An efficient synthesis of an 8-phenoxy aporphine derivative utilizing mono-ligated palladium ortho-phenol arylation

Ali, Ghada; Cuny, Gregory D.

doi:10.1016/j.tet.2019.04.011

Cited by 9 publications

(5 citation statements)

References 35 publications

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“…Encouraged by scattered reports on N-acyl-Pictet-Spengler reactions using N-alkoxycarbonyl activation [10,15,[18][19][20][21] (noteworthy, N-Boc is not reliably resistant to the strongly acidic cyclization conditions [22,23]) we further intended to replace the unstable and poorly accessible arylacetaldehyde building blocks [19,22] by more common equivalents, and ended up with ω-methoxystyrenes [18], which have been demonstrated to be advantageous arylacetaldehyde equivalents in strongly acidic, anhydrous media, used for N-acyl-Pictet-Spengler [18] and Povarov [23] reactions before. In order to avoid tedious protective group manipulations in the synthesis of alkaloids bearing free phenolic groups (e.g., with commonly used isopropoxy [19], TIPS or benzyl [24], or benzoyl [25] protection) we investigated the utilization of the ethoxycarbonyl group for phenol protection.…”

Section: Resultsmentioning

confidence: 99%

The ethoxycarbonyl group as both activating and protective group in N-acyl-Pictet–Spengler reactions using methoxystyrenes. A short approach to racemic 1-benzyltetrahydroisoquinoline alkaloids

Keller

Sauvageot-Witzku

Geisslinger

et al. 2021

Beilstein J. Org. Chem.

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We present a systematic investigation on an improved variant of the N-acyl-Pictet–Spengler condensation for the synthesis of 1-benzyltetrahydroisoquinolines, based on our recently published synthesis of N-methylcoclaurine, exemplified by the total syntheses of 10 alkaloids in racemic form. Major advantages are a) using ω-methoxystyrenes as convenient alternatives to arylacetaldehydes, and b) using the ethoxycarbonyl residue for both activating the arylethylamine precursors for the cyclization reaction, and, as a significant extension, also as protective group for phenolic residues. After ring closure, the ethoxycarbonyl-protected phenols are deprotected simultaneously with the further processing of the carbamate group, either following route A (lithium alanate reduction) to give N-methylated phenolic products, or following route B (treatment with excess methyllithium) to give the corresponding alkaloids with free N–H function. This dual use of the ethoxycarbonyl group shortens the synthetic routes to hydroxylated 1-benzyltetrahydroisoquinolines significantly. Not surprisingly, these ten alkaloids did not show noteworthy effects on TPC2 cation channels and the tumor cell line VCR-R CEM, and did not exhibit P-glycoprotein blocking activity. But due to their free phenolic groups they can serve as valuable intermediates for novel derivatives addressing all of these targets, based on previous evidence for structure–activity relationships in this chemotype.

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Section: Resultsmentioning

confidence: 99%

The ethoxycarbonyl group as both activating and protective group in N-acyl-Pictet–Spengler reactions using methoxystyrenes. A short approach to racemic 1-benzyltetrahydroisoquinoline alkaloids

Keller

Sauvageot-Witzku

Geisslinger

et al. 2021

Beilstein J. Org. Chem.

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“…Phenolic compounds are simple and naturally occurring organic compounds bearing an aromatic ring with one or more hydroxyl groups (with or without side chain), they received considerable attention due to their biological functions such as anti-carcinogen, anti-ageing, anti-diabetic, anti-mutagen and immunostimulatory roles [ 40 , 41 ]. Among the most extensively administered phenolic drugs, salbutamol, terbutaline, thymol, favipiravir, remdesivir, dexamethasone and hydrochloroquine are highly recognized β 2 -adrenergic receptor agonists, antiseptic, antimicrobial agent and antiviral agents, respectively ( Figure 3 ) [ 42 , 43 ].…”

