Expanding the Chemical Space of 1,2-Difunctionalized Cyclobutanes

Abstract

An efficient approach to the synthesis of previously unavailable or hardly accessible 1,2-difunctionalized cyclobutanes (mostly with NH 2 /NHBoc, OH, SH, or SO 2 F groups attached to the carbocycle either directly or via a CH 2 unit) relying on the divergent strategy is described. This class of compounds provides sp 3 -enriched and conformationally restricted building blocks that are of special demand for medicinal chemistry. The target compounds were prepared not only as pure racemic (±)-cis-and (±)-trans-diastereomers but in some cases also as single enantiomers. The developed procedures are readily scaled up and allow obtaining the target compounds on an up to hundred-gram scale. On the basis of the results of 20 X-ray diffraction experiments, structural characterization of the 1,2-difunctionalized cyclobutane core was performed using the extended Cremer−Pople puckering parameters and exit vector (EVP) plots.

Chemoselective Reactions of Functionalized Sulfonyl Halides

“…Photochemical [2 + 2] cycloaddition of vinyl sulfonyl fluoride with maleimides gave corresponding cyclobutanes 10. [135][136][137] [3 + 2] cycloadditions of alkenyl sulfonyl fluorides with various dipolarophiles were studied extensively. Thus, reaction with diazoalkanes bearing amide, [138] aryl, [139] CF 3 , [140] or C 2 F 5 [141] groups provided corresponding pyrazolines 11.…”

“…In particular, reaction of styryl sulfonyl fluoride 8 with sulfonium ylide resulted in cyclopropane‐derived sulfonyl fluoride 9 via formal [2+1] cycloaddition [60,134] (Scheme 16). Photochemical [2+2] cycloaddition of vinyl sulfonyl fluoride with maleimides gave corresponding cyclobutanes 10 [135–137] …”

Selective Hydrofunctionalization of N-Allenyl Derivatives with Heteronucleophiles Catalyzed by Brønsted Acids

“…Notably, the cyclobutane motif is present in a variety of compounds, showing significant pharmacological properties and, among the derivatives bearing two heteroatom-(O,N,S)-containing substituents, the 1,2-arrangement is the least reported in the literature. 40 Lastly, we applied the lightpromoted anti-Markovnikov hydrofunctionalization recently proposed by Nicewicz et al 41 to our γ-oxygenated enamide 4ba, obtaining 15 with excellent yield and regioselectivity.…”

Selective P450BM3 Hydroxylation of Cyclobutylamine and Bicyclo[1.1.1]pentylamine Derivatives: Underpinning Synthetic Chemistry for Drug Discovery

“…Usually, each ring size and regio- or stereoisomer requires its own bespoke synthetic route. Representative multistep sequences leading to cis -3-hydroxy-cyclobutylamine (CBA) derivatives 2 and the enantiomers of both cis- 4 and trans- 2-hydroxy-CBA 6 are summarized in Figure A. − …”

“…Representative multistep sequences leading to cis-3-hydroxycyclobutylamine (CBA) derivatives 2 and the enantiomers of both cis-4 and trans-2-hydroxy-CBA 6 are summarized in Figure 1A. [4][5][6][7]pent-1-ylamine (BCPA), a more globular CBA rigidified by virtue of an additional 1,3-methano bridge, presents defined potential exit vectors extending threedimensionally. 8 BCPA itself is incorporated into pharmaceutical candidates as an aniline bioisostere, and the readily accessible 3-substituted BCPAs act as bioisosteric replacements for para-substituted aniline linkages (e.g., 7, Figure 1B).…”