Ruthenium‐Catalyzed Asymmetric Hydrogenation of β‐Keto‐ enamines: An Efficient Approach to Chiral γ‐Amino Alcohols

Abstract

A highly efficient and enantioselective hydrogenation of unprotected b-ketoenamines catalyzed with ruthenium(II) dichloro{(S)-(À)-2,2'-bis[di(3,5-xylyl)phosphino]-1,1'-binaphthyl}[(2S)-(+)-1,1-bis(4-methoxyphenyl)-3-methyl-1,2-butane-A C H T U N G T R E N N U N G diamine] {Ru[(S)-xylbinap][(S)-daipen]Cl 2 } has been successfully developed. This methodology provides a straightforward access to free g-secondary amino alcohols, which are key building blocks for a variety of pharmaceuticals and natural products, with high yields (> 99%) and excellent enantioselectivities (up to 99% ee) in all cases.Keywords: asymmetric catalysis; enamines; enantioselectivity; hydrogenation; ruthenium Enantiomerically pure amino alcohols and their derivatives are of great importance in synthetic and pharmaceutical chemistry.[1] Especially, g-secondary amino alcohols 2 have drawn extensive attention as they are key intermediates for the synthesis of an important family of norepinephrine reuptake inhibitors, 1a-d.[2]Enantiomerically active compounds 1a-d are widely used as antidepressants in clinic medicine. Thus, a catalytic access to enantiomerically enriched amino alcohols 2 is of great significance and necessity for the pharmaceutical industry. The early synthesis of 2 mainly relied on chiral epoxide compounds [3] or enzyme catalysis [4] . Along with the development of catalytic asymmetric hydrogenation, several enantioselective syntheses of 2, as well as 1, have been reported based on hydrogenation of b-keto esters [5] or b-tertiary amino ketones.[6] However, the hydrogenation products need further tedious and complex transformations to afford the desired product 2. Shimizu reported an elegant and succinct method to prepare chiral alcohols with high enantioselectivity and chemoselectivity by Cu(I)-catalyzed asymmetric hydrogenation of several heteroaromatic ketones and enones. [7] It is highly desired to develop an economic and efficient protocol for the synthesis of 2 based on direct asymmetric hydrogenation. Our group has already reported a direct hydrogenation of protected bsecondary amino ketones to prepare 2 with [RhA C H T U N G T R E N N U N G (DuanPhos)A C H T U N G T R E N N U N G (NBD)]SbF 6 as catalyst, obtaining very high enantioselectivities (ee values up to 99%). [8] Another efficient method based on asymmetric hydrogenation of b-arylketoenamines was initially raised by a patent from Sumitomo Seika Chemicals Co., [9] but the following detailed investigation was never reported. Herein, we present a Ru-catalyzed asymmetric hydrogenation of b-ketoenamines with ee values of > 99% and turnover numbers (TON) = 1000 under mild reaction condition, which provides an alternative and efficient approach to chiral g-amino alcohols 2 and the related pharmaceuticals.The b-ketoenamine derivatives were synthesized directly from readily available methyl aryl ketones 4 through crossed Claisen condensation with ethyl formate, followed by amination with methylamine hydrochloride in a one-pot reaction (Scheme 1 and Table 1).[10] ...

The Design and Synthesis of Planar Chiral Ligands and Their Application to Asymmetric Catalysis

“…Several procedures can be used for this particular transformation; however, these normally require high hydrogen pressures and high temperatures. 39,40 By using the chiral complex 77, formed by dichlorotris(triphenylphosphine)ruthenium(II) with ligand 4b in toluene at 90°C (Scheme 23), a variety of β-amino ketones could be reduced with high enantioselectivities under mild conditions. 38 Our initial studies involved the hydrogenation of β-amino ketone 78 (Ar = Ph; R = Bn).…”

Yolk‐Shell‐Mesostructured Silica‐Supported Dual Molecular Catalyst for Enantioselective Tandem Reactions

“…So far, main methods to synthesize these chiral γ‐secondary amino alcohols depend heavily on the enantioselective reductions of prochiral β‐amino ketones in homogeneous conditions . Earlier works employed chiral Rh‐MCPPM complex (MCPPM: 4‐dicyclohexylphosphino‐2‐diphenylphosphinomethyl‐1‐( N ‐methylcarbamoyl)pyrrolidine) and chiral Rh‐Duanphos complex as catalysts converted β‐amino ketones into chiral γ‐secondary amino alcohols –. Recent reports utilized chiral Rh‐benzbisphosphine complex as a catalyst and ZnCl 2 as an activator via asymmetric hydrogenation– and chiral Ru‐diamine complexes via asymmetric transfer hydrogenation (ATH) [7h] to perform the highly efficient preparations of γ‐secondary amino alcohols.…”

Boron Tetrafluoride Anion Bonding Dual Active Species Within a Large–Pore Mesoporous Silica for Two–Step Successive Organic Transformaion to Prepare Optically Pure Amino Alcohols

“…In this contribution, we employ a large–pore size of FDU−12 as a support and assemble a Lewis base and a chiral ruthenium/diamine dual species within its regular nanopores via a anion–bonding approach, fabricating a bifunctional heterogeneous catalyst. This catalyst performs an efficient synthesis of valuable pharmaceutical intermediates of optically pure γ-secondary amino alcohols that had been explored extensively by various asymmetric catalysis in homogeneous conditions recently (Gao and Sharpless, 1988 ; Robertson et al, 1988 ; Kakei et al, 2004 ; Liu et al, 2005 ; Fujima et al, 2006 ; Geng et al, 2011 ; Träff et al, 2011 ; Wang et al, 2013a , 2015 ; Zhou et al, 2014 ; Hu et al, 2015 ; Wu et al, 2017 ). Benefits of this heterogeneous catalysis not only overcome the drawbacks of expensive transition–metal recycle and transition–metal contamination in homogeneous catalysis system, but also realize multi-step reactions to yield a series of synthetically useful amino alcohols under mild reaction conditions in environmental friendly fashion.…”