Iterative, Chemoselective, Enantiospecific, Protecting Group Free Cross-Coupling of Polyboronates

Abstract

The Suzuki-Miyaura cross-coupling reaction is broadly defined as a palladium or nickel catalyzed C-C bond forming reaction occurring between a halide or pseudo-halide electrophile and an organoboron nucleophile. The extreme importance and power of the Suzuki-Miyaura cross-coupling reaction was recognized in 2010 when its discoverer and prolific developer, Professor Akira Suzuki, was awarded one-third of the Nobel Prize ‘for palladium-catalyzed cross-couplings in organic synthesis’. This decision was widely applauded by the scientific community, both in industry and academia, which had long recognized the value and impact of this discovery. Despite its discovery in 1979 the Suzuki-Miyaura reaction has, until recently, remained confined to the realm of assembling ‘flat’ molecules. It is extremely efficient and reliable in its construction of Csp2- Csp2 bonds namely in the synthesis of stereodefined polyenes, vinylarenes, and biaryl motifs, but much less so when a Csp3 partner is involved. The poor performance of Csp3 coupling partners is particularly acute in secondary aliphatic compounds; these are the compounds required to engage in cross-coupling to synthesize stereodefined C-C bonds. However, since the turn of the century, solutions have begun to emerge to this persistent problem. The Crudden group contributed significantly to leading this charge when, in 2009, the first report of an enantiospecific cross-coupling of secondary benzylic pinacol boronates was published. This helped to ignite a renewed interest in developing an asymmetric variant for this Nobel Prize winning reaction. Described herein is the application of this innovative achievement to the successful development of an intriguing methodology. We have successfully exploited the difference in reactivity of B-Csp2 and B-Csp3 bonds towards an iterative cross-coupling strategy that is devoid of protecting groups. Furthermore, where stereodefined B-C bonds are subjected to the reaction, the stereochemical outcome of the reaction is good to excellent. The applicability of this methodology to a known active pharmaceutical ingredient was also achieved.