Section: Pharmacological Properties Of Phenol Derivativesmentioning

confidence: 99%

Pyridine Scaffolds, Phenols and Derivatives of Azo Moiety: Current Therapeutic Perspectives

et al. 2021

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Synthetic heterocyclic compounds have incredible potential against different diseases; pyridines, phenolic compounds and the derivatives of azo moiety have shown excellent antimicrobial, antiviral, antidiabetic, anti-melanogenic, anti-ulcer, anticancer, anti-mycobacterial, anti-inflammatory, DNA binding and chemosensing activities. In the present review, the above-mentioned activities of the nitrogen-containing heterocyclic compounds (pyridines), hydroxyl (phenols) and azo derivatives are discussed with reference to the minimum inhibitory concentration and structure–activity relationship, which clearly indicate that the presence of nitrogen in the phenyl ring; in addition, the hydroxyl substituent and the incorporation of a diazo group is crucial for the improved efficacies of the compounds in probing different diseases. The comparison was made with the reported drugs and new synthetic derivatives that showed recent therapeutic perspectives made in the last five years.

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“…This discovery was successfully applied toward the stereoselective synthesis of (À )-lirinine (80) 80) [126] (Scheme 15a). From 2015 to 2019, Cuny et al demonstrated the great potential of the catalytic system disclosed in 2012 [126] through the synthesis of several aporphine compounds, including (À )-oliveroline (81), [127] (À )-nornuciferidine (82), [127] and (�)-N-methylguattescidine (83), [128] as well as 7hydroxyaporphines (e. g., 84) [129] and 8-aryloxyaporphines (e. g., 85) [130] with important pharmacological properties (Scheme 15b).…”

Section: Palladium-catalyzed Reactionsmentioning

confidence: 99%

“…The first approach is derived from a retrosynthetic analysis involving a hypothetical one-bond disconnection, affording primarily 1-benzyl-1,2,3,4-tetrahydroisoquinoline compounds. This strategy is based on biosynthetic routes and has been implemented using different transformations, including the Pschorr cyclization, photochemical reactions, and palladium-catalyzed cyclizations [122,[124][125][126][127][128][129][130][131][132][133][134][135][136][137][138] (Scheme 1). Intramolecular cyclizations using phenolic oxidative coupling reactions [62,139] and via generation of arynes tethered with aromatic nucleophiles [140] have not been addressed in this article.…”

Section: Introductionmentioning

confidence: 99%

Advances Towards the Synthesis of Aporphine Alkaloids: C‐Ring Formation via Approaches Based on One‐ and Two‐Bond Disconnections

Silva

Rita

Raminelli

2021

The Chemical Record

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Aporphine compounds constitute a class of substances with important pharmacological properties, including anticancer, antiviral, anti-HIV, anti-inflammatory, and leishmanicidal activities. Consequently, several strategies to obtain the aporphine core have been reported. Herein this review, we provide an overview of two relevant approaches used to construct the Cring in the synthetic routes developed. The first approach, which is based on a one-bond disconnection, allows C-ring formation using a 1-benzyl-1,2,3,4-tetrahydroisoquinoline intermediate (mainly) employing cyclization reactions catalyzed by metals or promoted by light. The second approach, which is derived from a two-bond disconnection, leads to C-ring formation via a sequence of reactions starting with [4 + 2] cycloadditions. Through these approaches, aporphinoids with a diverse range of substitution patterns and biological activities can be synthesized.

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An efficient synthesis of an 8-phenoxy aporphine derivative utilizing mono-ligated palladium ortho-phenol arylation

Cited by 9 publications

References 35 publications

The ethoxycarbonyl group as both activating and protective group in N-acyl-Pictet–Spengler reactions using methoxystyrenes. A short approach to racemic 1-benzyltetrahydroisoquinoline alkaloids

The ethoxycarbonyl group as both activating and protective group in N-acyl-Pictet–Spengler reactions using methoxystyrenes. A short approach to racemic 1-benzyltetrahydroisoquinoline alkaloids

Pyridine Scaffolds, Phenols and Derivatives of Azo Moiety: Current Therapeutic Perspectives

Advances Towards the Synthesis of Aporphine Alkaloids: C‐Ring Formation via Approaches Based on One‐ and Two‐Bond Disconnections

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