Rapid and efficient entry to substituted 2-succinimidobenzoate-3-azabicyclo[3.3.1]nonanes: AE-bicyclic analogues of methyllycaconitine

Coates, Peter A; Blagbrough, Ian S.; Rowan, Michael G.; Potter, Barry V. L.; Pearson, D.; Lewis, Terence

doi:10.1016/s0040-4039(00)78478-4

Cited by 32 publications

(34 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This method proved more efficient than earlier methods developed by Kraus and Dneprovskaia [13] and by Bergmeier and co-workers, [8,9] which involved direct esterification using 2-(3-methyl-2,5-dioxopyrrolidin-1-yl)benzoic acid (27). The use of isatoic anhydride also developed by Blagbrough [20] has been adopted by others to append the anthranilate ester group to MLA analogues; [12,13] however, in general low yields (typically 40-65 %) of the desired anthranilate esters are obtained, which is attributed to the hindered neopentyl environment of the hydroxy group present in 2 and many of the simpler analogues.…”

Section: Resultsmentioning

confidence: 99%

“…The title compound was prepared from the β-keto ester 6 [20] (650 mg, 3.09 mmol), N,N-bis(ethoxymethyl)-3-phenylpropylamine 7 [19] (1.55 g, 6.18 mmol) and methyltrichlorosilane (726 µL, 6.18 mmol) in acetonitrile (15 mL) following the reported procedure. [19] Yield 882 mg (2.39 mmol, 77 %) of a clear oil.…”

Section: Ethyl 9-oxo-3-(3-phenylpropyl)-5-(2-propenyl)-3-azabicyclo[3mentioning

confidence: 99%

“…We have also recently reported that bis-aminoalkylation of cyclic β-keto esters using bis(aminol) ethers provides an efficient entry to azabicyclo[3.3.1]nonanes. [19] Previous use of a classical double Mannich reaction to construct the azabicyclo[3.3.1]-nonane AE ring system [14,15,20] only proceeded in low yield, and could not be readily extended to the use of alternative primary amines thus limiting our analogue development programme. We therefore herein report the synthesis of several rigid tricyclic analogues of MLA combining the use of our ring-closing metathesis strategy with our bis-aminoalkylation strategy to introduce the desired N-(3-phenylpropyl) substituent into the E ring.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Synthesis of N‐(3‐Phenylpropyl)‐Substituted Tricyclic ABE Ring Analogues of the Alkaloid Methyllycaconitine

et al. 2006

View full text Add to dashboard Cite

The synthesis of several ABE tricyclic analogues 5, 31 and 32 of the alkaloid methyllycaconitine (1) is reported. The analogues contain two key pharmacophores: a tertiary N-(3-phenylpropyl) substituent attached to a 3-azabicyclo-[3.3.1]nonane ring system and a 2-(3-methyl-2,5-dioxopyrrolidin-1-yl)benzoate ester. Double Mannich reaction of the cyclic β-keto esters 6 and 17 with the bis(aminol) ether 7 using methyltrichlorosilane as an activating agent provided an efficient method for the construction of the 3-azabicyclo[3.3.1]nonanes 8 and 18. Ring-closing metathesis of the derived dienes 11, 19, and 20 afforded the tricyclic ethers 12, 21, and 22, respectively, the C-8 ester of which was reduced

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Ethyl 9-oxo-3-(3-phenylpropyl)-5-(2-propenyl)-3-azabicyclo[3mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Synthesis of N‐(3‐Phenylpropyl)‐Substituted Tricyclic ABE Ring Analogues of the Alkaloid Methyllycaconitine

et al. 2006

View full text Add to dashboard Cite

show abstract

“…Finally, applications of this sequence to cyclic substrates such as 1,3,5‐tricarbonyl142−144 derivatives, β‐keto esters145 or β‐keto amides146 allowed access to azabicyclo[3.2.1]octanones or azabicyclo[3.3.1]nonanones (Figure 2). 147…”

