Iridium-Catalyzed Selective Isomerization of Primary Allylic Alcohols

Abstract

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.

Iridium‐Catalyzed Asymmetric Isomerization of Primary Allylic Alcohols Using MaxPHOX Ligands: Experimental and Theoretical Study

“…Here we have studied the use of the P-stereogenic ligands MaxPHOX to the catalytic asymmetric isomerization of allylic alcohols to aldehydes. This family of ligands has four possible diastereomers (1)(2)(3)(4) that can be fine-tuned by changing the oxazoline substituent (a: Ph; b: iPr or c: tBu). The isomerization of (E)-3,3-disubstituted allyl alcohols with aromatic and isopropyl groups gave excellent yields and enantioselectivities (up to 96 % ee) using catalyst 3 c. With less reactive substrates the reactivity can be improved using catalyst 3 b.…”

“…As a pioneering example, Noyori's asymmetric isomerization of allylic amines to optically active enamines, catalyzed by rhodium-BINAP complexes stands out as one of the most industrially relevant catalytic reactions. [3] In contrast, although some studies have been reported in the last decade, [4] the asymmetric isomerization of allylic alcohols still lacks general and efficient synthetic protocols.…”

Encapsulation of Crabtree's Catalyst in Sulfonated MIL‐101(Cr): Enhancement of Stability and Selectivity between Competing Reaction Pathways by the MOF Chemical Microenvironment

“…The reaction pathways for the hydrogenation or isomerization of olefinic alcohols with the homogeneous catalyst 2‐PF 6 likely share the same starting point, the formation of a cationic Ir III ‐dihydride complex in which the hydroxyl group is also coordinated to Ir (Scheme , intermediate I ), followed by migratory insertion (intermediate II ) . Bifurcation into separate, competitive pathways then occurs: i) hydrogenation to the respective alcohol via reductive elimination (pathway A ) or ii) isomerization to the internal olefin via β‐elimination, which requires an appropriately orientated vacant coordination site, followed by off‐cycle tautomerization to the aldehyde (pathway B ).…”

Encapsulation of Crabtree's Catalyst in Sulfonated MIL‐101(Cr): Enhancement of Stability and Selectivity between Competing Reaction Pathways by the MOF Chemical Microenvironment

“…Ther eaction pathways for the hydrogenation or isomerization of olefinic alcohols with the homogeneous catalyst 2-PF 6 likely share the same starting point, the formation of acationic Ir III -dihydride complex in which the hydroxyl group is also coordinated to Ir (Scheme 2, intermediate I), followed by migratory insertion (intermediate II). [13,14] Bifurcation into separate,competitive pathways then occurs:i )hydrogenation to the respective alcohol via reductive elimination (pathway A)orii) isomerization to the internal olefin via b-elimination, which requires an appropriately orientated vacant coordination site,f ollowed by off-cycle tautomerization to the aldehyde (pathway B).…”