Novel Sulfonium Reagents for the Modular Synthesis of Spiro[2.3]Hexanes and Heteroatom‐Containing Analogues: Synthesis, Application, and Evaluation as Bioisosteres
Abstract
Abstract Molecular scaffolds with a high fraction of sp 3 ‐hybridized centers have attracted considerable attention in medicinal chemistry as bioisosteres for a wide range of aromatic and nonstrained heterocycles. In particular, strained spiro‐heterocycles have garnered popularity for this purpose, although access to spiro[2.3]hexane analogues is underrepresented. We herein report modular access to nine different spiro[2.3]hexane analogues, including previously underdeveloped 5‐oxa‐1‐azaspiro[2.3]hexane and 1,5‐diazaspiro[2.3]hexane motifs. Our synthetic approach leverages novel cyclobutane‐, oxetane‐, and azetidine‐substituted sulfonium salts, which can undergo Johnson–Corey–Chaykovsky type reactions with alkenes, carbonyls and imines to provide access to the desired spiro[2.3]hexanes. Here, we also report the first comprehensive computational and predictive in silico evaluation of their bioisosteric potential, with validation provided by in vitro experiments.
Article Details
Authors (11)
Philipp Natho
Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, Via E. Orabona 4, Bari 70125, Italy
Annarita Vicenti
Department of Pharmacy‐Drug Sciences University of Bari Aldo Moro Bari Italy
Fabrizio Mastrolorito
Department of Pharmacy‐Drug Sciences University of Bari “A. Moro” Via E. Orabona 4 Bari 70125 Italy
Francesca De Franco
Tes Pharma S.r.l. Via Giovine Italia, 1, Solomeo Corciano (PG) 06073 Italy
Lee Walsh‐Benn
CAS – A division of the American Chemical Society ACS International, Ltd. 2540 Olentangy River Road Columbus Ohio 43202 USA
Marco Colella
Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, Via E. Orabona 4, Bari 70125, Italy
Ernesto Mesto
Department of Earth and Geoenvironmental Sciences University of Bari Aldo Moro Bari Italy
Emanuela Schingaro
Department of Earth and Geoenvironmental Sciences University of Bari Aldo Moro Bari Italy
Orazio Nicolotti
Department of Pharmacy‐Drug Sciences University of Bari “A. Moro” Via E. Orabona 4 Bari 70125 Italy
Antimo Gioiello
Department of Pharmaceutical Sciences University of Perugia Via del Liceo, 1 Perugia 06123 Italy
Renzo Luisi
Department of Pharmacy-Drug Sciences, University of Bari Aldo Moro, Via E. Orabona 4, Bari 70125, Italy