Atroposelective Synthesis of Axially Chiral Biaryl Compounds

Abstract

A rotationally hindered and thus stereogenic biaryl axis is the structurally and stereochemically decisive element of a steadily growing number of natural products, chiral auxiliaries, and catalysts. Thus, it is not surprising that significant advances have been made in the asymmetric synthesis of axially chiral biaryl compounds over the past decade. In addition to the classic approach (direct stereoselective aryl-aryl coupling), innovative concepts have been developed in which the asymmetric information is introduced into a preformed, but achiral-that is, symmetric or configurationally labile-biaryl compound, or in which an aryl--C single bond is stereoselectively transformed into an axis. This Review classifies these strategies according to their underlying concepts and critically evaluates their scope and limitations with reference to selected model reactions and applications. Furthermore, the preconditions required for the existence of axial chirality in biaryl compounds are discussed.

Photochemical direct perfluoroalkylation of phenols

“…Interestingly, the perfluoroalkylated adducts o-5b-d exhibited axial chirality. 16 This was due to the steric interactions between the ortho-methyl substituent on the pendant aryl moiety and the perfluoralkyl fragment which precluded the possibility for the aryl-aryl single bond to freely rotate. Rotationally hindered biaryl axes are important stereogenic elements found in a number of natural products, chiral auxiliaries, and catalysts.…”

A twist of nature – the significance of atropisomers in biological systems

“…2,3 It is important to note that more than one bond may be hindered to give rise to atropisomerism. Unlike stereogenicity arising from point chirality, which may only be altered through the breaking and reformation of chemical bonds, the configuration of atropisomers is governed primarily by their thermodynamic environment.…”

“…The past decade has seen a marked increase in the identification and appreciation of atropisomers as specific drug leads, which has driven the development of new synthetic techniques to allow the stereoselective generation of derivatives. 3 Given the significance of stereoisomerism and the wealth of molecular structures that natural product chemistry provides, there is a need to highlight the modern emphases in atropisomeric stereochemistry; in particular the requirement for more awareness of its existence, especially in emerging studies on natural products. This review is by no means a comprehensive overview of all natural molecules exhibiting atropisomerism.…”

“…11 and 12 are homodimers comprised of two atrochrysone moieties connected via the atropisomeric bond; wheras 13 and 14 are heterodimers comprised of an atrochrysone moiety (right of atropisomeric bond) and an ether derivative of atrochrysone (left of atropisomeric bond). Currently, there are no reported syntheses for these specific natural products, though it is evident that an atropselective biaryl coupling utilising one of the many well-established techniques (see review by Bringmann et al) 3 may be applied to such an end. The biosynthesis of these dimeric compounds also remains ambiguous; though related dihydroanthracenones have been reported for higher order plants, the pathways involved for fungal production may differ significantly, and so cannot be subjected to speculation.…”

Principles, Concepts and Strategies of Stereoselective Synthesis

“…As a result of the large energy barriers between different conformations, atropisomers interconvert slowly enough (by definition, with a half-life of >1000 s) so that they can be easily isolated. 21,22 To interconvert the BINAP-enantiomers, the PPh 2 group would have to force its way passed either the other PPh 2 group or the hydrogen. Both pathways are too strained for racemization to occur (Figure 1.24).…”