Vinylogous aldol reaction of heterocyclic silyloxy dienes. Application in synthesis

A versatile, readily accessible triad of 2-enoxy silane synthons derived from furan, pyrrole, and thiophene is presented. These heterocycles, in reacting with carbonyl and carbonyl- related acceptors, act as vinylogous nucleophile modules, giving rise to diverse, functionality- rich, γ-substituted α,β-unsaturated carbonyl constructs. These, in turn, are invaluable platforms onto which further functional elements and chirality may be introduced. A couple of appealing applications—the variable construction of a repertoire of carbasugars and a library of annonaceous acetogenin segments—have been chosen to illustrate the viability of this vinylogous aldol approach

Exploring the boundaries of vinylogous Mukaiyama aldol processes: stereoselective access to polyunsaturated homoallylic alcohols

Catalytic enantioselective vinylogous aldol reactions using extended enolates are of prominent value in synthetic organic chemistry. Here, we report our advances in the development of enantioselective bis-vinylogous and hyper-vinylogous Mukaiyama aldol reactions between a series of polyenylsilyloxy furans or polyenylsilyoxy indoles and aromatic aldehydes, realized by use of the enabling catalyst combination of silicon tetrachloride and Denmark’s chiral bis-phosphoramide base (R,R)-I. Several crucial issues such as the remote site-, enantio- and geometrical selectivity of the reaction will be highlighted, ultimately focusing on one main question: how far can we push the limits of the vinylogous reactivity transmittal?</i

Unlocking Access to Enantiopure Fused Uracils by Chemodivergent [4+2] Cross‐Cycloadditions: DFT‐Supported Homo‐Synergistic Organocatalytic Approach

The discovery of chemical methods enabling the construction of carbocycle‐fused uracils which embody a three‐dimensional and functional‐group‐rich architecture is a useful tool in medicinal chemistry oriented synthesis. In this work, an unprecedented amine‐catalyzed [4+2] cross‐cycloaddition is documented; it involves remotely enolizable 6‐methyluracil‐5‐carbaldehydes and β‐aryl enals, and chemoselectively produces two novel bicyclic and tricyclic fused uracil chemotypes in good yields with a maximum level of enantiocontrol. In‐depth mechanistic investigations and control experiments support an intriguing homo‐synergistic organocatalytic approach, where the same amine organocatalyst concomitantly engages both aldehyde partners in a stepwise eliminative [4+2] cycloaddition, whose vinylogous iminium ion intermediate product may diverge—depending upon conditions—to either bicyclic targets by hydrolysis or tricyclic products by a second homo‐synergistic trienamine‐mediated stepwise [4+2] cycloaddition

Nintedanib-Containing Dual Conjugates Targeting αVβ6 Integrin and Tyrosine Kinase Receptors as Potential Antifibrotic Agents

αVβ6 Integrin plays a fundamental role in the activation of transforming growth factor-β (TGF-β), the major profibrotic mediator; for this reason, αVβ6 ligands have recently been forwarded to clinical phases for the therapy of fibrotic diseases. Herein, we report the synthesis and in vitro biological evaluation as antifibrotic agents of three new covalent conjugates, constituted by c(AmpLRGDL), an αVβ6 integrin-recognizing small cyclopeptide, and nintedanib, a tyrosine kinase inhibitor approved for idiopathic pulmonary fibrosis (IPF) treatment. One of these conjugates recapitulates optimal in vitro antifibrotic properties of the two active units. The integrin ligand portion within the conjugate plays a role in inhibiting profibrotic stimuli, potentiating the nintedanib effect and favoring the selective uptake of the conjugate in cells overexpressing αVβ6 integrin. These results may open a new perspective on the development of dual conjugates in the targeted therapy of IPF

The 1,4- and 1,6-Addition of Vinylogous Donor Systems in on-Water and Organocatalyzed Reactions

The vinylogy principle, which explains the transmission of the electronic effects through a conjugated system, has increasingly attracted the curiosity of organic chemists while challenging their abilities. The design of new synthetic methodologies based on the application of this principle experienced an exponential growth in the past few years, especially when this topic was connected to other emerging fields such as eco-friendly synthetic methods or enantioselective catalysis. In this brief contribution we will present how the vinylogy principle was applied to on-water vinylogous Michael additions of pyrrole-based dienolates to diazadiene acceptors and to organocatalyzed 1,6-addition of vinylogous lactones to 2,4-dienals