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Beyond Chemoselectivity: Catalytic Site‐Selective Aldolization of Diketones and Exploitation for Enantioselective Alzheimer's Drug Candidate Synthesis
Author(s) -
Nugent Thomas C.,
Najafian Foad Tehrani,
Hussein Hussein Ali El Damrany,
Hussain Ishtiaq
Publication year - 2016
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201602900
Subject(s) - enantioselective synthesis , stereocenter , ketone , aldol reaction , selectivity , chemoselectivity , chemistry , combinatorial chemistry , yield (engineering) , stereochemistry , catalysis , organic chemistry , materials science , metallurgy
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.