Amino-oxetanes as amide isosteres by an alternative defluorosulfonylative coupling of sulfonyl fluorides

Abstract

Bioisosteres provide valuable design elements for medicinal chemists to adjust the structural and pharmacokinetic characteristics of bioactive compounds towards viable drug candidates. Aryl oxetane amines offer exciting potential as bioisosteres for benzamides, an extremely common pharmacophore, but are rarely examined due to the lack of available synthetic methods. Here, we describe a new class of reactions for sulfonyl fluorides to form aminooxetanes by an alternative pathway to the established SuFEx (sulfonyl-fluoride exchange) click reactivity. An unprecedented defluorosulfonylation forms planar oxetane carbocations simply on warming. This disconnection, comparable to a typical amidation, will allow the application of vast existing amine libraries. The reaction is tolerant to a wide range of polar functionalities and is suitable for array formats. Ten oxetane analogues of bioactive benzamides and marketed drugs are prepared.Kinetic and computational studies support the formation of an oxetane carbocation as the rate determining step, followed by a chemoselective nucleophile coupling step.New reaction classes have enormous potential to access underexplored chemical space and influence molecular design. 1,2 A limited set of reliable and predictable reactions continue to have a disproportionate influence on the ability to construct medicinal and agrochemical compounds. 3 Such reactions can enable rapid access to derivatives, while also influencing, and limiting, molecular design. Most notably, click reactions have had an enormous impact in the chemical and biological sciences, which proceed on complex substrates without stringent conditions. 4,5,6,7 In drug discovery, amide bond formation continues to be the most common reaction, 3 exploiting vast amine and carboxylic acid libraries available to pharmaceutical companies. Amides are therefore prevalent in marketed pharmaceutical and agrochemical compounds, and display valuable features being more stable than other carbonyl derivatives, powerful H-bond donors and acceptors, and ubiquitous as critical bonding units in natural peptides and proteins. 8 Nonetheless, the amide sub-structure will frequently not provide the subtle balance of properties that is required for a successful active ingredient. Consequently, bioisosteres of amides are also common, providing a mimic of the features of the amide and adjusting the global properties of a compound. 9,10,11 While amidation is extensively investigated, with powerful, mostly stoichiometric coupling reagents, 12 the same cannot be said for amide-isosteres, which often require bespoke synthetic efforts (Fig. 1a).3,3-Disubstituted oxetanes have garnered considerable interest as carbonyl replacements, due to the similar dipole moments, hydrogen-bonding capacity, and oxygen lone pair orientation. 13,14 Their use as a bioisostere or replacement group also introduces a more 3-dimensional element to a drug compound that can have beneficial binding and solubility effects. 15 The motif is exemplified by antiviral Ziresovir, bear...

Diastereoselective access to substituted oxetanes via hydrosilylation–iodocyclisation of homopropargylic alcohols

“…19 As well as being high value synthetic intermediates, oxetanes are privileged fragments in medicinal chemistry and are frequently utilised as bioisosteres. 20 In addition to this, the oxetane motif is found in a variety of natural products. Existing methods to access these scaffolds typically involve the use of stoichiometric amounts of strong base to realise an intramolecular Williamson ether synthesis, or require the use of complex photochemical reaction set-ups to carry out the Paterno-Buchi reaction (Fig.…”

Oxetan-3-ols as 1,2-bis-Electrophiles in a Brønsted-Acid-Catalyzed Synthesis of 1,4-Dioxanes

“…Further substitution patterns were tolerated in moderate to high yields with electron-rich aromatic substituents ( 3 – 10 ). The successful reaction of ortho -substituted examples 3 and 5 is noteworthy because in the presumed planar carbocation structure ortho -substituents may clash with the oxetane methylene groups . Dioxane 6 bears the 3,4,5-trimethoxyphenyl pharmacophore, a motif present in prominent bioactive compounds such as colchicine, mescaline, and eudesmic acid derivatives but which has been challenging to activate through an oxetane carbocation. , A different alkoxy substituent was tolerated ( 7 ), as well as free ( 8 ) and protected phenols ( 9 – 10 ).…”

“…The successful reaction of ortho -substituted examples 3 and 5 is noteworthy because in the presumed planar carbocation structure ortho -substituents may clash with the oxetane methylene groups . Dioxane 6 bears the 3,4,5-trimethoxyphenyl pharmacophore, a motif present in prominent bioactive compounds such as colchicine, mescaline, and eudesmic acid derivatives but which has been challenging to activate through an oxetane carbocation. , A different alkoxy substituent was tolerated ( 7 ), as well as free ( 8 ) and protected phenols ( 9 – 10 ). TIPS-protected dioxane 10 was partially deprotected by catalytic amounts of the acid catalyst.…”

Chiral α-Stereogenic Oxetanols and Azetidinols via Alcohol-Mediated Reductive Coupling of Allylic Acetates: Enantiotopic π-Facial Selection in Symmetric Ketone Addition

“…Despite the formation of congested acyclic vicinal tertiary–quaternary centers, complete branched regioselectivities are observed. This method enables entry to unique chiral oxetanes and azetidines, which serve as metabolically stable bioisosteres in pharmaceutical and agrochemical ingredients (Figure ). , Functional group compatibility and relevance to drug discovery are underscored by the use of allyl pronucleophiles incorporating the top 10 N-heterocycles found in the Food and Drug Administration (FDA)-approved drugs …”