Asymmetric synthesis of biaryl atropisomers by dynamic resolution on condensation of biaryl aldehydes with (−)-ephedrine or a proline-derived diamine

Abstract

Atropisomeric biaryl aldehydes undergo diastereoselective condensation with (−)-ephedrine and with a proline-derived diamine, with selectivity highly dependent on solvent, temperature and reaction conditions. Levels of thermodynamic control up to 5:1 may be obtained by heating the diamine with the aldehyde in a sealed tube. Alternatively, crystallisation-induced dynamic transformation allows isolation of a single diastereoisomer in up to 85% yield. Hydrolysis and reduction of the major diastereoisomeric product of the reaction yields atropisomeric biaryls in >99:1 enantiomeric ratios.

State of the Art in Crystallization‐Induced Diastereomer Transformations

“…Due to the fact that many different terms were employed to describe CIDT, it is likely that some relevant CIDT examples are easily and repeatedly overlooked by people conducting a literature survey. Hence it is worthwhile to note that over the last years, in addition to the terms stated above, the following alternative names have been used: [29] crystallizationinduced (CI) dynamic transformation, [30] CI dynamic atroposelective resolution, [31] CI configuration transformation, [32] asymmetric transformation by dynamic crystallization, [33] deracemization by dynamic salt formation, [34] diastereoconvergent crystallization, [35] and dynamic crystallization-driven condensation. [36] In principle, AT1 is an integral part of dynamic kinetic resolutions (DKR) [37] and dynamic thermodynamic resolutions (DTR).…”

“…With the aim of conformational control studies, the Clayden group prepared a series of proline-and ephedrine-derived biphenyl atropisomers. [30] They found out that upon reflux in toluene and a subsequent solvent switch to iPrOH, MeO-substituted substrates 184 and 186 underwent CIDT, providing P-184 and P-186 in 81% and 85% yield, respectively (Scheme 67). Interestingly, analogous experiments in benzene and xylenes were unsuccessful.…”

Biocatalytic Dynamic Kinetic Resolution for the Synthesis of Atropisomeric Biaryl N‐Oxide Lewis Base Catalysts

“…For a practical biocatalytic DKR this substrate racemization must take place on a timescale of minutes or less, within a temperature range at which the enzyme can operate (typically 20–50 °C), while the product must be atropisomerically stable over, at least, a time period of hours at this temperature. We reasoned that such a substantial decrease in racemization rate could be achieved by a functional‐group interconversion in which a small, planar substituent, such as an aldehyde, is converted into a larger, tetrahedral substituent . Atropisomeric alcohols of the general structure 3 (see Scheme ) are useful chiral ligands for asymmetric synthesis, so we set out to explore the possibility of making them enantioselectively by dynamic kinetic resolution of the biaryl aldehydes 1 .…”

Atropisomerism in Medicinal Chemistry: Challenges and Opportunities

“…While a large number of rapidly interconverting atropisomers are scaffolds such as biaryls or heterobiaryls that are readily recognized as potentially atropisomeric, there are also numerous instances of scaffolds whose atropisomerism is often overlooked. For example, diaryl ethers are often not considered to be atropisomeric as they possess lower stereochemical stabilities than biaryls; however, many diaryl ethers in the literature are known to have barriers to racemization >117 kJ/mol (28 kcal/mol) [34][35][36][37]. Diaryl ethers are also perhaps more complex than more traditional atropisomer classes as they innately have two potential axes of chirality.…”