Computationally Assisted Mechanistic Investigation and Development of Pd-Catalyzed Asymmetric Suzuki–Miyaura and Negishi Cross-Coupling Reactions for Tetra-ortho-Substituted Biaryl Synthesis

Abstract

Metal-catalyzed cross-coupling reactions are extensively employed in both academia and industry for the synthesis of biaryl derivatives for applications to both medicine and material science. Application of these methods to prepare tetra-ortho-substituted biaryls leads to chiral atropisomeric products that introduces the opportunity to use catalyst-control to develop asymmetric cross-coupling procedures to access these important compounds. Asymmetric Pd-catalyzed Suzuki-Miyaura and Negishi cross-coupling reactions to form tetra-ortho-substituted biaryls were studied employing a collection of P-chiral dihydrobenzooxaphosphole (BOP) and dihydrobenzoazaphosphole (BAP) ligands. Enantioselectivities of up to 95:5 and 85:15 er were identified for the Suzuki-Miyaura and Negishi cross-coupling reactions, respectively. Unique ligands for the Suzuki-Miyaura reaction vs the Negishi reaction were identified. A computational study on these Suzuki-Miyaura and Negishi cross-coupling reactions enabled an understanding in the differences between the enantiodiscriminating events between these two cross-coupling reactions. These results support that enantioselectivity in the Negishi reaction results from the reductive elimination step, whereas all steps in the Suzuki-Miyaura catalytic cycle contribute to the overall enantioselection with transmetalation and reductive elimination providing the most contribution to the observed selectivities.

Enantioselective Synthesis of Atropisomeric Biaryls using Biaryl 2,5‐Diphenylphospholanes as Ligands for Palladium‐Catalysed Suzuki‐Miyaura Reactions

“…Coupling of the more sterically hindered 2‐substituted napthalenylboronic acids proved to be challenging under these conditions. As has been reported with other catalyst systems, [8d,n] poor reactivity at room temperature and/or competitive protodeboronation was observed. For tetra‐ ortho substituted binaphthyls 7 u – w only trace amounts of product were obtained after extended reaction times at elevated temperatures.…”

“…The OA step can be highly selective for the distal channel and/or there is crossover between the two channels before the RE allowing a Curtin‐Hammett situation also at this stage. Equilibration of the distal and proximal ensembles could occur via ligand dissociation, reversible oxidative addition, [8d] or via the “oscillatory” mechanism proposed by Buchwald and co‐workers [13a] . Assuming that such a mechanism is also operative for the o‐ tolyl product 7 b , the lowest distal TS is again favoured over the lowest energy proximal TS, in this case by ∼14 kJ/mol.…”

“…To investigate the source of the stereoselectivity we studied the reaction pathways leading to product 7 b by DFT, for ligands L7 and L8 . Following a report by Patel et al ., [8d] we have located all intermediates after the oxidative addition (OA) and transmetallation (TM) steps, and the transition states for the reductive elimination (RE) steps, validated by QRC calculations [25] to confirm the connection to the preceding intermediate and the resulting enantiomer of the final coupling product. Calculations were performed at the B3LYP−D3/LACVP* level in Jaguar [26]…”

“…[5] Asymmetric transition-metal-catalysed cross-couplings are strategically attractive as the chiral axis can be forged directly from two pre-formed fragments, and the Suzuki-Miyaura reaction [6] offers additional practical advantages (air-and water-stability, low toxicity, ready availability) with regards to the coupling partners. [7] Although some noteworthy advances have been made recently, [8] the atroposelective variant of the Suzuki-Miyaura reaction remains under-developed. The discovery of new ligands for these transformations is therefore of interest to medicinal chemists as well as the wider synthetic community.…”

Pd-catalyzed asymmetric Suzuki–Miyaura coupling reactions for the synthesis of chiral biaryl compounds with a large steric substituent at the 2-position

“…No matter it was a straight alkyl chain, a branched alkyl chain, a heterocyclic group, an electron-rich aromatic or an electron-deficient aromatic group, the reaction always performed well with high yield and good enantioselectivity. We guess that the large sterically hindered π-plane formed between a carbonyl group and a benzene ring is the guarantee of high ee values of the product [13,39,42,57,65] along with the Pd•••O interaction [13,64] between carbonyl and palladium. The experimental results also show that the substituent of the arylboronic acid has an obvious effect on the reaction: the yield and ee value of the product decrease with the increase of the steric hindrance of the 4-substituted boronic acid.…”