Two-directional synthesis and biological evaluation of alkaloid 5-epi-cis-275B′

Procopiou, George; Aggarwal, Pooja; Newton, Annabella F.; Richards, David P.; Mellor, Ian R.; Harbottle, Gareth W.; Stockman, Robert A.

doi:10.1039/c4cc07287a

Cited by 6 publications

(3 citation statements)

References 33 publications

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“…Based on the above findings (Scheme ), a dynamic mechanism is proposed for the bridge‐forming process, whereby aza‐Michael addition occurs prior to reduction (Scheme ) , . Initial condensation of aldehyde 7 and the amine (RNH 2 ) would give imine (3‐ exo )‐ 10 , which could undergo reversible epimerization to diastereomer (3‐ endo )‐ 10 under the acidic conditions.…”

Section: Resultsmentioning

confidence: 99%

Nitrogen‐Bridged, Natural Product Like Octahydrobenzofurans and Octahydroindoles: Scope and Mechanism of Bridge‐Forming Reductive Amination via Caged Heteroadamantanes

Wales

Adcock²,

Lewis

et al. 2018

Eur J Org Chem

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The biological significance of sp3‐rich synthetic scaffolds with natural product like features yet distinct global frameworks is being increasingly recognized in medicinal chemistry and biochemistry. Taking inspiration from the vast array of bioactive, bridged alkaloids, we report the synthesis of unique, densely functionalized 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 epimerization, enabling intramolecular aza‐Michael 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.

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Section: Resultsmentioning

confidence: 99%

Nitrogen‐Bridged, Natural Product Like Octahydrobenzofurans and Octahydroindoles: Scope and Mechanism of Bridge‐Forming Reductive Amination via Caged Heteroadamantanes

Wales

Adcock²,

Lewis

et al. 2018

Eur J Org Chem

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show abstract

“…Two-directional strategies have found several applications in the generation of complex molecules [133][134][135] and as a versatile synthetic strategy in total synthesis of natural products. [136][137][138][139] This was recognized by O'Connell et al who applied a two-directional strategy in their effort to synthesize macrocycles, see Figure 33.…”

Section: Two-directional Synthesismentioning

confidence: 99%

“…Two-directional strategies have found several applications in the generation of complex molecules − and as a versatile synthetic strategy in total synthesis of natural products. − This was recognized by O’Connell et al, who applied a two-directional strategy in their effort to synthesize macrocycles, see Figure . Bis-enyne amides ( 33 - 1 ) generated in the “build” and “couple” phases were paired with bis-azides ( 33 - 3 ) using CuAAC conditions to afford the corresponding bis-triazole compounds (example 33 - 5 ).…”

Section: Algorithmic Strategiesmentioning

confidence: 99%

Strategies for the Diversity-Oriented Synthesis of Macrocycles

et al. 2019

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Macrocycles have long been recognized as useful chemical entities for medicine, with naturally occurring and synthetic macrocycles clinically approved for use as prescription drugs. Despite this promise, the synthesis of collections of macrocycles has been historically challenging due to difficulties in the formation of large rings. Diversity-Oriented Synthesis (DOS) emerged in the early 2000s as a powerful strategic solution to the construction of diverse molecular libraries. This review details the various strategies developed within the field of DOS for the synthesis of macrocycle libraries, utilizing modern synthetic methodology to deliver structurally diverse collections of macrocyclic molecules, and the exploration of their therapeutic potential.

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Synthesis and Ring‐Closing Reactions of Aminocyclohexane Derivatives Bearing Unsaturated Side Chains at C2: Stereocontrolled Approaches to cis‐ and trans‐Fused Perhydro‐indoles and ‐quinolines

Xing,

He,

Song

et al. 2024

Eur J Org Chem

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Two epimeric pairs of N‐Ts‐protected cyclohexylamines that incorporate an unsaturated side‐chain at the C2 position have been prepared. Contrary to expectations, none of these underwent clean, photochemically‐induced intramolecular hydroamination reactions to give the corresponding perhydro‐indole or ‐quinolines. However, they did participate in efficient olefin cross metathesis (OCM) reactions with methyl crotonate. Three of the four acrylates so‐formed engaged in base‐promoted and completely diastereoselective, intramolecular aza‐Michael addition (cyclisation) reactions to give the isomeric and C2‐substituted perhydro‐indoles or ‐quinolines with the structures of these being confirmed by single‐crystal X‐ray analyses. DFT calculations generated results consistent with the observed diastereoselectivities and the proposed transition states. Manipulation of the ester groups associated with the cyclization products allowed for their conversion, inter alia, into the corresponding n‐propyl residues and thus providing novel analogues of neurotoxic alkaloids such as pumiliotoxin C.

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Two-directional synthesis and biological evaluation of alkaloid 5-epi-cis-275B′

Cited by 6 publications

References 33 publications

Nitrogen‐Bridged, Natural Product Like Octahydrobenzofurans and Octahydroindoles: Scope and Mechanism of Bridge‐Forming Reductive Amination via Caged Heteroadamantanes

Nitrogen‐Bridged, Natural Product Like Octahydrobenzofurans and Octahydroindoles: Scope and Mechanism of Bridge‐Forming Reductive Amination via Caged Heteroadamantanes

Strategies for the Diversity-Oriented Synthesis of Macrocycles

Synthesis and Ring‐Closing Reactions of Aminocyclohexane Derivatives Bearing Unsaturated Side Chains at C2: Stereocontrolled Approaches to cis‐ and trans‐Fused Perhydro‐indoles and ‐quinolines

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