Resolution of Racemic 2-Aminocyclohexanol Derivatives and Their Application as Ligands in Asymmetric Catalysis

Abstract

A preparatively easy and efficient protocol for the resolution of racemic 2-aminocyclohexanol derivatives is described, delivering both enantiomers with >99% enantiomeric excess (ee) by sequential use of (R)- and (S)-mandelic acid. A simple aqueous workup procedure permits the isolation of the amino alcohols in analytically pure form and the almost quantitative recovery of mandelic acid. Debenzylation of enantiopure trans-2-(N-benzyl)amino-1-cyclohexanol by hydrogenation and subsequent derivatization give access to a broad variety of diversely substituted derivatives. Furthermore, the corresponding cis isomers are readily available. Applications of these optically active aminocyclohexanols in catalyzed asymmetric phenyl transfer reactions to benzaldehydes and transfer hydrogenations of aryl ketones lead to products with up to 96% ee.

Catalytic Asymmetric Transfer Hydrogenation of Ketones Using [Ru(p-cymene)Cl2]2 with Chiral Amino Alcohol Ligands

“…Thus, reaction did not proceed using 2-acetyl pyridine, while 99% conversion in 1 h reaction time with 64% enantioselectivity was achieved using 3-acetylpyridine as a reactant. 4-Methoxyacetophenone is known to be a challenging substrate probably because of its low redox potential, giving lower conversions and enantioselectivity [17,23,34]. In the present study, transfer hydrogenation of 4-methoxyacetophenone gave 54% conversion with 65% ee in 2 h reaction time.…”

“…Good to excellent yield with moderate enantioselectivity (up to 71%) was obtained using limonene derived amino alcohol (1S,2S,4R)-1-methyl-4-(1-methylethenyl)-2-(methylamino)cyclohexane (Scheme 1, E). Recently, Schiffers et al [34] have used 2-aminocyclohexanol derivatives for transfer hydrogenation of acetophenone using [RuCl 2 (p-cymene) 2 ] 2 as a catalyst. Enantiomers of 2-aminocyclohexanol derivatives were separated by resolution using (R)-and (S)-mandelic acid.…”

Diversity-Oriented Synthesis Based on the DPPP-Catalyzed Mixed Double-Michael Reactions of Electron-Deficient Acetylenes and β-Amino Alcohols

“…We prepared the pro-nucleophiles derived from L-leucine, L-alanine, L-phenylalanine, and L-serine efficiently according to protocols described by Moberg and Craig [46]; first, we protected the amino groups of L-leucine, L-alanine, L-phenylalanine, and L-serine with p -toluenesulfonyl (tosyl) chloride and then we reduced their carboxylic acid units using lithium aluminum hydride [47,48]. We prepared the 2-aminocyclohexanol–derived pro-nucleophile 1e from racemic cyclohexene oxide in three steps: opening of the epoxide with sodium azide, reduction of the azido group with palladium on charcoal [49,50], and then protection of the amino group with tosyl chloride [51]. …”

Enantioselective reduction of prochiral aryl ketones using a novel chiral auxiliary derived from a labdane diterpene

“…As such, the development of chiral auxiliaries or catalysts to perform reductions with high enantioselectivity has attracted much attention. New methods such as asymmetric transfer hydrogenation, 2 metal catalyzed hydrogenations, 3 enzymatic reactions 4 and the use of metal hydride transfer reagents, 5 have been reported.…”