One-Pot Access to Functionalised Malamides via Organocatalytic Enantioselective Formation of Spirocyclic
Alastair J Nimmo1, Kevin Kasten1, George White1
1EaStCHEM, School of Chemistry, University of St Andrews, St Andrews, Fife KY16 9ST, UK.
Abstract:
Malamides (diamide derivatives of malic acid) are prevalent in nature and of significant biological interest, yet only limited synthetic methods to access functionalised enantiopure derivatives have been established to date. Herein, an effective synthetic method to generate this molecular class is developed through in situ formation of spirocyclic β-lactone-oxindoles (employing a known enantioselective isothiourea-catalysed formal [2+2] cycloaddition of C(1)-ammonium enolates and isatin derivatives) followed by a subsequent dual ring-opening protocol (of the β-lactone and oxindole) with amine nucleophiles. The application of this protocol is demonstrated across twelve examples to give densely functionalised malamide derivatives with high enantio- and diastereo-selectivity (up to >95:5 dr and >99:1 er).
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