Enantioselective Ketone and β‐Keto Ester Hydrogenations (Including Mechanisms)

Abstract

Enantioselective hydrogenation of b-keto esters is a well-established procedure to produce chiral b-hydroxy esters in high optical purity [1][2][3][4]. Many important biologically active compounds have been synthesized through this procedure, even on a commercial scale [1][2][3][4]. Ru complexes [5] bearing appropriate chiral phosphine ligands [6][7][8] provide excellent catalytic efficiency for this reaction. Certain chiral Rh catalysts [3,4] and heterogeneous Ni catalysts [9] are also utilized. The recent development of the chiral diphosphine/diamine-Ru catalyst enables rapid and stereoselective hydrogenation of simple ketones without a hetero-atom functionality close to the carbonyl group [2,4]. These enantioselective transformations are summarized in the present chapter. Chiral LigandsIn enantioselective hydrogenation of ketonic substrates, the excellent catalytic performance such as high turnover number (TON), turnover frequency (TOF = -TON h -1 or s -1 ), and enantioselectivity is achievable only when (pre)catalysts are prepared by the appropriate combination of metal species and chiral ligands [6-8, 10, 11]. Stereo-repulsive interaction between substituents of ligands and substrates is normally utilized for the regulation of stereochemistry. The metal and ligand must be carefully selected because of the diversity of substrate structures [1][2][3][4][5]. Chiral diphosphine ligands with a C 2 symmetry (see Fig. 32.1) have played a main role in this respect. Recently, however, various effective C 1 phosphine ligands as well as phosphinite ligands have been developed, the structures of which are illustrated in Figures 32.2 and 32.3, respectively. Chiral amine and imine ligands (Fig. 32.4) are also useful, particularly when they are coupled with a chiral diphosphine ligand in the hydrogenation of simple ketones [2,4,5]. Immobilized BINAPs are detailed in Figure 32.5.

Ligand Design for Catalytic Asymmetric Reduction

“…85,87,93 The chiral environment of this catalyst system is easily modified by changing the combination of diphosphine and diamine ligands. 77,[96][97][98] Although the BINAP/1,2-diamine-Ru catalysts are feebly active for hydrogenation of 1-tetralones, this problem is solved simply by use of chiral 1,4-diamines instead of conventional 1,2-diamine ligands. 99 For example, hydrogenation of 5-methoxy-1-tetralone in the presence of an (S)-TolBINAP/(R)-IPHAN-Ru catalyst in 2-propanol results in the R alcohol in 98% ee (Figure 1.20).…”

Access to Optically Pure β-Hydroxy Esters via Non-Enzymatic Kinetic Resolution by a Planar-Chiral DMAP Catalyst

“…Several routes to produce optically pure 1,3-hydroxy esters have been explored, including asymmetric aldol reaction [13,14,15,16], the Reformatsky reaction [17,18,19,20,21,22], or regioselective epoxide ring opening [23,24,25,26]. The most widely studied method to achieve this kind of derivatives is asymmetric reduction, using either biocatalysts [4,27,28,29,30] or organometallic complexes [31,32,33,34,35,36] (Scheme 1).…”

Asymmetric hydrogenation of ketones: Tactics to achieve high reactivity, enantioselectivity, and wide scope

“…1) , 2) In the presence of an appropriate chiral catalyst, molecular hydrogen (H 2 ) is repeatedly activated and selectively added to the carbonyl moiety from one of two enantiofaces. An atomic efficiency of 100% contributes to provide an environmentally benign synthetic process.…”