Transition metal catalysts asymmetric epoxidation

Chiral epoxides and their corresponding vicinal diols are very important intermediates in asymmetric synthesis [163]. Chiral nonracemic epoxides can be obtained through asymmetric epoxidation using either chemical catalysts [164] or enzymes [165-167]. Biocatalytic epoxidations require sophisticated techniques and have thus far found limited application. An alternative approach is the asymmetric hydrolysis of racemic or meso-epoxides using transition-metal catalysts [168] or biocatalysts [169-174]. Epoxide hydrolases (EHs) (EC 3.3.2.3) catalyze the conversion of epoxides to their corresponding vicinal diols. EHs are cofactor-independent enzymes that are almost ubiquitous in nature. They are usually employed as whole cells or crude... 

The epoxidation of enones using chiral phase transfer catalysis (PTC) is an emerging technology that does not use transition metal catalysts. Lygo and To described the use of anthracenylmethyl derivatives of a cinchona alkaloid that are capable of catalyzing the epoxidation of enones with remarkable levels of asymmetric control and a one pot method for oxidation of the aUyl alcohol directly into... 

The heading substitution reactions has been used to describe the conversion of a stereogenic center to another. Of course, this means that the substrate stereogenic center has had to be obtained by one of the reaction types outlined earlier, from the chiral pool, or by resolution. Reactions that fall into this category include epoxide and cyclic sulfate openings and iodolactonizations (Chapter 22). Perhaps the most important reaction of this type for asymmetric synthesis is allylic substitution in the presence of a transition metal catalyst. 

The first catalytic asymmetric cyclopropanation using an ylide as catalyst was reported by Aggarwal et al. in 1997 [95, 96]. Phenyl diazomethane was added slowly to a mixture containing sulfide 12, an enone and Rh2(OAc)4 (1 mol%). A sulfur ylide was generated in situ from the sulfide and phenyl diazomethane in the presence of the transition-metal catalyst (see Scheme 10.20), as in the epoxidations discussed earlier (see Section 10.2.1.3). 

Hie first of Sharpless s reactions is an oxidation of alkenes by asymmetric epoxidation. You met vanadium as a transition-metal catalyst for epoxidation with r-butyl hydroperoxide in Chapter 33, and this new reaction makes use of titanium, as titanium tetraisopropoxide, Ti(OiPr)4, to do the same thing. Sharpless surmised that, by adding a chiral ligand to the titanium catalyst, he might be able to make the reaction asymmetric. The ligand that works best is diethyl tartrate, and the reaction shown below is just one of many that demonstrate that this is a remarkably good reaction. 

The hrst of Sharpless s reactions is an oxidation of alkenes by asymmetric epoxidation. You met vanadium as a transition-metal catalyst for epoxidation with f-butyl hydroperoxide in Chapter 33,... 

The development of simple systems that allow for the asymmetric oxidation of allyl alcohols and simple alkenes to epoxides or 1,2-diols has had a great impact on synthetic methodology as it allows for the introduction of functionality with concurrent formation of one or two stereogenic centers. This functionality can then be used for subsequent reactions tliat usually fall into the substitution reaction class. Because these transition metal catalysts do not require the use of low temperatures to ensure high degrees of induction, they can be considered robust. However, the sometimes low catalyst turnover numbers and the synthesis of the substrate can still be crucial economic factors. Aspects of asymmetric oxidations are discussed in Chapter 12. 

The highest stereoselectivities are reached with disubstituted (Z) -alkenes (with ee-values up to 99%) as well as trisubstituted alkenes, whereas mono-substituted olefins are poorer substrates. Concerning the mechanism of the Jacobsen epoxidation (see Ref. [21]), asymmetric epoxidation of non-activated olefins can be performed with numerous other transition-metal catalysts [22]. 

