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Carboxylate Salt Bridge‐Mediated Enamine Catalysis: Expanded Michael Reaction Substrate Scope and Facile Access to Antidepressant ( R )‐Pristiq
Author(s) -
Nugent Thomas C.,
Hussein Hussein Ali El Damrany,
Ahmed Shahzad,
Najafian Foad Tehrani,
Hussain Ishtiaq,
Georgiev Tony,
Aljoumhawy Mahmoud Khalaf
Publication year - 2017
Publication title -
advanced synthesis and catalysis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.541
H-Index - 155
eISSN - 1615-4169
pISSN - 1615-4150
DOI - 10.1002/adsc.201700801
Subject(s) - electrophile , chemistry , enantioselective synthesis , michael reaction , enamine , carboxylate , nucleophile , maleimide , catalysis , organic chemistry , combinatorial chemistry
We report broad guidance on how to catalyze enantioselective aldehyde additions to nitroalkene or maleimide Michael electrophiles in the presence of unprotected acidic spectator groups, e.g., carboxylic acids, acetamides, phenols, catechols, and maleimide NH groups. Remarkably, these l ‐threonine and l ‐serine potassium salt‐catalyzed reactions proceed even when the nucleophilic and electrophilic Michael partners simultaneously contain acidic spectator groups. These findings begin to address the historical non‐compatibility of enantioselective catalytic reactions in the presence of acidic moieties and simultaneously encroach on the spectator group tolerances normally associated with cellular environments. A carboxylate salt bridge, from the catalyst enabled enamine to the Michael electrophile, is thought to facilitate the expanded Michael substrate profile. A practical outcome of these endeavours is a new synthetic route to ( R )‐Pristiq, (−)‐ O ‐desmethylvenlafaxine, an antidepressant, in the highest yield known to date because no protecting groups are required.