General access to cubanes: ideal bioisosteres of ortho-, meta-, and para-substituted benzenes

Abstract

The replacement of benzene rings with sp3-hybridized bioisosteres in drug candidates generally improves pharmacokinetic properties while retaining biological activity. Rigid, strained frameworks such as bicyclo[1.1.1]pentane and cubane are particularly well-suited since the ring strain imparts high bond strength and thus metabolic stability on its C–H bonds. Cubane is the ideal bioisostere since it provides the closest geometric match to benzene. At present, however, all cubanes in drug design, like almost all benzene bioisosteres, act solely as substitutes for mono- or para-substituted benzene rings. This is due to the difficulty of accessing 1,3- and 1,2-disubstituted cubane precursors. The adoption of cubane in drug design has been further hindered by the incompatibility of cross-coupling reactions with the cubane scaffold, owing to a competing metal-catalyzed valence isomerization. Herein, we disclose expedient routes to 1,3- and 1,2-disubstituted cubane building blocks using a convenient cyclobutadiene precursor and a photolytic C–H carboxylation reaction, respectively. Moreover, we leverage the slow oxidative addition and rapid reductive elimination of copper to develop C–N, C–C(sp3), C–C(sp2), and C–CF3 cross-coupling protocols. Our research enables facile elaboration of all cubane isomers into drug candidates thus enabling ideal bioisosteric replacement of ortho-, meta-, and para-substituted benzenes.

Spiro[3.3]heptane as a Saturated Benzene Bioisostere**

“…The reaction was compatible with active chlorine (6, 7), and bromine (8, 9, 11, 12) atoms; silyl groups (13)(14)(15), N-Ts groups (17,18), and even with the azetidine ring (17). The reaction worked equally well for alkenes with aliphatic (1-18) and aromatic (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29) substituents. Amides of substituted cyclobutane carboxylic acids gave the desired racemic spiro-[3.3]heptanes 30-39 too.…”

“…In strict contrast to approved drugs, the use of racemic mixtures in primary biological testing in medicinal chemistry is common. [25] Therefore for the validation of the proof-of-concept, [26][27][28] we directly studied the biological activity of the available racemic compounds trans-76 and cis-76 (for details see the Supporting Information, pages 271-272).…”

Applications of Bioisosteres in the Design of Biologically Active Compounds

“…Articles and patent applications published between 2016 and 2022 where a CUB substructure is associated with a process or preparative procedure dominate those related to a biological study, typically by 2- to 3-fold, although the ratio is substantially higher prior to 2016, as summarized in Figure B. The number of publications exploring CUBs in a biological setting increased significantly in 2016, the year that Eaton’s hypothesis was affirmed experimentally, but the volume of literature amounts to approximately 10% of that for BCPs. , This may be surprising given that the interest in preparative methodologies to access CUB rings has a longer history than BCPs; however, there remains an abiding interest in the CUB chemotype as a potentially versatile phenyl mimic, with new approaches to the synthesis and decoration of this bicycle continuing to be developed …”

“…205,206 This may be surprising given that the interest in preparative methodologies to access CUB rings has a longer history than BCPs; however, there remains an abiding interest in the CUB chemotype as a potentially versatile phenyl mimic, with new approaches to the synthesis and decoration of this bicycle continuing to be developed. 222 Replacement of the red-colored phenyl rings in the histone deacetylase (HDAC) inhibitor vorinostat (170), the anesthetic benzocaine (172), the nerve growth factor stimulant leteprinim (173), and the insecticide diflubenzuron (174) with a CUB moiety fully preserved their biological properties, with the effect for the latter attributed to enhanced metabolic stability. 223 However, both CUB homologues of 171, which is a topical treatment for scabies and lice, as well as the analogue containing two CUB rings, were inactive.…”