Axial shielding of Pd(II) complexes enables perfect stereoretention in Suzuki-Miyaura cross-coupling of Csp3 boronic acids

Abstract

Stereocontrolled Csp3 cross-coupling can fundamentally change the types of chemical structures that can be mined for molecular functions. Although considerable progress in achieving the targeted chemical reactivity has been made, controlling stereochemistry in Csp3 cross-coupling remains challenging. Here we report that ligand-based axial shielding of Pd(II) complexes enables Suzuki-Miyaura cross-coupling of unactivated Csp3 boronic acids with perfect stereoretention. This approach leverages key differences in spatial orientation between competing pathways for stereoretentive and stereoinvertive transmetalation of Csp3 boronic acids to Pd(II). We show that axial shielding enables perfectly stereoretentive cross-coupling with a range of unactivated secondary Csp3 boronic acids, as well as the stereocontrolled synthesis of xylarinic acid B and all of its Csp3 stereoisomers. We expect these ligand design principles will broadly enable the continued search for practical and effective methods for stereospecific Csp3 cross-coupling.

Emerging Building Blocks for Medicinal Chemistry: Recent Synthetic Advances

“…Moreover, the preparative conditions for the ligand-controlled enantiodivergent cross-coupling were developed by Biscoe and Burke groups in 2018-2019. [68,69] Formation of stereopure products could be also achieved through the substrate control (see Scheme 1B). [70] A complementary approach based on single-electron transfer (SET) processes was proposed to overcome the challenges of the C(sp 3 )À C(sp 2 ) coupling related to lowered activity of saturated boronates, their propensity to β-hydride elimination, and in some cases -their modest stability under the reaction conditions.…”

Isolation and Catalytic Reactivity of Mononuclear Palladium(I) Complexes

“…In order to analyze the catalytic competency of the isolated Pd I complexes, the Kumada crosscoupling reaction between bromobenzene and a secondary alkyl nucleophile, cyclohexylMgCl, was employed, since such Csp 3 -Csp 2 cross-coupling reactions catalyzed by Pd are rare. 16,[35][36][37][38] The Pd-2 complex, either generated in situ or used as isolated, shows very good catalytic activity (86% by GC-FID) under mild conditions (Table 2, entries 1 and 2, respectively), and a gram-scale reaction reveals a similar yield (Fig. S38).…”

Saturated Boronic Acids, Boronates, and Trifluoroborates: An Update on Their Synthetic and Medicinal Chemistry

“…[64] Example can be provided by the works of Biscoe and Burke groups that independently described conditions for both stereoretentive and stereoinversive CÀ C coupling with trifluoroborates of type 47 (Scheme 14 C). [ 65,66] Analysis of the medicinal chemistry literature shows that among saturated boronic acids, boronates, and trifluoroborates, cyclopropane derivatives have been used most often in early drug discovery to date, with over 200 citations in J. Med. Chem., ACS Med.…”