CHAPTER 5 Atroposelective Reactions 5.1 Introduction Atropisomerism, the phenomenon of chirality due to restricted rotation about a single bond, has been an intellectually intriguing and practically widely applicable area of stereochemistry from the first resolution of a chiral atrop- isomeric biaryl by Kenner in 1921 through the discovery of numerous naturally occurring atropisomeric molecules and the development of atropisomeric chiral ligands." A high point in the history of atropisomerism must be the central role played by the atropisomeric ligand BINAP in Professor Noyori’s share of the Nobel Prize for Chemistry in 2001 The last 50 yeurs has scen biaryl atropisomers emerging as a class of com- pounds rich in utility for the development of valuable chiral ligands, catalysts and a number of natural products.” Besides the conventional approach of direct, atroposelective biaryl coupling, highly efficient alternative strategies have been found in which the construction of the target biaryl species is carried out over two separate steps: a non-stereoselective C-C coupling reaction and a second step that finally establishes the absolute configuration at the biaryl axis. In order to introduce the stereochemical information at a preformed axis, the biaryl substrate has to be either rotationally hindered but achiral, or chiral but configurationally unstable. Owing to rapid atropisomeric interconversion, nonsymmetrical biaryl compounds can be used as substrates for DKR. One option, though rarely used, is the atropoenantiomer-differentiating introduction of another ortho substituent, which establishes and simultaneously locks the axial conformation (Section 5.4). Alternatively, atropoenantiomer- differentiating bridging of the two aromatic halves of the nonsymmetrical biaryl compound delivers axially chiral biaryl species if this process is asso- ciated with an increase in the rotational barrier sufficient to reach configura- tional stability (Section 5.5). On the other hand, biaryl compounds that are configurationally stable under normal conditions can undergo atropodiaster- comerisation if transiently bridged by a transition metal; this protocol can be Chirality from Dynamic Kinetic Resolution By Helene Pellissier © Helene Pellissier 2011 Published by the Royal Society of Chemistry, www.rsc.org 243244 Chapter 5 used for the DKR of biaryl species that are stereochemically stable under ordinary conditions (Section 5.6). In addition, the cleavage of a short bridge that causes configurational instability allows an elegant access named the ‘lactone concept’ to axially chiral biaryl products (Section 5.2). These main approaches are summarised in Scheme 5.1. x Y DKR by formati ofa bridge *) % 2 i “Y R wy SS DKR by cleavage ) 7 *) of a bridge Y Y ey A ae ef oss Rt 7>x AY DKR via a bridged | intermediate S SS Rt. et. et x __. x x, y yu = ye 2 Z 2 = re Rd Scheme 5.1 Atroposelective approaches to biaryl compounds through DKR.Atroposelective Reactions 245 In addition, the last fifteen years have seen families of atropisomers based on structures other than biaryls come forward as potential new sources of such structures, and atropisomeric anilides, benzamides and naphthamides have been used as chiral ligands, catalysts, auxiliaries and various starting materials. Indeed, a number of non-biaryl atropisomers have been successfully investi- gated for DKR 5.2 DKR by Atroposelective Cleavage of a Bridge Among the few established methods for the atroposelective construction of biaryl systems, the ‘lactone concept’ introduced by Bringmann’s group holds a unique position since it separates the biaryl bond formation step from the actual introduction of stereo-information.* The fundamental concept is sum- marised in Scheme 5.2. A bromoarene carboxylic acid reacts with a phenol to give the corresponding ester. This array permits the biaryl coupling to occur intramolecularly, even against strong steric hindrance, providing the corre- sponding lactones which are configurationally unstable. These lactones are the key intermediates in the concept since they can be ring opened with chiral nucleophiles according to the principle of DKR, establishing the axial configu- ration at the resulting now configurationally stable final biaryl products. Tron COLp Br [Pd] LS R R Cou Cou, R. 0 R oO ie unstable C) R R CO ww CO Nu'ML, ‘ —_ oO ° "() R “() OH R R Scheme 5.2 ‘Lactone concept’.