Synthesis of stereodefined piperidines from aziridines and their transformation into conformationally constrained amino acids, amino alcohols and 2,7-diazabicyclo[3.3.1]nonanes

2-(2-Cyano-2-phenylethyl)azindines were converted into novel cis- and trans-2-chloromethyl-4-phenylpiperidine-4-carbonitriles via alkylation with 1-bromo-2-chloroethane followed by microwave-assisted 6-exo-tet cyclization and regiospecific ring opening The latter piperidines were used as eligible substrates for the synthesis of stereodefined 2-chloromethyl-, 2-hydroxymethyl-, and 2-carboxymethyl-4-phenylpiperidine-4-carboxylic acids, 2-hydroxymethyl-4-phenylpiperidine-4-carbonitriles, 3-hydroxy-5-phenylazepane-5-carbonitriles, and 5-phenyl-2,7-diazabicyclo[3 3 1]nonane

Synthesis of 2-(2-cyanoeyhyl)aziridines and their transformation into a variety of novel cyclic amino nitriles

Aminonitrillen vormen een zeer interessante klasse van verbindingen. Op biologisch vlak worden ze gebruikt bij de behandeling van diabetes, diarree, post-operatieve pijn en osteoporose. Vanuit chemisch standpunt zijn ze echter nog belangrijker als veelzijdige precursoren voor de synthese van overeenkomstige aminozuren en hun derivaten. Aminozuren worden vaak gebruikt als bouwstenen in peptidomimetica, maar ook als biologisch actieve verbindingen in de farmaceutische en agrochemische industrie. Aziridinen worden algemeen beschouwd als uitstekende bouwstenen in de organische chemie voor verdere omzetting tot een grote variëteit aan stikstof-bevattende acyclische en heterocyclishe doelverbindingen. Hiervoor wordt gebruik gemaakt van de spanningsenergie geassocieerd met de drieringstructuur. Vanuit dit standpunt werden 2-(2-cyaanethyl)aziridinen geselecteerd als nieuwe bouwstenen voor de synthese van een brede waaier aan aminonitrillen op een efficiënte en doelgerichte manier. Vervolgens werden deze aminonitrillen gemodificeerd tot analoga van gekende verbindingen met een specifieke biologische activiteit zoals het antidepressivum milnacipran. Tenslotte werd een evaluatie van een aantal nieuw-gesynthetiseerde piperidinen uitgevoerd met betrekking tot hun antiplasmodiumactiviteit (antimalaria). Uit deze resultaten werd een mogelijke nieuwe doelstructuur ontdekt die geschikt is voor verdere ontwikkeling

A new approach towards 1-phenyl and 1-benzyl substituted 2-(aminomethyl)cyclopropanecarboxamides as novel derivatives of the antidepressant Milnacipran

2-(2-Cyano-2-phenylethyl)aziridines were converted into novel trans-2-aminomethyl-1-phenylcyclopropanecarboxamides via regiospecific ring opening and 3-exo-tet cyclisation, thus providing the first convenient entry into the trans-isomer of Milnacipran as a useful template for further derivatisation. Furthermore, unprecedented 2-aminomethyl-1-benzylcyclopropanecarboxamides have been synthesized using two different routes starting from 2-( 2- cyanoethyl) aziridines, both involving alpha-benzylation with respect to the nitrile group and aziridine to cyclopropane ring transformation

LiAlH4-Induced selective ring rearrangement of 2-(2-cyanoethyl)aziridines toward 2-(aminomethyl)pyrrolidines and 3-aminopiperidines as eligible heterocyclic building blocks

2-(2-Cyanoethyl)aziridines and 2-aryl-3-(2-cyanoethyl)aziridines were deployed as substrates for an In(OTf)(3)-mediated regio- and stereoselective ring rearrangement upon treatment with LiAlH4, affording a variety of novel 2-(aminomethyl)pyrrolidines and 3-aminopiperidines, respectively. Further synthetic elaboration of the obtained 3-aminopiperidines resulted in the formation of a peculiar and unexplored conformationally constrained imidazolidinone and diketopiperazine scaffold

Radical-mediated nitrile translocation as the key step in the stereoselective transformation of 2-(4-chloro-2-cyanobutyl)aziridines to methyl cis-(1-arylmethyl-4-phenylpiperidin-2-yl)acetates

Non-activated 2-(4-chloro-2-cyano-2-phenylbutyl)aziridines were used as building blocks for the stereoselective synthesis of novel cis-2-cyanomethyl-4-phenylpiperidines via a microwave-assisted aziridine to piperidine ring expansion followed by a radical-induced nitrile translocation through initial formation and subsequent cleavage of intermediate bicyclic iminyl radicals. Furthermore, these 2-(cyanomethyl)piperidines were shown to be eligible substrates for the preparation of methyl cis-(1-arylmethyl- 4-piperidin-2-yl)acetates through a Pinner reaction using gaseous HCl in methanol

Chemical and enzymatic synthesis of 2-(2-carbamoylethyl)- and 2-(2-carboxyethyl)aziridines and their conversion into δ-lactams and γ-lactones

Treatment of 1-arylmethyl-2-(2-cyanoethyl)aziridines with a nitrile hydratase afforded the corresponding 2-(2-carbamoylethyl)aziridines, which underwent rearrangement into 5-hydroxypiperidin-2-ones upon heating under microwave irradiation. In addition, treatment of 2-(2-cyanoethyl)aziridines with a nitrilase selectively afforded 5-hydroxypiperidin-2-ones in good yields. On the other hand, chemical hydrolysis of 2-(2-cyanoethyl)aziridines using KOH In EtOH/H2O furnished the corresponding potassium 3-(aziridin-2-yl)propanoates, which, upon acidification with acetic acid, smoothly rearranged into 4-(aminomethyl)butyrolactones