Asymmetric dihydroxylations mechanism

Extensive studies have been made of the mechanism of asymmetric dihydroxylation, but it is still difficult to conclusively determine the mechanism. Thus, the experimental data supporting each mechanism are highlighted below. 

Recent developments in the understanding of the mechanisms of catalytic and asymmetric dihydroxylation reactions are discussed in Section V,E,l,b. An important aspect of this work is the kinetics and thermodynamics of the formation of adducts with N heterocycles, which have an important role in promoting many reactions. The crystal structure of the [0s04] adduct with the cinchona alkaloid ligand (dimethyl-... 

Dihydroxylation (especially asymmetric reactions) of alkenes is a very important synthetic tool for the introduction of a new functionality into organic molecules. The reader is referred to recent reviews on the synthetic utility and mechanisms of asymmetric dihydroxylation for useful background material regarding synthetic outcomes84- 88. 

Osmium-catalysed dihydroxylation has been reviewed with emphasis on the use of new reoxidants and recycling of the catalysts.44 Various aspects of asymmetric dihydroxylation of alkenes by osmium complexes, including the mechanism, acceleration by chiral ligands 45 and development of novel asymmetric dihydroxylation processes,46 has been reviewed. Two reviews on the recent developments in osmium-catalysed asymmetric aminohydroxylation of alkenes have appeared. Factors responsible for chemo-, enantio- and regio-selectivities have been discussed.47,48 Osmium tetraoxide oxidizes unactivated alkanes in aqueous base. Isobutane is oxidized to r-butyl alcohol, cyclohexane to a mixture of adipate and succinate, toluene to benzoate, and both ethane and propane to acetate in low yields. The data are consistent with a concerted 3 + 2 mechanism, analogous to that proposed for alkane oxidation by Ru04, and for alkene oxidations by 0s04.49... 

With this aim, the group of Norrby developed a transition state force field for the study of the asymmetric dihydroxylation reaction [91]. This force field is purely developed from quantum mechanical reference data [92]. In their studies they use different ligands from the first generation (where the amine ligands are the alkaloids dihydroquine or dihydroquinidine) and second generation (where a symmetric linker couples two alkaloid units), and several alkenes. The calculated ee s are in very good agreement with experiment. 

Asymmetric dihydroxylation (Chapter 45) is straightforward though you might like to comment on the chemoselectivity. The diol is converted into the epoxide and you should explain the regio- and chemoselectivity of this step. The next step is perhaps the most interesting what is the mechanism of the cyclization, what is the role of silicon, and how is the stereochemistry controlled ... 

Of particular interest are asymmetric dihydroxylation (AD) reactions. Depending on the oxidant employed, which is commonly either NMO or K3[Fe(CN)6]/K2C03, two different mechanisms may apply (see Schemes 5.12 and 5.13).[701 One essential difference is that A-morpholinc-A -oxide is typically used in a homogeneous acetone-water solvent mixture while a biphasic reaction mixture is usually observed with aqueous K3[Fe(CN)6 /K.2C03 as oxidant. In the latter case the olefin is oxidised... 

Scheme 1 Proposed mechanism of the osmium-catalyzed asymmetric dihydroxylation of alkenes...

Norrby, P.-O., Rasmussen, T., Haller, J., Strassner, T., Houk, K. N. Rationalizing the Stereoselectivity of Osmium Tetroxide Asymmetric Dihydroxylations with Transition State Modeling Using Quantum Mechanics-Guided Molecular Mechanics. J. Am. Chem. Soc. 1999, 121, 10186-10192. 

Lohay, B. B., Bhushan, V. Mechanism of osmium-catalyzed asymmetric dihydroxylation (ADH) of alkenes. Tetrahedron Lett. 1992, 33, 5113-5116. 

Bruckner, C., Dolphin, D. Temperature effects in asymmetric dihydroxylation evidence for a stepwise mechanism. Chemtracts Org. Chem. 1993, 6, 364-367. 

