title: Beyond Chemoselectivity: Catalytic Site-Selective Aldolization of Diketones and Exploitation for Enantioselective Alzheimer's Drug Candidate Synthesis.
abstract: Site selectivity, differentiating instances of the same functional group type on one substrate, represents a forward-looking theme within chemistry: reduced dependence on protection/deprotection protocols for increased overall yield and step-efficiency. Despite these potential benefits and the expanded tactical advantages afforded to synthetic design, site selectivity remains elusive and especially so for ketone-based substrates. Herein, site-selective intermolecular mono-aldolization has been demonstrated for an array of prochiral 4-keto-substituted cyclohexanones with concomitant regio-, diastereo-, and enantiocontrol. Importantly, the aldol products allow rapid access to molecularly complex ketolactones or keto-1,3-diols, respectively containing three and four stereogenic centers. The reaction conditions are of immediate practical value and general enough to be applicable to other reaction types. These findings are applied in the first enantioselective, formal, synthesis of a leading Alzheimer's research drug, a γ-secretase modulator (GSM), in the highest known yield.
authors.affiliation: Department of Life Sciences and Chemistry, Jacobs University Bremen, Campus Ring 1, 28759, Bremen, Germany. t.nugent@jacobs-university.de.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Nugent
authors.affiliation: Department of Life Sciences and Chemistry, Jacobs University Bremen, Campus Ring 1, 28759, Bremen, Germany.
authors.forename: Foad Tehrani
authors.initials: FT
authors.lastname: Najafian
authors.affiliation: Department of Life Sciences and Chemistry, Jacobs University Bremen, Campus Ring 1, 28759, Bremen, Germany.
authors.forename: Hussein Ali El Damrany
authors.initials: HA
authors.lastname: Hussein
authors.affiliation: Department of Life Sciences and Chemistry, Jacobs University Bremen, Campus Ring 1, 28759, Bremen, Germany.
authors.forename: Ishtiaq
authors.initials: I
authors.lastname: Hussain
mesh_terms: D000447:Aldehydes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D060326:Chemistry Techniques, Synthetic / Q000379:methods; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D000447:Aldehydes; D007659:Ketones; D010880:Piperidines; C032727:piperidine; C116609:3-hydroxybutanal; D053829:Amyloid Precursor Protein Secretases
keywords: Alzheimer's disease; diketones; enamines; enantioselective aldol; gamma-secretase modulator; organocatalysis; site selectivity