Asymmetric epoxidation concentration

Finally, a titanium(IV) pillared clay (Ti-PILC) catalyst has been prepared.71 In the presence of tartaric acid esters as chiral ligands Ti-PILC is an effective, heterogeneous catalyst for the asymmetric epoxidation of allylic alcohols. Enantioselectivities were comparable to those observed in the homogeneous system - and reactions could be carried out at concentrations up to 2M with a simple work-up via filtration of the catalyst. 

The concentration of substrate used in the asymmetric epoxidation must be given consideration because competing side reactions may increase with increased reagent concentration. The use of catalytic quantities of the Ti-tartrate complex has greatiy reduced this problem. The epoxidation of most substrates under catalytic conditions may be performed at a substrate concentration up to 1 M. By contrast, epoxidations using stoichiometric amounts of complex are best run at substrate concentrations of 0.1 M or lower. Even with catalytic amounts of the complex, a concentration of 0.1 M may be maximal for substrates such as cinnamyl alcohol, which produce sensitive epoxy alcohol products [4]. 

Much of the experimental success of asymmetric epoxidation lies in exercising proper control of Eq. 6A.4 [6]. Both TI(OR)4 and Ti(tartrate)(OR)2 are active epoxidation catalysts, and because the former is achiral, any contribution by that species to the epoxidation will result in loss of enantioselectivity. The addition to the reaction of more than one equivalent of tartrate, relative to Ti, will have the effect of minimizing the leftward component of the equilibrium and will suppress the amount of Ti(OR)4 present in the reaction. The excess tartrate, however, forms Ti(tartrate)2, which has been shown to be a catalytically inactive species and will cause a decrease in reaction rate that is proportional to the excess tartrate added. The need to minimize Ti(OR)4 concentration and, at the same time, to avoid a drastic reduction in rate of epoxidation is the basis for the recommendation of a 10-20 mol % excess of tartrate over Ti for formation of the catalytic complex. After the addition of hydroperoxide and allylic alcohol to the reaction, the concentration of ROH will increase accordingly, and this will increase the leftward pressure on the equilibrium shown in Eq. 6A.4. Fortunately, in most situations this shift apparently is extremely slight and is effectively suppressed by the use of excess tartrate. A shift in the equilibrium does begin to occur, however, when the reaction is run in the catalytic mode and the amount of catalyst used is less than 5 mol % relative to allylic alcohol substrate. Loss in enantioselectivity then may be observed. This factor is the basis of the recommendation for use of 5-10 mol % of Ti-tartrate complex when the catalytic version of asymmetric epoxidation is used. 

Asymmetric epoxidation of allylic alcohols is a very reliable chemical reaction. More than a decade of experience has confirmed that the Ti-tartrate catalyst is extremely tolerantof structural diversity in the allylic alcohol substrate for epoxidation yet is highly selective in its ability to discriminate between the enantiofaces of the prochiral olefin. Today the practitioner of organic chemistry need provide only the allylic alcohol to perform the reaction. All other reagents and materials required for the reaction are available from supply houses and usually are sufficiently pure as received to be used directly in the asymmetric epoxidation process. [When purchasing f-butyl hydroperoxide in prepared solutions, however, the more concentrated 5.5-M solution in isooctane (2,2,4-trimethylpentane) should always be chosen over the 3.0-M solution.] If the considerations presented in this chapter are observed, with attention to the moderately stringent technique outlined, no difficulty should be encountered in performing this reaction. 

Most studies on sulfur ylide-mediated asymmetric epoxidation have concentrated on the development of the methodology. The usefulness of this approach has been demonstrated in the synthesis of a number of biologically interesting compounds. Furaldehyde-derived epoxides can be oxidized to produce glycidic esters that are versatile intermediates in several syntheses (see Scheme 10.9) [46]. The... 

The first example of a catalytic enantioselective epoxidation by cyclohexanone monooxygenase was shown with a fosfomycin-related model compound [75]. The efficient asymmetric epoxidation of styrene to (S)-styrene oxide by recombinant styrene monooxygenase has been achieved by increasing biocatalyst concentrations and reducing the exposure time of the biocatalyst to the product [76]. 

The original report32 of the titanium-catalyzed asymmetric epoxidation of allylic alcohols in 1980 has been followed by hundreds of applications, the majority of which use the initially reported conditions. In the decade since the introduction of this reaction numerous improvements have been made41. The most complete discussion of the preparative aspects of both the asymmetric epoxidation and the kinetic resolution was presented by the Sharpless group42. This paper details the effects of reagent stoichiometry and concentration, substrate concentration, aging of the catalyst and variation of oxidant, solvent and tartrate as well as workup procedures. What is particularly noteworthy in this presentation is that significant amounts of unpublished work are drawn upon to develop recommendations for successful reaction. 

