Synthesis Pathways to Erythrina Alkaloids and Erythrina Type Compounds

Reimann, Eberhard

doi:10.1007/978-3-211-49389-2_1

Cited by 35 publications

(21 citation statements)

References 97 publications

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“…[10][11][12][13][14][15][16][17][18][19][20] Most of the available nAChR antagonists are natural products such as methyllycaconitine (MLA), αbungarotoxin, ibogaine, d-tubocurarine, α-conotoxins and dihydro-β-erythroidine (DHβE), the latter being a widely used selective antagonist of β2-containing heteromeric nAChRs and a semisynthetic member of the Erythrina alkaloid family. 21,22 We recently reported the design, synthesis and pharmacological evaluation of 21 analogs of aromatic Erythrina alkaloids as nAChR antagonists and found that the structurally simple tetrahydroisoquinoline 1 (also known as O-methylcorypalline) 23,24 displayed submicromolar binding affinity at the α4β2 nAChR and more than 300-fold binding selectivity over the α4β4, α3β4 and α7 subtypes (see Figure 1A). 25 Ligands containing quaternary nitrogens have previously been shown to possess high activity at the nAChR.…”

Section: Introductionmentioning

confidence: 99%

Dual Nicotinic Acetylcholine Receptor α4β2 Antagonists/α7 Agonists: Synthesis, Docking Studies, and Pharmacological Evaluation of Tetrahydroisoquinolines and Tetrahydroisoquinolinium Salts

et al. 2018

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We describe the synthesis of tetrahydroisoquinolines and tetrahydroisoquinolinium salts together with their pharmacological properties at various nicotinic acetylcholine receptors. In general, the compounds were α4β2 nAChR antagonists, with the tetrahydroisoquinolinium salts being more potent than the parent tetrahydroisoquinoline derivatives. The most potent α4β2 antagonist, 6c, exhibited submicromolar binding K and functional IC values and high selectivity for this receptor over the α4β4 and α3β4 nAChRs. Whereas the (S)-6c enantiomer was essentially inactive at α4β2, (R)-6c was a slightly more potent α4β2 antagonist than the reference β2-nAChR antagonist DHβΕ. The observation that the α4β2 activity resided exclusively in the (R)-enantiomer was in full agreement with docking studies. Several of tetrahydroisoquinolinium salts also displayed agonist activity at the α7 nAChR. Preliminary in vivo evaluation revealed antidepressant-like effects of both (R)-5c and (R)-6c in the mouse forced swim test, supporting the therapeutic potential of α4β2 nAChR antagonists for this indication.

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Section: Introductionmentioning

confidence: 99%

Dual Nicotinic Acetylcholine Receptor α4β2 Antagonists/α7 Agonists: Synthesis, Docking Studies, and Pharmacological Evaluation of Tetrahydroisoquinolines and Tetrahydroisoquinolinium Salts

et al. 2018

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“…Selected erythrina alkaloids (with an aromatic D ring) of the C5-C13 bond (completing the C-ring, Figure 1) by means of a Pictet-Spengler-type cyclization (in which an N-acyliminium ion 6 acts as the electrophile in a substitution reaction with the aromatic moiety) has emerged as a particularly versatile approach. 2,3,5 It should be noted that the aromatic erythrina alkaloids can be subdivided into two categories the dienoid type (1 and 2, Figure 1) which have a diene unit spanning the A and B rings and the alkenoid type (3 and 4, Figure 1) which have a single isolated double bond in the A ring. Despite the existence of a large body of synthetic work targeting both the dienoid and alkenoid erythrina alkaloids, only very rarely have researchers successfully constructed all the requisite non-aromatic rings (A, B and C) in the same reaction sequence.…”

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confidence: 99%

One-pot Synthesis of the Tetracyclic Framework of the Aromatic Erythrina Alkaloids from Simple Furans

et al. 2013

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Conversion of a simple furan into the intact erythrinane skeleton in one synthetic operation has been accomplished. The one-pot reaction sequence begins with singlet oxygen photooxygenation of the furan and proceeds via a 2pyrrolidinone formation, cyclization of the pendant aldehyde moiety and an N-acyliminium ion formation and terminates with a Pictet-Spengler-type aromatic substitution. The method has been used to achieve a rapid and highly effective formal synthesis of erysotramidine. The aromatic (D ring) erythrina alkaloids (Figure 1) have long captured researchers' imaginations due to their characteristic and wide-ranging profile which combines a complex web of biogenetic relationships, potent biological activities, and synthetically challenging polycyclic molecular architectures. 1 Strategies for the assembly of their tetracyclic frameworks are, as expected, numerous, 2, 3, 4 but, right from the outset, 5 construction Programme (FP7/2007-2013)/ERC grant agreement no. 277588 Supporting Information Available. Experimental procedures, full spectroscopic data and copies of 1 H and 13 C-NMR spectra for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

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“…Dihydro-β-erythroidine (DHβE) is a member of the family of tetracyclic Erythrina alkaloids which were isolated from Erythrina species in the end of the 19th century; the majority of this family possesses neuromuscular blocking effects [2]. DHβE is one of the most potent nAChR antagonists of this class and displays prominent selectivity for the α4β2 subtype ( K i = 0.82 µM in a [ 3 H]epibatidine binding assay) [3].…”

Section: Introductionmentioning

confidence: 99%

“…However, the syntheses of the lactonic Erythrina alkaloids are more complex [11–12] as illustrated by more than 150 total syntheses reported for aromatic erythrinanes [2] whereas only four total syntheses of lactonic erythrinanes have been published so far [13–16]. Hence, for the DHβE-based CD fragments, we faced a significantly more challenging synthesis due to the complex nature of the [6,6]-bicyclic lactone moiety for which synthetic procedures are extremely scarce.…”

Section: Introductionmentioning

confidence: 99%

A strategic approach to [6,6]-bicyclic lactones: application towards the CD fragment of DHβE

Jepsen¹,

Glibstrup²,

Crestey³

et al. 2017

Beilstein J. Org. Chem.

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We report an effective synthetic protocol to access [6,6]-bicyclic lactone moieties through a regio- and stereoselective intramolecular Mizoroki–Heck cross-coupling reaction followed by a 6π-electrocyclization. This method enabled the first synthesis of the elusive CD fragment of the Erythrina alkaloid DHβE. Preliminary pharmacological evaluations support the notion that the key pharmacophores of DHβE are located in the A and B rings.

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Synthesis Pathways to Erythrina Alkaloids and Erythrina Type Compounds

Cited by 35 publications

References 97 publications

Dual Nicotinic Acetylcholine Receptor α4β2 Antagonists/α7 Agonists: Synthesis, Docking Studies, and Pharmacological Evaluation of Tetrahydroisoquinolines and Tetrahydroisoquinolinium Salts

Dual Nicotinic Acetylcholine Receptor α4β2 Antagonists/α7 Agonists: Synthesis, Docking Studies, and Pharmacological Evaluation of Tetrahydroisoquinolines and Tetrahydroisoquinolinium Salts

One-pot Synthesis of the Tetracyclic Framework of the Aromatic Erythrina Alkaloids from Simple Furans

A strategic approach to [6,6]-bicyclic lactones: application towards the CD fragment of DHβE

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