Indene Derived Phosphorus‐Thioether Ligands for the Ir‐Catalyzed Asymmetric Hydrogenation of Olefins with Diverse Substitution Patterns and Different Functional Groups

Abstract

A family of phosphite/phosphinite‐thioether ligands have been tested in the Ir‐catalyzed asymmetric hydrogenation of a range of olefins (50 substrates in total). The presented ligands are synthesized in three steps from cheap indene and they are air‐stable solids. Their modular architecture has been crucial to maximize the catalytic performance for each type of substrate. Improving most Ir‐catalysts reported so far, this ligand family presents a broader substrate scope, covering different substitution patterns with different functional groups, ranging from unfunctionalized olefins, through olefins with poorly coordinative groups, to olefins with coordinative functional groups. α,β‐Unsaturated acyclic and cyclic esters, ketones and amides were hydrogenated in enantioselectivities ranging from 83 to 99% ee. Enantioselectivities ranging from 91 to 98% ee were also achieved for challenging substrates such as unfunctionalized 1,1′‐disubstituted olefins, functionalized tri‐ and 1,1′‐disubstituted vinyl phosphonates, and β‐cyclic enamides. The catalytic performance of the Ir‐ligand assemblies was maintained when the environmentally benign 1,2‐propylene carbonate was used as solvent.

P-Stereogenic Ir-MaxPHOX: A Step toward Privileged Catalysts for Asymmetric Hydrogenation of Nonchelating Olefins

“…In particular, we considered the hydrogenation of α,α-unsaturated exocyclic enones and α,α-unsaturated lactones and lactams, since the reduced products of these olefins are encountered in natural products and drugs . These substrates suffer from the same ring size limitation that was discussed for exocyclic olefins without a neighboring polar group . In our case, however, the hydrogenation of the exocyclic enones S49 and S50 using 4a proceeded with high enantioselectivities (up to 97%), comparable to the best ones, regardless of the size of the ring.…”

“…Even for the most studied trisubstituted olefins, there is still room for improvement. For example, the reduction of the so-called purely alkyl-trisubstituted olefins, those without functional groups or aryl substituents, has been achieved in very few cases and the effectiveness for exocyclic substrates needs to be improved . For tetrasubstituted olefins, only a few specific Ir-catalysts have provided high performance for certain substrates, with variable enantioselectivity and low functional group tolerance.…”

“…For example, the reduction of the so-called purely alkyl-trisubstituted olefins, those without functional groups or aryl substituents, has been achieved in very few cases 6 and the effectiveness for exocyclic substrates needs to be improved. 7 For tetrasubstituted olefins, only a few specific Ir-catalysts have provided high performance for certain substrates, with variable enantioselectivity and low functional group tolerance. Most of the substrates studied were restricted to cyclic olefins and only a few were acyclic, mainly trimethyl styrene derivatives, 7b , 8 until recently when Gosselin′s group in collaboration with Bigler, Pfaltz, and Denmark 9 presented the reduction of a wide range of acyclic olefins with two or more aryl substituents.…”

Towards Data‐Driven Design of Asymmetric Hydrogenation of Olefins: Database and Hierarchical Learning

“…These results are consistent with the substituent-based data extraction in methyl (Z)-2-acetamido-3-phenylacrylate (Figure 4d), which demonstrated that the hierarchical learning approach can apply to additional structural evaluation methods.U sing Morgan fingerprints-based data extraction, we also tested the hierarchical learning approach with out-of-sample examples from an ew AHO reference in 2021. [48] Consistently,t he hierarchical learning model led to improved predictive performance as compared to naive training and training with target substrate set (Table S8 and Figure S13-S15).…”

The Implications of the Brønsted Acidic Properties of Crabtree-Type Catalysts in the Asymmetric Hydrogenation of Olefins

“…Aside, olefin migration prior to hydrogenation can potentially lead to the reduction of unreactive olefins. Hydrogenations using deuterium gas are sometimes reported to give substantial amounts of deuterium incorporation in the allylic position, which is suggested to occur as a consequence of olefin migration. ,, Despite that other pathways can also lead to the observed deuterium scrambling, the migration of olefins under hydrogenative conditions remains a topic for further study …”