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Your search keyword '"Adcock, Holly V."' showing total 3 results
Start Over Author "Adcock, Holly V." Topic heterocycles
3 results on '"Adcock, Holly V."'

1. Nitrogen-bridged, natural product-like octahydrobenzofurans and octahydroindoles: scope and mechanism of bridge-forming reductive amination via caged heteroadamantanes

Author

Wales, Steven M., Adcock, Holly V., Lewis, William, Hamza, Daniel, and Moody, Christopher J.

Subjects
heterocycles, aza-Michael addition, bridged compounds, reductive amination, drug discovery
Abstract

The biological significance of sp3-rich synthetic scaffolds with natural product-like features yet distinct global frameworks is being increasingly recognised in medicinal chemistry and biochemistry. Taking inspiration from the vast array of bioactive, bridged alkaloids, we report the synthesis of unique, densely functionalised tricyclic scaffolds based on nitrogen-bridged, octahydrobenzofurans and octahydroindoles. These heterocycle-rich frameworks were assembled by a one-pot, two-step bridge-forming reductive amination process, which was shown to proceed via caged, heteroadamantane intermediates that thermodynamically drive an exo–endo epimerisation, enabling intramolecular azaMichael addition over the concave face of the fused bicyclic precursors. In addition to evaluating the scope of this aza bridge-forming reaction, further stereochemical complexity was introduced by subsequent diastereoselective ketone reductions and other manipulations. Finally, strategic diversity points (amino, carboxy) were decorated with common medicinal chemistry fragments, providing a set of exemplar derivatives with Lipinski compliant physicochemical properties.

Published
2018

2. Diastereoselective Synthesis of Highly Substituted, Amino‐ and Pyrrolidino‐Tetrahydrofurans as Lead‐Like Molecular Scaffolds.

Author

Wales, Steven M., Merisor, Elena G., Adcock, Holly V., Pearce, Christopher A., Strutt, Ian R., Lewis, William, Hamza, Daniel, and Moody, Christopher J.

Subjects
STEREOSELECTIVE reactions, TETRAHYDROFURAN synthesis, TETRAHYDROFURAN derivatives, LEAD analysis, DRUG development, AMINATION
Abstract

Abstract: A series of highly substituted tetrahydrofurans (THFs), decorated with modifiable 2‐aryl, 3‐carboxy and 4‐amino substituents, has been prepared for biological evaluation within the European Lead Factory. Diastereoselective reductive amination of pre‐functionalised 4‐oxofurans, readily prepared from cinnamate esters via oxa‐Michael/Dieckmann annulation, provided the requisite THF cores on gram scale with three contiguous stereocentres, including full substitution at C‐3. In a second series, a pyrrolidine ring was fused to the same oxofuran scaffold via an intramolecular reductive amination, inverting the configuration at C‐4 relative to the other ring substituents. The resulting compounds, which displayed desirable physical properties as lead‐like scaffolds, were derivatised into a small library of 24 compounds, demonstrating their ability to serve as starting points for drug discovery. Ultimately, this chemistry enabled the preparation of 1948 THF‐containing compounds for inclusion in the Joint European Compound Library. [ABSTRACT FROM AUTHOR]

Published
2018
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3. π-iAewcid Mediated Insertion of Alkynes into Carbon-Heteroatom σ-Bonds.

Author

Adcock, Holly V. and Davies, Paul W.

Subjects
*ALKYNES, *CARBON, *HETEROCHAIN polymers, *CHEMICAL bonds, *PLATINUM catalysts, *GOLD catalysts, *METAL activation, *NUCLEOPHILIC addition (Chemistry)
Abstract

The rapidly expanding field of gold and platinum π-acid catalysis has led to the discovery of diverse transformations that are initiated with nucleophilic attack onto a metal-activated alkyne. This review brings together those reactions which employ a heteroatom nucleophile bearing a functional group that can subsequently migrate to effect a formal insertion of the alkyne into a carbon- heteroatom σ-bond. This reactivity profile is encountered in a range of efficient and powerful cycloisomerisations for the preparation of carbo- and heterocycles. 1 Introduction 2 1,2-Addition of Carbon-Heteroatom Bonds across Alkynes 2.1 Heteroatom-to-Carbon Allyl Migrations 2.2 Accessing Sigmatropic Rearrangements 2.3 Related Palladium-Catalysed 1,2-Carboalkoxylations and Carboaminations 2.4 Beyond Allyl Migration in the 1,2-Carbofunctionalisation of Alkynes 2.5 Oxonium Ion Migration 2.6 Migrating Centres at Higher Oxidation Levels 2.7 Migration of Heteroatoms 3 1,5 Heteroatom-to-Carbon Migrations 3.1 Alkynyl Benzoates as Alkylating Agents 4 Internal versus External Migrations 4.1 Internal Migrations of Oxonium Species 5 1,1-Carbofunctionalisations 6 Application in Natural Products 7 Summary and Conclusions [ABSTRACT FROM AUTHOR]

Published
2012
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