Unusual Diastereoselection in the Synthesis of Nine-Membered Ring Lactams and Conformation-Controlled Transannular Reactions to Generate Optically Active Indolizidinones

Sudau, Alexander; Nubbemeyer, U.

doi:10.1002/(sici)1521-3773(19980504)37:8<1140::aid-anie1140>3.0.co;2-w

Cited by 37 publications

(1 citation statement)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Annulated medium-sized heterocycles, typically 8–11-membered rings, could have importance in medicinal chemistry for a 2-fold reason: (i) They constitute core structures of natural and nature-inspired molecules and medicinal products (e.g., alkaloids, novel anticancer and antiparasitic drugs) and (ii) can serve as key intermediates in the synthesis of bioactive bridged azabicyclic systems through selective transformations (e.g., transannular ring-contraction, cycloaddition). , Albeit their biological potential, medium-sized heterocyclic rings, unlike the normal-sized (5–7-membered) ones and macrocycles (>12-membered), still remain largely unexploited in marketed drugs and in chemical libraries for drug discovery, due to the lack of general feasible synthetic methods. In addition to the search for novel CNS-targeted 7-membered azacyclic compounds, − the study of medium-sized azacyclic frameworks, particularly annulated 8–10-membered rings, have long engaged our research groups in developing new efficient synthetic routes to medium-sized azaheterocyclic derivatives investigated, in particular, for their suitability as hits/leads targeted at Alzheimer’s disease (AD).…”

Section: Introductionmentioning

confidence: 99%

Away from Flatness: Unprecedented Nitrogen-Bridged Cyclopenta[a]indene Derivatives as Novel Anti-Alzheimer Multitarget Agents

Титов

Kobzev

Catto

et al. 2021

ACS Chem. Neurosci.

View full text Add to dashboard Cite

Nature-inspired, bridged polycyclic molecules share low similarity with currently available drugs, containing preferentially planar and/or achiral moieties. This "Escape from Flatland" scenario, aimed at exploring pharmacological properties of atypical molecular scaffolds, finds interest in synthetic routes leading to tridimensional-shaped molecules. Herein we report on the synthesis of N-bridged cyclopenta[a]indene derivatives, achieved through microwave-assisted thermal rearrangement of allene 3benzazecines with high diastereoselectivity. The biological evaluation disclosed selective inhibition of human acetylcholinesterase or butyrylcholinesterase, depending on the substitution around the molecular core, which was rationalized by means of docking simulations. The most potent BChE inhibitor 31 was effective in neuroprotection from glutamatergic excitotoxicity and displayed low intrinsic cytotoxicity and good brain penetration. Overall, compound 31 and its close congeners 34 and 35 acted as multitarget agents addressing different biological events involved in neurodegeneration, particularly in the progression of Alzheimer's disease.

show abstract

Section: Introductionmentioning

confidence: 99%

Away from Flatness: Unprecedented Nitrogen-Bridged Cyclopenta[a]indene Derivatives as Novel Anti-Alzheimer Multitarget Agents

Титов

Kobzev

Catto

et al. 2021

ACS Chem. Neurosci.

View full text Add to dashboard Cite

show abstract

Reductive Aminations of Carbonyl Compounds with Borohydride and Borane Reducing Agents

2002

View full text Add to dashboard Cite

Reductive amination is an important tool for synthetic organic chemists in the construction of carbon‐nitrogen bonds. This reaction, also termed reductive alkylation, involves condensation of an aldehyde or ketone with an amine in the presence of a reducing agent. A wide variety of substrates can be used including aliphatic and aromatic aldehydes and ketones, and even benzophenones. A range of amines from ammonia to aromatic amines, including those with electron‐withdrawing substituents, can be employed. For particularly sluggish reactions, such as those involving weakly electrophilic carbonyl groups, poorly nucleophilic amines, or sterically congested reactive centers, additives such as molecular sieves or Lewis acids are often useful. This chapter focuses on those conditions in which the carbonyl component, amine, and reducing reagent react in the same vessel. This review is restricted to reductive aminations using borohydride and borane reducing agents. This chapter concentrates on reductive amination chemistry mediated by borohydride and other boron‐containing reducing agents from 1971, the year when sodium cyanoborohydride was introduced, through the middle of 1999. In addition to reductive aminations of aldehyde and ketone substrates, reactions of related structures including acetals, aminals, ketals, carboxylic acids, nitriles, and dicarbonyls that form a nitrogen‐containing ring are reviewed. Intramolecular processes in which the substrate contains both the carbonyl and amine moieties are described. The intramolecular variant is a useful method for preparing cyclic amines. All of the various boron‐containing hydride sources in reductive aminations, including labeled metal hydrides, are reviewed. Instances of reductive aminations that failed are described. Applications of this method to a solid support in parallel synthesis in combinatorial chemistry as well as reductive aminations that proceed in tandem with a second reaction such as reductive lactamizations are discussed.

show abstract

Planar Chirality − Synthesis and Transformations of 8- to 10-Membered Heterocycles Bearing (E)-Olefins

Nubbemeyer

2001

Eur. J. Org. Chem.

Self Cite

View full text Add to dashboard Cite

Medium‐sized heterocycles (8‐membered to 10‐membered) are prevalently found in organic chemistry as key intermediates in the synthesis of more complex structures or as core structures in natural products or pharmaceutically important compounds. At present, the production of such rings remains a challenge in organic synthesis. During the past decade, an increasing amount of interest has focused on the generation of cyclic lactones and peptides, as well as on hairpins and β‐turn mimics, and such medium‐sized rings were thought to represent suitable fragments. Furthermore, heterocyclic structures of this type are a characteristic of a range of complex natural products, and total synthesis of these is a broad field for organic chemists to test new strategies and to develop new methods. The aim of this review is to discus some modern strategies for synthesizing unsaturated 8‐ to 10‐membered heterocycles, with the scope restricted to the production of ring systems incorporating a N, O, and S function in combination with (E)‐olefins. The planar‐chiral properties thus induced have been exploited for further stereoselective and regioselective reactions. Although a number of conversions has described only the generation of simple structures without complicated stereogenic properties, most of them seem to offer undiscovered potential in terms of stereoselective syntheses. However, the emphasis of the methods is focused on stereoselective processes. The review is subdivided into two major chapters: ring‐closure and ring‐enlargement reactions, and additional information is given on cycloadditions and fragmentations.

show abstract

Unusual Diastereoselection in the Synthesis of Nine-Membered Ring Lactams and Conformation-Controlled Transannular Reactions to Generate Optically Active Indolizidinones

Cited by 37 publications

References 8 publications

Away from Flatness: Unprecedented Nitrogen-Bridged Cyclopenta[a]indene Derivatives as Novel Anti-Alzheimer Multitarget Agents

Away from Flatness: Unprecedented Nitrogen-Bridged Cyclopenta[a]indene Derivatives as Novel Anti-Alzheimer Multitarget Agents

Reductive Aminations of Carbonyl Compounds with Borohydride and Borane Reducing Agents

Planar Chirality − Synthesis and Transformations of 8- to 10-Membered Heterocycles Bearing (E)-Olefins

Contact Info

Product

Resources

About