Asymmetric manganese-salen-catalyzed epoxidation of unfunctionalized olefins was reported by Jacobsen et al. [74] in 1990, which allowed the enantioselective epoxidation of unfunctionalized olefins. In particular, the high enantioselectivities obtained for Jacobsen epoxidation on cis-olefins, nicely complement the Sharpless epoxidation and dihydroxylation protocols, which give reduced enantioselectivities for these substrates. The Sharpless and Jacobsen procedures are frequently used asymmetric oxidative reactions in API synthesis. More recently, organocatalytic procedures such as Shi epoxidations [75] were also employed to avoid toxic transition metal catalysts. 

Sharpless asymmetric epoxidation (SAE) is the epoxidation of allylic alcohols into asymmetric epoxides in high chiral purity (high enantioselectiv-ity). Transition metal catalyst Ti(OPr ) with chiral additive, diethyl tartarate (DET), generates chiral catalyst (Scheme 9.40) which is responsible for the enantioselective outcome, while, tert-butyl hydroperoxide (TBHP) serves as an oxidant. Although, this eatalytic system holds disadvantage of low turnover number (TON) with potential safety coneems for using concentrated solutions of peroxides, the reaction has nevertheless been extensively used in pharmaceutical industry [76]. 

This chemical bond between the metal and the hydroxyl group of ahyl alcohol has an important effect on stereoselectivity. Asymmetric epoxidation is weU-known. The most stereoselective catalyst is Ti(OR) which is one of the early transition metal compounds and has no 0x0 group (28). Epoxidation of isopropylvinylcarbinol [4798-45-2] (1-isopropylaHyl alcohol) using a combined chiral catalyst of Ti(OR)4 and L-(+)-diethyl tartrate and (CH2)3COOH as the oxidant, stops at 50% conversion, and the erythro threo ratio of the product is 97 3. The reason for the reaction stopping at 50% conversion is that only one enantiomer can react and the unreacted enantiomer is recovered in optically pure form (28). 

Michael-aldol reaction as an alternative to the Morita-Baylis-Hillman reaction 14 recent results in conjugate addition of nitroalkanes to electron-poor alkenes 15 asymmetric cyclopropanation of chiral (l-phosphoryl)vinyl sulfoxides 16 synthetic methodology using tertiary phosphines as nucleophilic catalysts in combination with allenoates or 2-alkynoates 17 recent advances in the transition metal-catalysed asymmetric hydrosilylation of ketones, imines, and electrophilic C=C bonds 18 Michael additions catalysed by transition metals and lanthanide species 19 recent progress in asymmetric organocatalysis, including the aldol reaction, Mannich reaction, Michael addition, cycloadditions, allylation, epoxidation, and phase-transfer catalysis 20 and nucleophilic phosphine organocatalysis.21... 

A recent discovery that has significantly extended the scope of asymmetric catalytic reactions for practical applications is the metal-complex-catalyzed hydrolysis of a racemic mixture of epoxides. The basic principle behind this is kinetic resolution. In practice this means that under a given set of conditions the two enantiomers of the racemic mixture undergo hydrolysis at different rates. The different rates of reactions are presumably caused by the diastereo-meric interaction between the chiral metal catalyst and the two enantiomers of the epoxide. Diastereomeric intermediates and/or transition states that differ in the energies of activation are presumably generated. The result is the formation of the product, a diol, with high enantioselectivity. One of the enantiomers of... 

This class of catalysts covers chemocatalysts that do not contain a transition metal. The class has been known for many years, but it is relatively recently that the term organocatalyst has been used (209). A wide variety of transformations can be performed, which is currently an area of intense research (209-218). Table 5 (220-252) summarizes some key transformations in which organocatalysis can be useful. Reactions range from the asymmetric epoxidation of alkenes, which need not be conjugated to another functional group, to aldol reactions and... 

AE reactions of simple olefins. The Sharpless AE reaction has been supplemented by other approaches to asymmetric epoxide synthesis the most evident goal being to obviate the need for an allylic alcohol. Attempts to carry out asymmetric epoxidation reactions on simple olefins have utilized transition-metal-containing catalysts such as porphyrins as well as stoichiometric chiral reagents (peroxides, dioxiranes, and oxaziridines). These approaches have been summarized [19]. 

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