a two-step sequence. Insertion of the rhodium-carbene generated from dimethyl-diazomalonate gave ether in 72% yield, along with 20% recovered . Cyclization to this malonate with formamidine afforded dihydroxypyrimidine in 82% yield. The initial approach developed to generate intermediate involved a three-step sequence of silyl group deprotection, Mitsunobu cyclization and chlorination. However, it was subsequently found that heating with phosphorus oxychloride in toluene directly afforded in 62% yield. Displacement of the chloride with -methoxybenzylamine, deprotection with trifluoro-acetic Rizatriptan Benzoate and ester hydrolysis provided -isomer in 47% overall yield from . Compound was confirmed to be of high stereochemical purity (>95% ee) by chiral HPLC. -Enantiomer was prepared according to Scheme 1 by substituting AD-mix-β in the dihydroxylation step. Primary amide was prepared from via reaction of the acid chloride with ammonia in -dioxane. Dehydration of this amide with oxalyl chloride and catalytic DMF afforded nitrile . Oxadiazole was accessed by reaction of the acid chloride of with -hydroxyacetamidine, followed by dehydrative cyclization (). Attempted synthesis of the quaternary substituted analog via the synthetic route depicted in was not successful. The inability to cyclize the corresponding dihydroxypyrimidine intermediate to the fused bicyclic system necessitated development of an alternative route (). Synthesis of racemic diol proceeded in a straightforward manner from triflate . Reaction of the preformed sodium alkoxide of with 5-bromo-4,6-dichloropyrimidine regioselectively provided ether in 72% yield. Palladium-catalyzed intramolecular cyclization then afforded bicyclic . Displacement of the chloride with bis(-methoxybenzyl)amine, deprotection of the amine with trifluoroacetic acid and hydrolysis of the ester afforded in 10% overall yield from . Compound was determined to be a potent inhibitor of human DGAT-1 and to effectively suppress DGAT-1-mediated triglyceride synthesis in the HT-29 intestinal cells (). While comparable in activity to both and , is significantly more potent than the dihydro-analog . Since and are predicted to have very similar conformations, the ∼25-fold reduction in DGAT-1 inhibitory activity is likely driven by the amino functionality of . As predicted from the initial conformational analysis, -stereoisomer has DGAT-1 inhibitory activity comparable to . SAR studies on have shown that neutral, isosteric replacements of the carboxylic acid functionality can retain potent DGAT-1 inhibitory activity, suggesting they serve a hydrogen bond acceptor role in binding to the enzyme. However, incorporation of primary amide (), nitrile () or oxadiazole () functionalities in this series led to substantially reduced DGAT-1 inhibitory potencies relative to acid . This divergent SAR between the two series is likely the result of a subtle difference in trajectories of the phenylcyclohexyl sidechain relative to their respective bicyclic cores.