Beyond Chemoselectivity: Catalytic Site‐Selective Aldolization of Diketones and Exploitation for Enantioselective Alzheimer's Drug Candidate Synthesis. Issue 40 (22nd August 2016)

• Record Type: Journal Article
• Authors: Nugent, Thomas C.; Najafian, Foad Tehrani; Hussein, Hussein Ali El Damrany; Hussain, Ishtiaq
• Is Part Of: Chemistry. Volume 22:Issue 40(2016)
• Page Start: 14342
• Page End: 14348
• Publication Date: 2016-08-22
• Subjects: Alzheimer's disease -- diketones -- enamines -- enantioselective aldol -- gamma-secretase modulator -- organocatalysis -- site selectivity; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201602900
• Languages: English
• ISSNs: 0947-6539

Abstract

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. Abstract : Let your enamines play : Ketone site selectivity for cyclohexanone‐based diketones has been firmly established and permits a high yielding synthesis of a γ‐secretase modulator (GSM). The achievements embody a forward‐looking theme within chemistry; reduced dependence on protection/deprotection protocols for increased step efficiency in biomolecule synthesis.