Diastereoselective Synthesis of a cis-1,3-Disubstituted Cyclobutane Carboxylic Acid Scaffold for TAK-828F, a Potent Retinoic Acid Receptor-Related Orphan Receptor (ROR)-γt Inverse Agonist

Abstract

A scalable synthesis of the cis-1,3-disubstituted cyclobutane carboxylic acid scaffold of TAK-828F (1) has been developed, featuring the diastereoselective reduction of a cyclobutylidene Meldrum's acid derivative with NaBH 4 . Controlling acidic impurities was crucial for improving the diastereomeric ratio by recrystallization. Furthermore, reaction optimization and the streamlining of several steps established a scalable synthetic method free from column chromatography purification with an overall yield improved from 23 to 39%.

Functionalized Alkylidenecyclobutanes from a Cyclopent‐2‐enone Substrate via a Tandem Photochemical Transformation and an Allylic Substitution Protocol

“…Classical approaches for the synthesis of alkylidenecyclobutanes include reactions of nucleophilic carbon reagents with cyclobutanones [8] and allene‐alkene cycloadditions [9] and have been comprehensively reviewed [4] . More recent strategies include transformations of α‐cyclobutylallylboronates, [10] ring expansion of alkynylcyclopropanes, [11] vinylidene insertion into cyclopropanones [12] and transition‐metal catalyzed cyclizations [13] .…”

C(sp2)–H cyclobutylation of hydroxyarenes enabled by silver-π-acid catalysis: diastereocontrolled synthesis of 1,3-difunctionalized cyclobutanes

“…Cyclobutanes represent important structural units in natural products and other biologically significant molecules. 1 Moreover, the cyclobutane scaffold, especially the 1,3-difunctionalized cyclobutane skeleton, is often incorporated in drug design, such as PF-03654746, 2 linsitinib, 3 and TAK-828F 4 ( Scheme 1A ). In these cases, a 1,3-substituted cyclobutane linker can act as an aryl isostere with reduced planarity; flexible ethyl- or propyl-linkers can also be replaced by conformationally restricted 1,3-disubstituted cyclobutanes to limit the number of possible conformations.…”

C(sp2)−H Cyclobutylation of hydroxyarenes enabled by silver-π-acid catalysis: diastereocontrolled synthesis of 1,3-difunctionalized cyclobutanes

“…Cyclobutanes represent important structural units in natural product and other biologically significant molecules. 1 Moreover, the cyclobutane scaffold, especially 1,3-difunctionalized cyclobutane skeleton, is often incorporated in drug design, such as PF-03654746, 2 linsitinib, 3 and TAK-828F 4 (Scheme 1A). In these cases, 1,3-substituted cyclobutane linker can act as an aryl isosteres with reduced planarity; flexible ethyl-or propyl-linkers can also be replaced by conformationally restricted 1,3disubstituted cyclobutanes to limit the number of possible conformations.…”