Recent work with main group catalysts has concentrated on the use of Oxone (potassium peroxymonosulfate) as co-oxidant with organic ketone derivatives. Shing et al. have described an arabinose ketone catalyst containing a tuneable butanediacetal functionality (Fig. 1.2e) which can be used for asymmetric epoxidation with up to 90% ee [198]. The group of Shi reports on a range of ketones bearing... 

The temperature required for the formation of diazoalkanes can be significantly decreased by using phase-transfer catalysis. This method has allowed the use of transition metals in the catalytic asymmetric epoxidation of carbonyl compounds (eq 19). The use of phase-transfer catalysis and moderate temperatures promotes the formation of diazoalkanes at a very low rate, achieving low concentrations of diazoalkane during the reaction, which is critical for the outcome of the process. The use of trisylhydrazone has shown better results in some cases compared to its tosyl analog. Presumably, the bulkier sulfonyl group may facilitate the... 

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]. 

Jacobsen et al. reported enhanced catalytic activity by cooperative effects in the asymmetric ring opening (ARO) of epoxides.[38] Chiral Co-salen complexes (Figure 4.27) were used, which were bound to different generations of commercial PAMAM dendrimers. As a direct consequence of the second-order kinetic dependence on the [Co(salen)] complex concentration of the hydrolytic kinetic resolution (HKR), reduction of the catalyst loading using monomeric catalyst leads to a sharp decrease in overall reaction rate. 

A variety of ie.so-epoxidcs could be selectively ring-opened this way with e.e. s as high as 97% [28], The azides can be converted to 1,2-amino alcohols, which are very desirable synthetic intermediates. Surprisingly, the mechanism of the ARO (asymmetric ring-opening) was more complicated than expected [29], First, it turned out that the chloride ion in Cr-salen was replaced by azide. Secondly, water was needed and HN3 rather than Me3SiN3 was the reactant nucleophile. Thirdly, the reaction rate was found to be second order in catalyst concentration, minus one in epoxide (cyclopentene oxide), and zero order in HN3 [30],... 

Catalytic reactions in Sharpless epoxidation were achieved in 1986 by addition of molecular sieves, which suppress the formation of nonenantioselective complexes by moisture already present in the medium or produced during the reaction [33]. Similar problems needed to be solved in the asymmetric oxidation of sulfides because a decrease in the concentration of a... 

Modern reactions While there is no shortage of new chemical reactions to present in an organic chemistry test, I have chosen to concentrate on new methods that introduce a particular three-dimensional arrangement in a molecule, so-called asymmetric or enanti-oselective reactions. Examples include Sharpless epoxidation (Chapter 12), CBS reduction (Chapter 20), and enantioselective synthesis of amino acids (Chapter 28). 

Contrary to the catalytic systems employed for the epoxidation, meehanistie studies of asymmetric ring opening have shown that eooperative interactions between eatalyst imits are needed [209]. Thus, high local concentration of catalyst was necessary and high-loading support should increase the catalytic reactivity. 

With environmental consideration in mind, the group has developed a version in concentrated media, i.e. without dichloromethane and only three equivalents of isopropanol. ° For instance, the ketone 64 was converted into the alcohol 65 in 93% yield and 95% enantiomeric excess using only 10 mol% of titanium-BINOL catalyst (Conditions B, Scheme 7.36). A slight decrease of efficiency was observed using 5 mol% of catalyst (Conditions C). The efficiency of the method was illustrated by a tandem asymmetric ally-lation/diastereoselective epoxidation reaction of cyclic enones that is based on the use of the allylation catalyst for a subsequent epoxidation with TBHP, as illustrated in Scheme 7.37. ° ... 

More recently, Jacobsen and coworkers have found that epoxides undergo a highly enantioselective ring-opening with TMS-azide when catalysed by (salen)Cr(III) complexes such as (5,5)-4. This asymmetric ring opening shows a second-order rate dependence on catalyst concentration . Applications of the process have included kinetic resolution of terminal epoxides , an efficient synthesis of (/ )-4-(trimethylsilyloxy)cyclopent-2-enone, the dynamic kinetic resolution (equation 11) of epichlorohydrin, an enantioselective route to carbocyclic nucleoside analogues and a formal synthesis (equation 12) of the protein kinase inhibitor 5. 

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