Section: Mcrs Based On the Mannich Reactionmentioning

confidence: 99%

Utilisation of 1,3‐Dicarbonyl Derivatives in Multicomponent Reactions

2004

View full text Add to dashboard Cite

Although isocyanide‐based multicomponent reactions (MCRs), introduced in 1921 by Passerini, largely predominate nowadays in the construction of widely diverse heterocycles, one of the first substrate classes involved in a MCR was that of 1,3‐dicarbonyl derivatives, with Hantzsch’s dihydropyridine synthesis appearing as early as 1882. The aim of this microreview is to present an overview of the great synthetic potential of MCRs involving the specific reactivity of easily accessible 1,3‐dicarbonyl derivatives and to stress their more recent utilisation for the development of new and useful methodologies valuable for the selective construction of highly functionalised small organic molecules of high synthetic and biological value. After a short general introduction, we present chronologically the different methodologies developed on the bases of the reactivity of 1,3‐dicarbonyl systems towards many other substrates involved in a variety of synthetic pathways, including Knoevenagel condensations, Michael and Mannich reactions, cyclodehydrations, electrocyclisations, cycloadditions and metal‐promoted transformations. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

show abstract

“…The primary finding in comparing Delphinium alkaloids is the difference in activity between those with the C-18 ester functionality and those without. The LD 50 of MLA (4) in mice has been found to be 4.8 mg/kg while the LD 50 of lycoctonine (5) was found to be 449 mg/ kg, 26 a decrease of nearly two orders of magnitude. Other compounds containing the C-18 ester show similar increased potency over their de-esterified counterparts.…”

Section: Structure-activity Relationships Of Delphinium Alkaloidsmentioning

confidence: 95%

A Review of Advances in the Synthesis of Analogues of the Delphinium Alkaloid Methyllycaconitine

Goodall¹,

Barker²,

Brimble³

2005

Synlett

View full text Add to dashboard Cite

Neuronal nicotinic acetylcholine receptors of the a7 subtype are potential targets for drug development in the treatment of Alzheimer's disease. The Delphinium alkaloid methyllycaconitine is a potent and selective a7 sub-type selective nicotinic acetylcholine receptor antagonist. The total synthesis of this pharmacologically active alkaloid has not yet been achieved. A summary of semisynthetic methods to prepare methyllycaconitine is presented. Existing synthetic strategies used to prepare E, AE, AEF, ABE, ABDE, ABEF ring analogues of methyllycaconitine are reviewed for the first time.

show abstract

Rapid and efficient entry to substituted 2-succinimidobenzoate-3-azabicyclo[3.3.1]nonanes: AE-bicyclic analogues of methyllycaconitine

Cited by 32 publications

References 14 publications

Synthesis of N‐(3‐Phenylpropyl)‐Substituted Tricyclic ABE Ring Analogues of the Alkaloid Methyllycaconitine

Synthesis of N‐(3‐Phenylpropyl)‐Substituted Tricyclic ABE Ring Analogues of the Alkaloid Methyllycaconitine

Utilisation of 1,3‐Dicarbonyl Derivatives in Multicomponent Reactions

A Review of Advances in the Synthesis of Analogues of the Delphinium Alkaloid Methyllycaconitine

Contact Info

Product

Resources

About

Rapid and efficient entry to substituted 2-succinimidobenzoate-3-azabicyclo[3.3.1]nonanes: AE-bicyclic analogues of methyllycaconitine

Cited by 32 publications

References 14 publications

Synthesis of N‐(3‐Phenylpropyl)‐Substituted Tricyclic ABE Ring Analogues of the Alkaloid Methyllycaconitine

Synthesis of N‐(3‐Phenylpropyl)‐Substituted Tricyclic ABE Ring Analogues of the Alkaloid Methyllycaconitine

Utilisation of 1,3‐Dicarbonyl Derivatives in Multicomponent Reactions

A Review of Advances in the Synthesis of Analogues of the Delphinium ­Alkaloid Methyllycaconitine

Contact Info

Product

Resources

About

A Review of Advances in the Synthesis of Analogues of the Delphinium Alkaloid Methyllycaconitine