Ligand optimization

Ten years after Sharpless s discovery of the asymmetric epoxidation of allylic alcohols, Jacobsen and Katsuki independently reported asymmetric epoxidations of unfunctionalized olefins by use of chiral Mn-salen catalysts such as 9 (Scheme 9.3) [14, 15]. The reaction works best on (Z)-disubstituted alkenes, although several tri-and tetrasubstituted olefins have been successfully epoxidized [16]. The reaction often requires ligand optimization for each substrate for high enantioselectivity to be achieved. 

Fig. 2 HN(CO)CA-derived experiment for the measurement of /nhc dipole-CSA CCR-rates. Various ratios of NBD peptide and NEMO were used. A 200-fold excess of ligand optimal conditions. B 100-fold excess auto relaxation and cross relaxation are too fast. The resonance assignment of the peptide is indicated...

Widenhoefer and co-workers have developed an effective Pd-catalyzed protocol for the asymmetric cyclization/ hydrosilylation of functionalized 1,6-dienes that employed chiral, non-racemic pyridine-oxazoline ligands." " " Optimization studies probed the effect of both the G(4) substituent of the pyridine-oxazoline ligand (Table 7, entries 1-6) and the nature of the silane (Table 7, entries 6-15) on the yield and enantioselectivity of the cyclization/ hydrosilylation of dimethyl diallylmalonate. These studies revealed that employment of isopropyl-substituted catalyst (N-N)Pd(Me)Gl [N-N = (i )-( )-4-isopropyl-2-(2-pyridinyl)-2-oxazoline] [(i )-43f and a stoichiometric amount of benzhydryldimethylsilane provided the best combination of asymmetric induction and chemical yield, giving the corresponding silylated cyclopentane in 98% yield as a single diastereomer with 93% ee (Table 7, entry 15). 

Figure2.24 The 3,6-substituted pyridazine 90 (K 5-HT3 = 425 nM), which is chemically closely related to minaprine 83 (Figure 2.22), is a low-affinity 5-HT3 receptor ligand. Optimization of this side activity to the phenyl-substituted phthalazine 91 (K( 5-HT3 =...

Dimethyl 1-oxoalkylphosphonates react with benzoic anhydride and DBU in THF at room temperature to form enolbenzoates in moderate to good yields (43-86%). Only the ( )-isomer is observed. Catalytic asymmetric hydrogenation of enolbenzoate phosphonates has been performed in MeOH at room temperature under hydrogen pressure (4 atm) with DuPHOS-Rh and BPE-Rh catalysts (Scheme 7.83). Ligand optimization studies have been perfonned with each enolbenzoate to provide optimum ee s. "... 

Obviously, basic research is needed to provide a more comprehensive insight into the dependence of enantioselectivities on ligand electronics which is only poorly understood compared to steric effects. Nevertheless the concept of electronic asymmetry to enhance enantio selectivity in other ligand systems is very appealing and should be considered to a greater extent for future ligand optimization studies. 

Another approach based on peptides is used by the Italian company Xeptagen (www.xeptagen.com). The D-PAM ligand optimized from a peptide library of 5832 randomized tripeptides is a tetramer of tripeptides linked together by a tetradentate lysine core [structure formula ([NH2-[l ]Arg-(Ji,S)Thr-[JJ]Tyr)4—(S)Lys2-(S)Lys-Gly]. All amino acids are in their artificial D-form giving the selector a higher proteolytic stability (Fassina et al, 2001). 

Ligand optimization studies for hydroformylation in ionic liquids... 

Knowledge of the macromolecule structure and its interactions with small-molecule ligands can provide useful information in the design and optimization of lead compounds with enhanced binding affinities as the examples in the previous sections of this chapter have illustrated. - s Structure-based ligand optimization requires two pieces of information. 

BRIEF GUIDE FOR FREE ENERGY CALCULATIONS AND THEIR USE IN LIGAND OPTIMIZATION... 

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