Hoch regioselektive Addition von allylischen Zinkhalogeniden und verschiedenen Zinkenolaten an [1.1.1]Propellan

Abstract

Wirb erichten über eine Reihe von hochregioselektiven Öffnungen von [1.1.1]Propellan mit verschiedenen allylischen Zinkhalogeniden, sowie mit Zinkenolaten von Ketonen, Estern und Nitrilen. Die resultierenden zinkierten Bicyclopentane (BCPs) wurden mit einer Reihe von Elektrophilen abgefangen, einschließlich Carbonsäurechloriden, Sulfonothioaten, Hydroxylaminobenzoaten, Tosylcyanid sowie Arylund Allylhalogeniden. Dadurchwurden hochfunktionalisierte BCP-Derivate erzeugt. Die ungewçhnlichh ohe Regioselektivitätd ieser Reaktionen wurde mittels DFT-Berechnungen rationalisiert. Ein Bioisoster des synthetischen Opioids Pethidin wurdem it Hilfe dieser Methodik in einem Schritt in 95 % Ausbeute hergestellt. Schema 1. A) Reaktion von [1.1.1]Propellan (1)mit Radikalen und Anionen. B) BCP-Analoga ausgewählter pharmazeutischer Verbindungen. Schema 2. Reaktionen von [1.1.1]Propellan (1)m it organometallischen Reagenzien.

Visible‐Light‐Induced 1,3‐Aminopyridylation of [1.1.1]Propellane with N‐Aminopyridinium Salts

“…[7b] In addition, the photocatalytic strategy used for N-centered radical addition to propellane was first demonstrated by the Leonori group,i nw hich ar ange of external SOMOphiles,s uch as halide,s ulfur, and selenium, could be efficiently installed on the BCPAb uilding blocks (d). [7c] Considering the utility of BCPAand pyridyl groups in the pharmaceutical industry, [3,4,8] the development of am ethod for the efficient synthesis of 1,3-aminopyridyl-functionalized BCP scaffolds is highly demanded for the rapid construction of complex and druglike BCP targets.I ng eneral, the preparation of heteroaryl-functionalized BCPAs requires further elaboration of BCPA-halide intermediates with prefuntionalized heteroarenes, [9] thus limiting their wide application to lead optimization in medicinal chemistry.I n this context, the goal of this work is to develop anew strategy to efficiently access 1,3-aminopyridylated BCP scaffolds from the direct transformation of propellane in acontrollable and selective manner.I np revious work, our laboratory has demonstrated that N-aminopyridinium salts can be efficiently leveraged as bifunctional reagents [10] in avisible-light-enabled platform for the difunctionalization of alkenes to directly access amine-and pyridine-containing molecules. [11] In view of our previous experience on the use of pyridinium salts and the susceptibility of propellane to radical opening, we were intrigued by the possibility of embracing the intrinsic reactivity of the strained CÀCb ond in propellane by using N-aminopyridinium salts in strain-release settings (Scheme 1C).…”

Visible‐Light‐Induced 1,3‐Aminopyridylation of [1.1.1]Propellane with N‐Aminopyridinium Salts

“…[7b] In addition, the photocatalytic strategy used for N-centered radical addition to propellane was first demonstrated by the Leonori group,i nw hich ar ange of external SOMOphiles,s uch as halide,s ulfur, and selenium, could be efficiently installed on the BCPAb uilding blocks (d). [7c] Considering the utility of BCPAand pyridyl groups in the pharmaceutical industry, [3,4,8] the development of am ethod for the efficient synthesis of 1,3-aminopyridyl-functionalized BCP scaffolds is highly demanded for the rapid construction of complex and druglike BCP targets.I ng eneral, the preparation of heteroaryl-functionalized BCPAs requires further elaboration of BCPA-halide intermediates with prefuntionalized heteroarenes, [9] thus limiting their wide application to lead optimization in medicinal chemistry.I n this context, the goal of this work is to develop anew strategy to efficiently access 1,3-aminopyridylated BCP scaffolds from the direct transformation of propellane in acontrollable and selective manner.I np revious work, our laboratory has demonstrated that N-aminopyridinium salts can be efficiently leveraged as bifunctional reagents [10] in avisible-light-enabled platform for the difunctionalization of alkenes to directly access amine-and pyridine-containing molecules. [11] In view of our previous experience on the use of pyridinium salts and the susceptibility of propellane to radical opening, we were intrigued by the possibility of embracing the intrinsic reactivity of the strained CÀCb ond in propellane by using N-aminopyridinium salts in strain-release settings (Scheme 1C).…”