17. Iridium-Catalyzed Selective Isomerization of Primary Allylic Alcohols
This Account presents the development of the iridium-catalyzed isomerization of primary allylic alcohols in our laboratory over the past 8 years. Our initial interest was driven by the long-standing challenge associated with the development of a general catalyst even for the nonasymmetric version of this seemingly simple chemical transformation. The added value of the aldehyde products and the possibility to rapidly generate molecular complexity from readily accessible allylic alcohols upon a redox-economical isomerization reaction were additional sources of motivation. Certainly inﬂuenced by the success story of the related isomerization of allylic amines, most catalysts developed for the selective isomerization of allylic alcohols were focused on rhodium as a transition metal of choice. Our approach has been based on the commonly accepted precept that hydrogenation and isomerization are often competing processes, with the latter being usually suppressed in favor of the former. The cationic iridium complexes [(Cy3P)(pyridine)Ir(cod)]X developed by Crabtree (X = PF6) and Pfaltz (X = BArF) are usually considered as the most versatile catalysts for the hydrogenation of allylic alcohols. Using molecular hydrogen to generate controlled amounts of the active form of these complexes but performing the reaction in the absence of molecular hydrogen enabled deviation from the typical hydrogenation manifold and favored exclusively the isomerization of allylic alcohols into aldehydes. Isotopic labeling and crossover experiments revealed the intermolecular nature of the process. Systematic variation of the ligand on the iridium center allowed us to identify the structural features beneﬁcial for catalytic activity. Subsequently, three generations of chiral catalysts have been investigated and enabled us to reach excellent levels of enantioselectivity for a wide range of 3,3-disubstituted aryl/alkyl and alkyl/alkyl primary allylic alcohols leading to β-chiral aldehydes. The combination of the isomerization reaction with enamine catalysis in a sequential process gave access to α,β-chiral aldehydes in high diastereomeric ratio and excellent enantioselectivity. Catalyst-controlled diastereoselective isomerization of stereochemically complex steroid scaﬀolds has been achieved, giving access indiﬀerently to derivatives with the natural and unnatural C20 conﬁguration, a long-standing challenge in the ﬁeld. Structural diversiﬁcation at close proximity of the reactive site and within the polycyclic domain served to further demonstrate the generality and the potential of the method. Models based on quadrant diagrams enabled rationalization of the high levels of enantio- and diastereocontrol obtained in the isomerization of allylic alcohols.