title: A facile synthesis of 5,5-dideutero-4-dimethyl(phenyl)silyl-6-undecyl-tetrahydropyran-2-one as a deuterium labeled synthon for (-)-tetrahydrolipstatin and (+)-δ-hexadecanolide.
abstract: Deuterium-labeled biologically active compounds are gaining importance because they can be utilized as tracers or surrogate compounds to understand the mechanism of action, absorption, distribution, metabolism, and excretion. Deuterated drug molecules (heavy drugs) become novel as well as popular because of better stability and bioavailability compared with their hydrogen analogs. Labeling of organic molecules with deuterium at specific positions is thus gaining popularity. In this work, we have exploited a highly regioselective and enantioselective direct Michael addition of methyl-d3 alkyl ketones to dimethyl(phenyl)silylmethylene malonate that was catalyzed by (S)-N-(2-pyrrolidinylmethyl)pyrrolidine/trifluoroacetic acid/ D2 O combination with high yield and isotopic purity. The 5,5-dideutero-4-dimethyl(phenyl)silyl-6-undecyl-tetrahydropyran-2-one was obtained from the adduct of methyl-d3 undecanyl ketone and dimethyl(phenyl)silylmethylene malonate by a silicon controlled diastereoselective ketone reduction, lactonization, and deethoxycarbonylation. The dideuterated silylated tetrahydropyran-2-one is the precursor for geminal (2) H2 -labeled (+)-4-hydroxy-6-undecyl-tetrahydropyran-2-one, an advanced intermediate for gem-dideutero (-)-tetrahydrolipstatin and (+)-δ-hexadecanolide syntheses.
authors.affiliation: Bio-Organic Division, Bhabha Atomic Research Centre, Trombay, Mumbai, 400085, India.
authors.forename: Sandip J
authors.initials: SJ
authors.lastname: Wagh
authors.forename: Raghunath
authors.initials: R
authors.lastname: Chowdhury
authors.forename: Sulekha
authors.initials: S
authors.lastname: Mukhopadhyay
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Ghosh
mesh_terms: D003903:Deuterium / Q000737:chemistry*; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry; D017646:Organosilicon Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D000077403:Orlistat; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D007783:Lactones; D018942:Macrolides; D017646:Organosilicon Compounds; D019275:Radiopharmaceuticals; C571589:hexadecanolide; D000077403:Orlistat; D003903:Deuterium
keywords: 4,4-dideuterated 3-silyl-5-keto ester; 5,5-dideutero-4-dimethyl(phenyl)silyl-6-undecyl-tetrahydropyran-2-one; Michael addition; deuterium labeling; methyl-d3 alkyl ketones, dimethyl(phenyl)silylmethylene malonate; organocatalysis