The development of straightforward strategies to access azetidines, and their unsaturated analogs azetines, is highly demanded given the increasing attention received by strained ring systems in drug discovery programs. The introduction of the azetidine scaffold in drug candidates is prompted by the peculiar robustness (i.e. chemical stability) and strong molecular rigidity of this scaffold. Recently, our group reported the convenient preparation of C2-functionalized azetines under continuous flow conditions. We demonstrate that flow chemistry, in combination with the use of the ecofriendly cyclopentyl methyl ether (CPME) as the solvent, allows for obeying sustainability concerns. In this contribution, we focused our attention on the manipulation of the prepared 2-substituted azetines. In particular, we developed the continuous flow hydrogenation of the azetine ring producing the corresponding C2-functionalized azetidines, not easily accessible through a simple lithiation/trapping sequence. Moreover, we discovered that, under acidic conditions, the 2-substituted azetines undergo an unprecedented rearrangement producing interesting polyfunctionalized systems. Lastly, a light-driven methodology for the selective addition of thiols to the C3 position of the azetine ring is discussed.
The development of straightforward strategies to access azetidines, and their unsaturated analogs azetines, is highly demanded given the increasing attention received by strained ring systems in drug discovery programs. The introduction of the azetidine scaffold in drug candidates is prompted by the peculiar robustness (i.e. chemical stability) and strong molecular rigidity of this scaffold. Recently, our group reported the convenient preparation of C2-functionalized azetines under continuous flow conditions. We demonstrate that flow chemistry, in combination with the use of the ecofriendly cyclopentyl methyl ether (CPME) as the solvent, allows for obeying sustainability concerns. In this contribution, we focused our attention on the manipulation of the prepared 2-substituted azetines. In particular, we developed the continuous flow hydrogenation of the azetine ring producing the corresponding C2-functionalized azetidines, not easily accessible through a simple lithiation/trapping sequence. Moreover, we discovered that, under acidic conditions, the 2-substituted azetines undergo an unprecedented rearrangement producing interesting polyfunctionalized systems. Lastly, a light-driven methodology for the selectiveaddition of thiols to the C3 position of the azetine ring is discussed.
Use of Flow Technologies and Photochemical Methods for the Preparation and Synthetic Manipulation of Functionalized Azetines
Marco Colella;Pantaleo Musci;Leonardo Degennaro;Renzo Luisi
2022-01-01
Abstract
The development of straightforward strategies to access azetidines, and their unsaturated analogs azetines, is highly demanded given the increasing attention received by strained ring systems in drug discovery programs. The introduction of the azetidine scaffold in drug candidates is prompted by the peculiar robustness (i.e. chemical stability) and strong molecular rigidity of this scaffold. Recently, our group reported the convenient preparation of C2-functionalized azetines under continuous flow conditions. We demonstrate that flow chemistry, in combination with the use of the ecofriendly cyclopentyl methyl ether (CPME) as the solvent, allows for obeying sustainability concerns. In this contribution, we focused our attention on the manipulation of the prepared 2-substituted azetines. In particular, we developed the continuous flow hydrogenation of the azetine ring producing the corresponding C2-functionalized azetidines, not easily accessible through a simple lithiation/trapping sequence. Moreover, we discovered that, under acidic conditions, the 2-substituted azetines undergo an unprecedented rearrangement producing interesting polyfunctionalized systems. Lastly, a light-driven methodology for the selectiveaddition of thiols to the C3 position of the azetine ring is discussed.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
