Lithium‐Catalyzed Thiol Alkylation with Tertiary and Secondary Alcohols: Synthesis of 3‐Sulfanyl‐Oxetanes as Bioisosteres

Abstract

Abstract3‐Sulfanyl‐oxetanes are presented as promising novel bioisosteric replacements for thioesters or benzyl sulfides. From oxetan‐3‐ols, a mild and inexpensive Li catalyst enables chemoselective C−OH activation and thiol alkylation. Oxetane sulfides are formed from various thiols providing novel motifs in new chemical space and specifically as bioisosteres for thioesters due to their similar shape and electronic properties. Under the same conditions, various π‐activated secondary and tertiary alcohols are also successful. Derivatization of the oxetane sulfide linker provides further novel oxetane classes and building blocks. Comparisons of key physicochemical properties of the oxetane compounds to selected carbonyl and methylene analogues indicate that these motifs are suitable for incorporation into drug discovery efforts.

Catalytic Friedel‐Crafts Reactions on Saturated Heterocycles and Small Rings for sp3‐sp2 Coupling of Medicinally Relevant Fragments

“…We recently reported methods for the synthesis of 3,3‐diaryloxetanes using oxetanols with phenols and a lithium triflimide catalyst (Figure b). Under related conditions, we reported Li‐catalyzed thiol alkylation procedures with oxetanols . We also reported 3,3‐diarylazetidines by Friedel–Crafts alkylation of electron rich aromatics with azetidinols, where a calcium triflimide catalyst was optimal (Figure b) .…”

Oxetane ethers are formed reversibly in the lithium-catalyzed Friedel–Crafts alkylation of phenols with oxetanols: Synthesis of dihydrobenzofurans, diaryloxetanes, and oxetane ethers

“…Recent years has seen significant interest in the use of oxetanes as synthetic intermediates, and as replacement groups in medicinal chemistry. [7,8,9] Particular interest has arisen through the use of oxetanes as polar replacement groups with improved metabolic stability for gem-dimethyl [10] or tert-butyl groups, [11] and as bioisosteres for ketones, [12,13] amides, [14] thioesters, [15] and carboxylic acids [16] (Figure 2A). These bioisosteric replacements can afford improvements in physicochemical properties and increased options for medicinal chemists.…”

Investigating 3,3-Diaryloxetanes as Potential Bioisosteres in Drug Discovery

“…18 Mechanistic understanding enabled the development of other interesting 3,3-disubstituted oxetanes. 11,19 Furthermore, we have been able to demonstrate that 3,3-diaryloxetanes are robust to a range of chemical transformations, enabling access to a range of compounds with diverse functionality.…”

“…Developments of oxetane bioisosteres 3-aminooxetanes, 9 as well as oxetan-3-ol as an alternative isosteric replacement of carboxylic acid. 10,11 3-Mono-and 2-substituted-oxetanes have also seen significant synthetic and medicinal investigation, and are increasingly investigated in SAR studies, and are present in bioactive compounds. 5,12,13 However, it is 3,3-disubstituted derivatives that have seen the most attention, as they benefit from not introducing a stereocenter, and increase steric protection to avoid ring opening pathways.…”