2-(Aryl-sulfonyl)oxetanes as designer 3-dimensional fragments for fragment screening: synthesis and strategies for functionalisation

Abstract

2-Sulfonyl-oxetanes have been prepared, affording non-planar structures with desirable physicochemical properties for fragment based drug discovery. The oxetane motif was formed by an intramolecular C-C bond formation. The fragments were further functionalised via organometallic intermediates at the intact oxetane and aromatic rings.

Studies on the synthesis, stability and conformation of 2-sulfonyl-oxetane fragments

“…Therefore, a different approach was required to access the proposed 2-sulfonyl oxetanes, for which we examined a C-C bond forming cyclisation approach (Scheme 1). 14,15,26 We envisaged that deprotonation next to the sulfone would provide a more reactive carbanion (vs an oxy-anion) that may facilitate cyclisation to the 4-membered ring.…”

“…2,4,7 In this context, we considered that novel substituted oxetanes could provide interesting chemical motifs and fragments. 14,15 The oxetane motif is found in a variety of natural products and biologically active compounds ( Figure 1A). 16 However, the recent increased interest in applying oxetanes in medicinal chemistry follows studies by Carreira and co-workers, in which the incorporation of 3,3-disubstituted oxetanes in place of gem-dimethyl groups was studied ( Figure 1B).…”

“…Functionalisation of 2--aryl sulfonyl oxetanes directly on the intact oxetane ring via lithiation. 14 We were interested in the viability of the 2-sulfonyl oxetane units as cross-coupling partners, to access functionalised biaryl systems. This was realised through Suzuki-Miyaura crosscoupling using Pd(OAc) 2 with Buchwald's SPhos ligand (Scheme 5).…”

Recent Advances in the Synthesis of 2-Substituted Oxetanes

“…18 Traditional cyclization approaches to synthesize these compounds were unsuitable due to the instability of the required intermediates. Therefore, a C-C bond forming cyclization was developed, which had not been previously investigated for oxetane synthesis (Scheme 4a).…”

2-(tert-Butyl)-4-phenyloxetane

“…Nowadays, photochemical Paternò-Büchi [2+2] reactions of carbonyl compounds with alkenes [10], intramolecular Williamson etherification [11] and ring expansion of epoxides with sulfoxonium ylides [12] are already established general methods for their synthesis. More functionalized derivatives can be prepared by regioselective lithiation-electrophilic trapping processes starting from 2-aryloxetanes, 2-sulphonyloxetanes and hydrazones of oxetan-3-one [13][14][15][16][17]. The synthesis of stereodefined 2,4-disubstituted oxetane scaffolds still remains a challenge in contemporary organic synthesis.…”