Employing the Structural Diversity of Nature: Development of Modular Dipeptide‐Analogue Ligands for Ruthenium‐Catalyzed Enantioselective Transfer Hydrogenation of Ketones

Abstract

A library of novel dipeptide-analogue ligands based on the combination of tert-butoxycarbonyl(N-Boc)-protected alpha-amino acids and chiral vicinal amino alcohols were prepared. These highly modular ligands were combined with [[RuCl(2)(p-cymene)](2)] and the resulting metal complexes were screened as catalysts for the enantioselective reduction of acetophenone under transfer hydrogenation conditions using 2-propanol as the hydrogen donor. Excellent enantioselectivity of 1-phenylethanol (up to 98 % ee) was achieved with several of the novel catalysts. Although most of the ligands contained two stereocenters, it was demonstrated that the absolute configuration of the product alcohol was determined by the configuration of the amino acid part of the ligand. Employing ligands based on L-amino acids generated S-configured products, and catalysts based on D-amino acids favored the formation of the R-configured alcohol. The combination N-Boc-L-alanine and (R)-phenylglycinol (Boc-L-Ab) or its enantiomer (N-Boc-D-alanine and (S)-phenylglycinol, Boc-D-Aa) proved to be the best ligands for the reduction process. Transfer hydrogenation of a number of aryl alkyl ketones were evaluated and excellent enantioselectivity, up to 96 % ee, was obtained.

Oxazoline‐Substituted Prolinamide‐Based Organocatalysts for the Direct Intermolecular Aldol Reaction between Cyclohexanone and Aromatic Aldehydes

“…A comparison of -and -proline-based diastereoisomers 1b and 1bЈ, respectively, clearly shows that the absolute stereochemistry is determined by the proline fragment and that catalyst 1b should be considered the matched combination and 1bЈ the mismatched diastereoisomer. Furthermore, a comparison of the performance of prolinamides 1a-c against their unsubstituted N-aryl counterpart 9, [14,15] prepared according to the peptide coupling procedure in Scheme 2, strongly suggests that the oxazoline fragment influences both the conversion and enantioselectivity (Table 3, Entry 5) and could be used to fine-tune/ optimise the catalyst. At this stage, the use of a stereochemical model to explain the influence of the oxazoline fragment on the enantioselectivity would be too speculative and a more detailed structure-selectivity study will be required to establish the role of this substituent in determining catalyst performance.…”

“…Purification of the crude product by column chromatography on silica gel (CH 2 Cl 2 /methanol, 9:1) gave the pure title compounds. N-{2-[(3aS,8aR)-8,8a-Dihydro-3aH-indeno(1,2-d) (S)-tert-Butyl-2-(phenylcarbamoyl)pyrrolidine-1-carboxylate (8): [15] N-methylmorpholine (0.91 mL, 8.25 mmol) and isobutylchloroformate (1.08 mL, 8.25 mmol) were added slowly to a solution of Boc--proline (1.62 g, 7.50 mmol) in THF (10 mL) at -15°C and stirred for 3 h. After this time, aniline (0.70 g, 7.50 mmol) was added, and the reaction mixture was stirred overnight at r.t. The reaction mixture was then filtered through silica with ethyl acetate (200 mL), and the solvent was removed under reduced pressure to leave a white powder.…”

“…m/z (%) = 290 (15) (S)-N-Phenylpyrrolidine-2-carboxamide (9): [14] This compound was prepared by the same procedure as that described above for 1a-c from (S)-tert-butyl-2-(phenylcarbamoyl)pyrrolidine-1-carboxylate (8) (1.20 g, 4.13 mmol). Yield: 0.382 g, 49 %.…”

Phosphite–oxazoline ligands for Rh-catalyzed asymmetric hydrosilylation of ketones

“…The results of using the rest of the phosphite-oxazoline ligands (1)(2)(3)(4)(5)(6)(7)(8) under the optimized conditions are showed in Table 2.…”

Optically Active (Peptido‐carbene)palladium Complexes: Towards True Solid‐Phase Combinatorial Libraries of Transition Metal Catalysts

“…Recently, Adolfsson used dipeptide-derived ligands for ruthenium-catalysed enantioselective transfer hydrogenation. [20] Inspired by these contributions, we now report the first solid-phase synthesis of carbene ligands and their palladium complexes with peptide backbones as chiral architectures. With a suitable carbene precursor containing the necessary functional groups for incorporation into the peptide chain, the combinatorial synthesis of carbene ligands is feasible.…”