Norrby, P.-O., Kolb, H. C., Sharpless, K. B. Toward an Understanding of the High Enantioselectivity in the Osmium-Catalyzed Asymmetric Dihydroxylation. 2. A Qualitative Molecular Mechanics Approach. J. Am. Chem. Soc. 1994, 116, 8470-8478. 

Key Words Nonheme, Iron, Biomimetic, Bio-inspired, Cytochrome P450, Rieske dioxygenases. Hydrogen peroxide. Peroxide activation. Homogeneous catalysis, c/s-Dihydroxylation, Mechanism, Catalytic additives. Asymmetric... 

Abstract The asymmetric dihydroxylation of olefins by osmium tetroxide is one of the most useful reactions in organic synthesis. Apart from the enormous experimental work, an extensive theoretical effort has been applied to study this reaction. A vast number of computational methods like QM, MM, Q2MM, QM/MM, and those commonly applied to enzymatic studies like docking. Molecular Dynamics (MD) and Genetic Algorithms (GA) have been employed. The computational studies performed to date in order to understand the mechanism of this reaction are reviewed here, with special focus on those directed to study the origin of the high enantioselectivity. 

Fig. 6 The intermediate in the asymmetric dihydroxylation of styrene adopting the [2+2] mechanism, highlighting the function of each of the parts of the catalyst...

In 1999, Norrby, Houk and co-workers used a more elaborated Q2MM method [60] to broaden their previous studies on the asymmetric dihydroxylation reaction [61]. They used QM calculations on several similar reactants to find the transition state, and used these parameters to build up an unbiased molecular mechanics force field. The most important improvement is that with this method they were able to calculate transition states using the developed force field. 

The asymmetric dihydroxylation of olefins by 0s04 NR3 catalysts is an extremely useful reaction in organic synthesis. It is able to introduce two vicinal functional groups simultaneously on olefins not functionahsed. The apphca-tion of theoretical methods to study this reaction has proven to be critical in order to determine the reaction mechanism, and to identify the origin of the enantioselectivity. 

Asymmetric Dihydroxylation Reactions. A substantial amount of work has been reported on the development of the asymmetric dihydroxylation (AD) reaction as originally described by Sharpless. A greater understanding has emerged of the functional group tolerance of the AD reaction and also its applicability towards differing alkene substitution patterns. The mechanism of the AD reaction has been the subject of intense debate especially with respect to the question of whether a [2 + 2] or [3 + 2] pathway is followed, and some insightful mechanistic studies have followed from this discussion. ... 

The reason for this must come from the way in which the substrate interacts with the osmium-ligand complex. However, the detailed mechanism of the asymmetric dihydroxylation is stUl far from clear-cut. What is known is that the ligand forms some sort of chiral pocket, like an enzyme active site, with the osmium sitting at the bottom of it. Alkenes can only approach the osmium if they are correctly aligned in the chiral pocket, and steric hindrance forces the alignment shown in the scheme above. The analogy with an enzyme active... 

Abstract The oxidative functionalization of olefins is an important reaction for organic synthesis as well as for the industrial production of bulk chemicals. Various processes have been explored, among them also metal-catalyzed methods using strong oxidants like osmium tetroxide. Especially, the asymmetric dihydroxylation of olefins by osmium(Vlll) complexes has proven to be a valuable reaction for the synthetic chemist. A large number of experimental studies had been conducted, but the mechanisms of the various osmium-catalyzed reactions remained a controversial issue. This changed when density functional theory calculations became available and computational studies helped to unravel the open mechanistic questions. This mini review will focus on recent mechanistic studies on osmium-mediated oxidation reactions of alkenes. 

A series of hydrolytically stable monophenyl phosphonates (177) has been synthesized and found to serve as irreversible and mechanism-based inhibitors of Escherichia coli and human y-glutamyl transpeptidase. Phosphonic add analogues of acylcarni-tyne (178) have been prepared in an optically active form expecting camityne palmitoyltransferase CPTI inhibitory activities. The synthetic methodology was based on catalytic asymmetric dihydroxylation of p,y-unsaturated phosphonates (179) and subsequent regioselective amination via cyclic sulfates (Scheme 60). ... 

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