Enantioselective Cross-Coupling for Axially Chiral Tetra-ortho-Substituted Biaryls and Asymmetric Synthesis of Gossypol

Abstract

The axially chiral tetra-ortho-substituted biaryl skeleton exists in numerous biologically important natural products, pharmaceutical molecules, chiral catalysts, and ligands. The efficient synthesis of chiral tetra-ortho-substituted biaryl structures remains a challenging but unsolved problem. Among various asymmetric synthetic protocols, enantioselective Suzuki-Miyaura cross-coupling represents one of the most straightforward and versatile approaches. Herein we describe a powerful Suzuki-Miyaura coupling enabled by a P-chiral monophosphorus ligand BaryPhos, providing a broad range of synthetically challenging chiral tetra-ortho-substituted biaryls in excellent enantioselectivities and yields. In addition to the enhanced reactivity for sterically hindered cross-coupling, the rational design of BaryPhos also enabled a new catalysis mode of asymmetric cross-coupling involving noncovalent interactions between the ligand and two coupling partners to effect efficient stereoinduction. This protocol is robust and practical, allowing for a concise enantioselective synthesis of therapeutically valuable male contraceptive and antitumor agent gossypol.

Recent Developments in Enantioselective Transition Metal Catalysis Featuring Attractive Noncovalent Interactions between Ligand and Substrate

“…Recently, Tang and co-workers reported an enantioselective Suzuki-Miyaura cross-coupling to access axially chiral tetra- ortho -substituted biaryl molecules ( Figure 41 a). 154 The cross-coupling was enabled by a novel P -chiral monophosphorus ligand, BaryPhos, building on previous designs from the same group ( Figure 41 b). 155 A hydrogen bond donor was incorporated into the scaffold which was anticipated to allow for interaction with one of the coupling partners and provide organization during enantiodetermining reductive elimination.…”

Enantioselective total synthesis of parnafungin A1 and 10a-epi-hirtusneanine

“…Initial experiments on sterically hindered cross-coupling between aryl iodide 30 and 1, entry 4) did not provide any activities. Surprisingly, the addition of water turned out to be crucial for the transformation and AntPhos, a prominent ligand for both Miyaura borylation and Suzuki coupling with sterically hindered substrates, [38][39][40][41] providing the best yield for this transformation (67% yield) (Scheme 2, Table 1, entry 5 and 6). With 31 in hand, the Pd-catalyzed cross-coupling between 31 and 14 was carried out in THF/H 2 O with DIPEA as the base (Scheme 2, Table 2).…”

Biomimetic Approaches to the Synthesis of Natural Disesquiterpenoids: An Update

“…A completely different approach to obtain (−)-(R)-gossypol (108) was proposed in 2020 by Tang's group, where an enantioselective Suzuki-Miyaura cross-coupling was used as key reaction of the synthetic pathway [80]. Enatiomerically pure (−)-108 was obtained in ten synthetic steps from the easily accessible quinone 121 that was efficiently manipulated to obtain naphthylene 122.…”