Recent advances and new concepts for the synthesis of axially stereoenriched biaryls

Abstract

Axial chirality is a key feature of many important organic molecules, such as biologically active compounds, stereogenic ligands and optically pure materials. Significant efforts in the field of the atropisomeric synthesis of biaryls have hence been undertaken over the past decade. Several major improvements of the already known methods to build up such chiral backbones (e.g. oxidative couplings and stereoselective Suzuki-Miyaura arylations) have been achieved and, in parallel, novel concepts have emerged enabling unprecedented synthetic routes toward molecules of this kind. These outstanding steps further unlocked the door to the preparation of previously difficult-to-access precursors of privileged ligands like BINOL, BINAM, QUINAP and many other molecules of interest.

Synthesis of axially chiral biaryl compounds by asymmetric catalytic reactions with transition metals

“…Two of them present a positive action on the reaction, promoting the transmetalation and reductive elimination steps whereas the last one, i.e. the formation of a boronate anion [Ar'B(OH) 3 ] -, shows a negative effect. The reaction rate increases with the base concentration, as the addition of OH -to L 2 Pd(X)Ar gives rise to L 2 Pd(OH)Ar, a more reactive compound for the transmetalation step (pathway A -Scheme 3.4).…”

“…After the early attempts of naphthol enantioselective oxidative coupling with Co(acac) 3 in the presence of chiral Ru(II) complexes as photosensitizers [173] or by electrocatalytic coupling on a TEMPO-modified graphite felt electrode [174], the first successful use of complexes with metals other than copper in this reaction was described by Katsuki and coworkers using a chiral ruthenium salen complex (95) (Scheme 6.11) [175]. Good yields (up to 93%) and enantioselectivities (up to 69% ee) of various disubstituted 1,1'-bis-2,2'-binaphthols were obtained.…”

“…Computational studies on a PdX(Ar)L 2 model (Ar = C 2 H 3 and L = PH 3 ) have shown that even if the direct isomerization (through an unstable tetrahedral d 8 complex) is energetically consistent (around 20 kcal/mol), there is an alternative, less energetically demanding pathway (< 6 kcal/mol) involving phosphine dissociation or other ligand coordination (such as OH-) [53,60]. These results indicate that the isomerization step should not be a critical barrier for the overall process.…”

“…The ligands proved particularly active for the coupling of chloroarenes and sterically hindered substrates. However when an enantioenriched version of ligand 34 (37-40% ee) was engaged in the coupling of 1-bromo-2-methylnaphthalene with 2-methoxyphenylboronic acid in the presence of Pd 2 (dba)3 (0.5 mol% in Pd, Pd/L* = 1/2), reasonable yields of the biaryls were obtained (54% at 50°C and 91% at 100°C) but ees were very poor (1-4%). One obvious explanation would be the low ee of the chiral ligand, but the enantiopure version of the latter was not described.Recently, Deydier, Manoury et al[103] reported a kinetic study using P,O ligands bearing planar or planar and central chirality, 35 and 36(Figure 3.9), with a different steric the most crowded ligand 36 (slower kinetics), presenting both planar and central chirality, afforded the best results with 60% conversion and 37% ee at 40°C in toluene after 2 h (75% conversion after 24 h with a total selectivity in the expected product).d) P,aryl ligands with planar chiralityIn 2003, Johannsen et al reported the synthesis and application in the Suzuki-Miyaura coupling of a series of electron-rich aryl-ferrocenyl dicyclohexylphosphines[101] (37,Figure 3.10, Scheme 3.22) considered as pseudo-dialkylbiarylphosphines such as those developed by the group of Buchwald.…”

“…The atroposelective synthesis of axially chiral biaryl compounds has been highlighted in a few recent reviews [1,2,3], but in contrast to those, ours will focus exclusively on the generation of axially chiral biaryl structures by means of asymmetric catalytic reactions with transition metals. The present review is meant to give a comprehensive contribution to the field as it includes, to our knowledge, all the references that appeared in the relevant areas from the first report up to the end of 2014.…”