Chiral (salen) manganese (III) complexes (Mn-salen complexes) bearing chiral centers at their ethylenediamine moiety and chiral binaphthyl units in the salicylaldehyde moiety are excellent catalysts for asymmetric oxidation and the relative configuration between the two chiral units (at the ethylenediamine and salicylaldehyde moieties) has been found to strongly relate to the substrate-specificity of the Mn-salen complexes. In this paper, we describe asymmetric C-H bond oxidation using new Mn-salen complexes prepared by tuning the relative configuration and substituents on the salen ligand. The relationship between relative configuration and the conformation of the ligand which affects asymmetric induction by Mn-salen complexes, is also discussed. Ligand conformation has also been found to be dynamically controlled by external chiral donor ligand. Thus, achiral Mn-salen complex can be used as a chiral catalyst by simply controlling the ligand conformation. New features of Mn-salen chemistry brought by the control of ligand conformation are also discussed in this paper.
Sequential and iterative asymmetric reaction on achiral substrates with two prochiral centers caused an enantiomeric enhancement and its synthetic application to C2 symmetric azacycloalkanes and 2, 6 disubstituted piperidines is described. Repeated asymmetric dihydroxylation (AD) for terminal olefins also improved stereoselectivity (ee) and a number of syntheses of alkaloids are demonstrated.
An attractive feature of the allylic coupling reaction catalyzed by a transition metal is the possibility to create a secondary carbon at an allylic position. To examine this possibility, we have developed reactive borates of types 2-4 (eq 2), which react with secondary allylic carbonates and acetates efficiently in the presence of a nickel catalyst. Regarding reactivity, 4 is the most reactive reagent. In addition, it is possible to replace the Me or butanediol-ligands or the Li counter cation by others in order to raise the reactivity of 4 for specific substrates and purpose. This idea was successful to create new reagents 5, 6, and 14 : 5 for reaction with monoacetate 9 (eq 3) and aryl mesylates 12 (eq 4); 6, reagents possessing a carbonyl group (eq 16, Fig.5); 14 for reaction with sterically congested cis bromides 13 (eq 5). By using these reactions, synthesis of prostaglandins, aristeromycin, brefeldin A, 10, 11-dihydroleukotriene B4, korormicin was accomplished successfully (Fig.1 and 2).
This review deals with two important kinetic effects based on concentration changes of radical and radical ion intermediates, which in some cases dominate the efficiency and selectivity of photoinduced electron transfer (PET) reactions. One is the persistent radical ion effect suggesting the predominant reaction of a more stable radical ion rather than that of less stable, i. e., more reactive, intermediate, just as the Ingold-Fischer persistent radical one which predicts high yields of the cross-reaction product from two radicals with markedly different self-termination constants. In PET reactions between D and A, reactions under continuous irradiations are in principle governed by the steady-state concentrations of radical ion intermediates, the ratios of D+· and A-· being quite different from 1 : 1 depending on their relative stabilities. The kinetics are more simple and the ratio of D+· and A-·becomes 1 : 1 when intermediates are generated by pulsed irradiation. Such a contrast was demonstrated for the redox between diphenylmethyl radical and simultaneously generated aromatic radical cation/anion, and for the photosensitized redox reaction of carboxylates. Another important effect is based on abortive equilibria, indicating that a reactive intermediate exists in an equilibrium with stable species not leading to products. Kinetic consequences of this effect are described for the deprotonation of diarylmethane radical cations with pyridines, and for the PET oxidative C-C cleavage of 1, 1, 2, 2-tetraphenylethane.
Interestingly, 4A1, an antibody against p-nitrophenyl phosphonate, showed a significant rate acceleration against substrates that differ from the given haptenic structure in the carrier-proximal region. The rate acceleration (kcatkuncat) for one of the specific substrates is 6.4 × 104, 20-fold higher than that of a substrate congruent with the hapten. Kinetic analysis of Km and kcat values, as well as the affinity constant (Kd) values of the corresponding transition-state analogs, indicated that the rate enhancement is associated with a decrease in the activation energy due to stabilization of the transition -state in the cleavage reaction. In addition, the inactivation of 4A1 upon hydrolysis of a particular substrate was observed. The 600 MHz 13C NMR measurement clearly showed that the 13C-labeled fragment attached covalently to the 4A1 antibody, proving formation of an acyl-antibody. Further kinetic analysis study demonstrated that the 4A1 catalytic antibody uses a multistep kinetic sequence for the hydrolytic reaction.
Recently, it has been reported that some unsaturated aldehyde terpenoids inhibit phospholipase A2 (PLA2), which catalyzes hydrolysis of the ester linkage at the sn-2 position of glycerophospholipids. Since the release of arachidonic acid from glycerophospholipids is the rate-limiting step in the production of eicosanoid mediators of inflammation, the inhibitory mechanism of PLA2 by these aldehyde terpenoids has been of biochemical and medicinal interest. It is known at present that the three aldehyde terpenoids, scalaradial, manoalide, and (E) -3methoxycarbonyl-2, 4, 6-trienal compound A strongly inactivate PLA2. As the inhibitory mechanism of PLA2 by manoalide, our group has found that the irreversible modification of Lys 56 in the interfacial recognition site of bovine PLA2 by manoalide is responsible for the inactivation of this enzyme. Although the real reaction mechanism between manoalide and the lysine residues of PLA2 has not been elucidated, our model studies on the reactions between manoalide analogs and mono- and diamines strongly suggested that manoalide reacted with the two close lysine residues to give polymerized compounds. In the case of the (E) -3-methoxycarbonyl-2, 4, 6-trienal compound A, it would inhibit the hydrolytic activity of bovine pancreatic PLA2 by the formation of the dihydropyridine derivatives resulting from the reaction with lysine residues of PLA2via 6π-electrocyclization of the intermediary Schiff bases. Moreover, scalaradial also irreversibly reacts with lysine residues to inactivate PLA2, and the production of the pyrrole derivative has been proposed by Cimino and coworkers based on the model reaction with methylamine. Thus, it would be concluded that the irreversible formation of the product by the reaction with the lysine residue in the interfacial recognition site of PLA2 is essential for sufficient inactivation of PLA2 by unsaturated aldehyde terpenoids such as manoalide, scalaradial, and the (E) -3-methoxycarbonyl2, 4, 6-trienal compounds.
Medicinal chemistry efforts on optimization of the endothelin receptor antagonistic natural products toward highly potent and selective ETA, ETB or ETA/B dual receptor antagonists are summarized. In order to get adequate biological tools for elucidating physiological and/or pathophysiological roles of endothelin as well as to identify highly potent antagonists possessing appropriate profiles, liquid phase and solid phase peptide synthesis, and their modification have been carried out. During these efforts, we have realized physiological roles of endothelin and its receptors, and have confirmed drug discovery values of its receptor antagonists as clinical drugs to modulate various kinds of disease.