Tuning the Peri Effect for Enantioselectivity: Asymmetric Hydrogenation of Unfunctionalized Olefins with the BIPI Ligands

Abstract

The modular nature of the BIPI ligands allows for systematic optimization of each ligand region. The development of ligands optimized for asymmetric hydrogenation of the challenging unfunctionalized olefin substrate class is described. The naphthyl peri position, C-8, has been identified as a critical stereocontrol element in the design of these ligands. Highly enantioselective ligands suitable for hydrogenation of tri-and tetrasubstituted olefins are detailed. COMMUNICATIONSA variety of structurally diverse BIPI ligands ( Figure 2) were converted to their cationic iridium-A C H T U N G T R E N N U N G (COD)BAr F complexes, and all were purified by silica gel chromatography. Only N-acyl-containing ligands were chosen, as we have previously shown that all successful AH ligands require this functionality. [5,6,9] There are four subclasses of possible substitution patterns when either aryl or alkyl groups are chosen for the phosphorus and imidazoline substituents of the ligand. Examples of all four types were thus selected so that the different systems could be compared. Methanol, CH 2 Cl 2 and toluene were examined as hydrogenation solvents for several of these complexes, and the highest conversions were consistently observed in CH 2 Cl 2 . Examination of these ligands in the asymmetric hydrogenation of dimethylindene 1 was then carried out under 1 bar of H 2 in CH 2 Cl 2 . The results for this screening set are shown in Table 1.The complexes derived from ligands with dialkylphosphines and diarylimidazolines (BIPI 81, 83, and 84) showed low conversion, low selectivity, or both. Ligands with aryl groups on phosphorus and carbon (BIPI 93,(201)(202)(203) 205) all gave full conversion, yet the highest selectivity observed was 89:11 er (BIPI 93). Aryl P-substitution paired with C-alkyl groups (BIPI 206) gave full conversion yet a diminished er of 84:16. The fourth subclass, with alkyl substitution for both elements, proved to be optimum as long as small alkyl groups (Et, i-Pr) were avoided. BIPI 207, with a phenyl ligand core and cyclohexyl on phosphorus, provided product 2 with full conversion and 94:6 er. When the analogous naphthyl core ligand to BIPI 207, (BIPI 210), was examined, quantitative conversion with a slightly higher selectivity (95:5 er) was observed.Thus, the advantage of the naphthyl core ligands over the phenyl core, first observed in functionalized olefin hydrogenations, may also be in effect for the unfunctionalized substrates. For the former substrate class, strong evidence for the importance of the naphthyl peri proton (H-8) was gathered. [6] This may involve conformational restriction of the phosphine substituents leading to increased selectivity.Efforts to incorporate a larger peri substituent on the naphthalene core were then undertaken. Fluoro-A C H T U N G T R E N N U N G imidazoline 3 with a methyl group at the peri position was prepared, yet the subsequent S N Ar reaction with the anion of dicyclohexylphosphine·borane failed (Scheme 1). The most likely explanation for this is the severe ste...

Asymmetric Hydrogenation of Unfunctionalized Tetrasubstituted Acyclic Olefins

“…The substrate scope is not restricted to the ( E )‐1,2‐dimethyl‐1,2‐diaryl substructure: several other ( E )‐1,2‐dialkyl‐1,2‐diaryl olefins (( E )‐ 2 r – y ), but also 1,1‐dialkyl‐2,2‐diaryl olefins ( 2 z and 2 aa ) and very challenging alkyl‐triaryl olefins ( 2 ae – ai ) were all hydrogenated with excellent yield, er, and dr. Importantly, catalyst ( R )‐ 1 o provided optimal results for all tested substrates, thus obviating the need to build up large catalyst libraries often required for other iridium‐based catalyst systems . Low enantioselectivity was observed only for extremely challenging substrates, that is, in which the Re ‐ and Si ‐faces are differentiated only by the electronic properties of the aromatic substituents (( Z )‐ 2 c and 2 ac ) or the length of an alkyl substituent ( 2 ab ) as well as for trialkyl‐aryl substrate 2 ad .…”

Sequential C–H Arylation and Enantioselective Hydrogenation Enables Ideal Asymmetric Entry to the Indenopiperidine Core of an 11β-HSD-1 Inhibitor

“…When the catalyst loading was decreased to an economically feasible level of 0.1 mol % [Ir(COD)Cl] 2 , less than 15% product formation was observed (last four ligands in bracket). Existing P,N-ligands including PHOX ligands, 23b Ph-LalithPhos, 28 and BIPI 210 29 produced unsatisfactory reactivity and enantioselectivity even with 1 mol % of [Ir(COD)Cl] 2 .…”

A Mild Dihydrobenzooxaphosphole Oxazoline/Iridium Catalytic System for Asymmetric Hydrogenation of Unfunctionalized Dialins

“…value of 99:1 at 10 °C with the opposite chirality. The ligand 5 c is more selective than the phosphine imidazoline ligands reported lately 18. The catalyst with the aminoindanyl‐substituted ligand 5 e produced an 80 % conversion in 89:11 e.r.…”