Abstract
An isothiourea-catalysed enantioselective synthesis of novel tetrahydroindolizine derivatives is reported through a one-pot tandem sequential process. The application of 2-(pyrrol-1-yl)acetic acid in combination with either a trifluoromethyl enone or an α-keto-β,γ-unsaturated ester in an enantioselective Michael addition–lactonisation process, followed by in situ ring-opening and cyclisation, led to a range of 24 tetrahydroindolizine derivatives containing three stereocentres in up to >95 : 5 dr and >99 : 1 er.
Highlights
Pyrrole derivatives are found as a common structural motif within many natural products that can display a wide range of biological activities.[1]
A number of catalytic enantioselective methods for synthesising tetrahydroindolizine derivatives have been developed,[3] with the majority of enantioselective syntheses focusing on applications towards rhazinilam.2b,3a,b,h,i Catalytic enantioselective methodologies that provide access to polyfunctionalised tetrahydroindolizine architectures from simple starting materials are much less developed, but have the potential to allow greater exploration of 3D chemical space around the tetrahydroindolizine core.[4]
C(1)-Ammonium enolates can be generated in situ from a range of carboxylic acid derivatives and have been most widely applied in formal cycloaddition processes, in which an aldol or Michael addition is followed by a lactonisation or lactamisation event.5a,b Within this eld, C(1)-isothiouronium enolates, generated from Lewis basic isothiourea catalysts,[6] have been shown to be effective for Michael addition–lactonisation/lactamisation processes (Scheme 1a).[7,8]
Summary
Pyrrole derivatives are found as a common structural motif within many natural products that can display a wide range of biological activities.[1]. A wide variety of Michael acceptors have been applied,[7] a limitation for intermolecular processes is the common requirement for the isothiouronium enolate precursor to be an acetic acid derivative bearing an a-aryl or a-alkenyl substituent. To address this limitation we recently reported the use of 2(pyrrol-1-yl)acetic acid 1 in an isothiourea-catalysed Michael addition–lactonisation process using trichloromethyl enones 2 (Scheme 1b).[9] The dihydropyranone products were unstable, ring-opening using an alcohol or amine allowed. We describe the use of tri uoromethyl enones and a-keto-b,gunsaturated esters in this process, leading to a range of tetrahydroindolizine derivatives in up to >95 : 5 dr and >99 : 1 er (Scheme 1c)
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