Stereoselective, Multicomponent Approach to Quaternary Substituted Hydroindole Scaffolds

Abstract

The Amaryllidaceae alkaloids have been a target of synthesis for decades due to their complex architectures and biological activity. A central feature of these natural product cores is a quaternary substituted hydroindole heterocycle. Building off the foundation of our previous multicomponent approach to highly functionalized pyrrolidinones, herein we report a highly convergent, diastereoselective, multicomponent approach to access the hydroindole cores present within crinine, haemanthamine, pretazettine, and various other bioactive alkaloids. These scaffolds are additionally useful as building blocks for druglike molecules and natural product like library generation.

Regioselective α-addition of vinylogous α-ketoester enolate in organocatalytic asymmetric Michael reactions: enantioselective synthesis of Rauhut–Currier type products

“…It was reported that vinylogous α-keto esters could exist as stable dienol forms, depending on the properties of substituents on the terminal double bond. 17 Thus, it persuaded us to prepare two types of vinylogous α-ketoesters to investigate their reactivities ( Scheme 2 , compounds 1 and 1′, eqn (1).…”

The Chemical Synthesis of the Crinine and Haemanthamine Alkaloids: Biologically Active and Enantiomerically-Related Systems that Serve as Vehicles for Showcasing New Methodologies for Molecular Assembly

“…More recently, however, the crinines have become vehicles for showcasing the value of new methodologies. Precisely how this topic might evolve over the next few decades is difficult to predict and may well be influenced by the identification, if any, of crinines with real clinical value [ 104 ]. Given the capacity of crinines to serve as precursors to other ring systems, including those associated with various natural products [ 6 , 7 , 105 , 106 , 107 , 108 ], new uses of the title compounds are likely to emerge and provide yet further impetus for establishing distinctive routes to them.…”

Leveraging Marine Natural Products as a Platform to Tackle Bacterial Resistance and Persistence

“…During our efforts to develop a method to access 4-oxazolidinones bearing a benzylidene motif (e.g., 62 ), we encountered conditions that provided predominantly 2,3-pyrrolidinedione heterocycles (e.g., 63 ) in modest yields (Figure A). We subsequently optimized the preparation of these heterocycles via a three-component reaction under extremely mild and scalable conditions to yield a variety of monocyclic and bicyclic heterocycles (Figure B). − This multicomponent reaction (MCR) is extremely functional-group-tolerant and has been successfully conducted on a 10 g scale, followed by subsequent conversion to a number of value-added products such as β-lactams and β-amino acids. Furthermore, this MCR has also provided direct access to natural-product-like cores such as bicyclic γ-lactams as well as an efficient route to quaternary substituted hydroindole scaffolds present within crinane alkaloids and enabled the total synthesis of the marine natural product phenopyrrozin and analogues. − As part of these efforts, we also evaluated the antimicrobial activities of the 2,3-pyrrolidinedione heterocycles and were pleased to find that a number of them had modest activity against a panel of Gram-positive bacteria (Figure C) .…”

“…We subsequently optimized the preparation of these heterocycles via a three-component reaction under extremely mild and scalable conditions to yield a variety of monocyclic and bicyclic heterocycles (Figure B). − This multicomponent reaction (MCR) is extremely functional-group-tolerant and has been successfully conducted on a 10 g scale, followed by subsequent conversion to a number of value-added products such as β-lactams and β-amino acids. Furthermore, this MCR has also provided direct access to natural-product-like cores such as bicyclic γ-lactams as well as an efficient route to quaternary substituted hydroindole scaffolds present within crinane alkaloids and enabled the total synthesis of the marine natural product phenopyrrozin and analogues. − As part of these efforts, we also evaluated the antimicrobial activities of the 2,3-pyrrolidinedione heterocycles and were pleased to find that a number of them had modest activity against a panel of Gram-positive bacteria (Figure C) . We are currently expanding the SAR of this class and further evaluating the properties of these molecules, but these results highlight the new chemistry that can emerge from ongoing natural product synthesis projects and the unexpected biology that can subsequently result.…”