Synthesis of cis-2-alkoxycyclopropylamines via intramolecular cyclization of 2-azaallylic anions derived from alkoxybrominated N-(arylidene)-2-methyl-2-propenylamines

Mangelinckx, Sven; Kadam, Santosh T.; Semina, Elena; Callebaut, Gert; Colpaert, Filip; Smaele, Dirk De; Kimpe, Norbert De

doi:10.1016/j.tet.2013.02.094

Cited by 6 publications

(5 citation statements)

References 36 publications

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“…The cis ‐cyclopropylamine compounds, synthesized as described previously , were tested against LSD1 for which TCP is an established inhibitor. In the LSD1 enzyme assay , the compounds were inactive at the maximum tested concentration of 25 μ m .…”

Section: Resultsmentioning

confidence: 99%

“…Reversible binding may be predicted by docking, so this was used to guide the selection of previously synthesized compounds used in this study, and then to explore whether the enantiomers bind differently to MAO A and MAO B (Table ). Molecular modelling was performed to determine binding energies and estimate K i values for the cis ‐cyclopropylamines with MAO A and MAO B (Table S1).…”

Section: Resultsmentioning

confidence: 99%

“…cis‐ isomers of primary and secondary cyclopropylamines with an alkoxy group at the 2‐position of the cyclopropyl ring replacing the more common phenyl substitution were synthesized as previously described .…”

Section: Methodsmentioning

confidence: 99%

“…Here we describe inhibition of the two forms of MAO by selected cis isomers of primary and secondary cyclopropylamines with an alkoxy group at the 2‐position of the cyclopropyl ring, replacing the more common phenyl substitution . The trans compound TCP, which was already well‐established as a drug before the full impact of the existence of two forms of MAO was appreciated , is included as a reference compound.…”

Section: Introductionmentioning

confidence: 99%

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cis‐cyclopropylamines as mechanism‐based inhibitors of monoamine oxidases

et al. 2015

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Cyclopropylamines, inhibitors of monoamine oxidases (MAO) and lysinespecific demethylase (LSD1), provide a useful structural scaffold for the design of mechanism-based inhibitors for treatment of depression and cancer. For new compounds with the less common cis relationship and with an alkoxy substituent at the 2-position of the cyclopropyl ring, the apparent affinity determined from docking experiments revealed little difference between the enantiomers. Using the racemate, kinetic parameters for the reversible and irreversible inhibition of MAO were determined. No inhibition of LSD1 was observed. For reversible inhibition, most compounds gave high IC50 values with MAO A, but sub-micromolar values with MAO B. After pre-incubation of the cyclopropylamine with the enzyme, the inhibition was irreversible for both MAO A and MAO B, and the activity was not restored by dilution. Spectral changes during inactivation of MAO A included bleaching at 456 nm and an increased absorbance at 400 nm, consistent with flavin modification. These derivatives are MAO B-selective irreversible inhibitors that do not show inhibition of LSD1. The best inhibitor was cis-N-benzyl-2-methoxycyclopropylamine, with an IC 50 of 5 nM for MAO B and 170 nM for MAO A after 30 min pre-incubation. This cis-cyclopropylamine is over 20-fold more effective than tranylcypromine, so may be studied as a lead for selective inhibitors of MAO B that do not inhibit LSD1.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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cis‐cyclopropylamines as mechanism‐based inhibitors of monoamine oxidases

et al. 2015

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“…Due to the interest in the chemistry of functionalized cyclopropanes, a variety of methods describing the preparation of these strained carbocycles have recently been reported in the literature. − One of the most commonly used approaches is based on intramolecular nucleophilic substitution (S N ) reactions involving the attack of a carbanion-like nucleophile on a pre-existing electrophilic site, these two reaction centers being separated by one carbon atom. While this strategy has been successfully explored with substrate A containing different “X” leaving groups − and also with epoxides of the B type − (Scheme ), the need for the use of strong bases or sensitive organometallic reagents in an anhydrous environment is a serious restriction in terms of its wider application. Furthermore, in many circumstances the availability of the starting materials poses a challenge, the structural diversity is limited to a few examples, and the stereoselectivity related to the resulting substituted cyclopropane is only moderate.…”

Section: Introductionmentioning

confidence: 99%

Lithium Chloride-Mediated Stereoselective Synthesis of Cyclopropanecarboxamides from γ,δ-Epoxy Malonates through a Domino Cyclopropanation/Lactonization/Aminolysis Process

Marques

Sá

2014

J. Org. Chem.

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The stereoselective synthesis of novel multifunctionalized cyclopropanes from γ,δ-epoxy malonates and amines mediated by LiCl under mild conditions was carried out. This domino reaction involves the initial cyclopropanation via intramolecular ring-opening of γ,δ-epoxy malonates through the cooperative catalysis of LiCl (acting as a Lewis acid) and a Brønsted base (a primary or, in selected cases, a secondary amine). The sequential events consisted of lactonization and aminolysis of the lactone ring, which ultimately furnished cyclopropanecarboxamides with different substitution patterns in good isolated yields. In all cases, a quaternary stereogenic center could be perfectly assembled, with a single diastereoisomer being obtained. This method proceeds with high atom economy, is remarkably modular and operationally simple, and tolerates a variety of functional groups. The involvement of readily available starting materials, the broad scope, and the use of a sustainable solvent (methanol or ethanol) at ambient temperature make this domino process highly effective. A reaction mechanism is proposed on the basis of the experimental observations involving the preparation and reactivity of cyclopropylidene lactones as possible intermediates of the domino process.

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A Deprotonation Approach to the Unprecedented Amino‐Trimethylenemethane Chemistry: Regio‐, Diastereo‐, and Enantioselective Synthesis of Complex Amino Cycles

Trost

Wang

2018

Angewandte Chemie

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The first realization of the amino‐trimethylenemethane chemistry is reported using a deprotonation strategy to simplify the synthesis of the amino‐trimethylenemethane donor in two steps from commercial and inexpensive materials. A broad scope of cycloaddition acceptors (seven different classes) participated in the chemistry, chemo‐, regio‐, diastereo‐, and enantioselectively generating various types of highly valuable complex amino cycles. Multiple derivatization reactions that further elaborated the initial amino cycles were performed without isolation of the crude product. Ultimately, we applied the amino‐trimethylenemethane chemistry to synthesize a potential pharmaceutical in 8 linear steps and 7.5 % overall yield, which previously was achieved in 18 linear steps and 0.6 % overall yield.

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Synthesis of cis-2-alkoxycyclopropylamines via intramolecular cyclization of 2-azaallylic anions derived from alkoxybrominated N-(arylidene)-2-methyl-2-propenylamines

Cited by 6 publications

References 36 publications

cis‐cyclopropylamines as mechanism‐based inhibitors of monoamine oxidases

cis‐cyclopropylamines as mechanism‐based inhibitors of monoamine oxidases

Lithium Chloride-Mediated Stereoselective Synthesis of Cyclopropanecarboxamides from γ,δ-Epoxy Malonates through a Domino Cyclopropanation/Lactonization/Aminolysis Process

A Deprotonation Approach to the Unprecedented Amino‐Trimethylenemethane Chemistry: Regio‐, Diastereo‐, and Enantioselective Synthesis of Complex Amino Cycles

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