Alkenes Jacobsen epoxidation

Diaminocyclohexane [(R,R)- and ( S, S)-enantiomer] forms an imine (SCHIFF base) with 2,5-di-/ rr-butylsalicylaldehyde, which gives a chiral Mn(III) (salen) complex with Mn(II)acetate and oxygen. In contrast to the Sharpless-Katsuki protocol (p 20), this complex effects the stereoselective oxygen transfer (from oxidants, e.g. monopersulfate or NMO) to unfunctionalized alkenes (Jacobsen epoxidation [1], extended by Katsuki [2]) giving rise to enantiomeric oxiranes with 90-98% ee. 

The first application of ionic hquids for salen complexes dealt with the epoxidation of alkenes [14]. Jacobsen s Mn complex was immobilized in [bmimjlPFe] and different alkenes were epoxidized with aqueous NaOCl solution at 0 °C. As the ionic solvent sohdified at this temperature, dichloromethane was used as a cosolvent. The recychng procedure consisted of washing with water, evaporation of dichloromethane, and product extraction with hexane. The results (Table 3) were excellent and only a slow decay in activity and enantioselectivity was detected after several cycles. 

Shi s method gives good results for disubstituted /f-alkenes compared to the Jacobsen epoxidation previously described, which is more specific for disubstituted Z-alkenes. Concerning the epoxidation of trisubstituted alkenes, the epoxidation of 1-phenyl-1-cyclohexene could not be validated because of... 

Jacobsen epoxidation turned out to be the best large-scale method for preparing the cis-amino-indanol for the synthesis of Crixivan, This process is very much the cornerstone of the whole synthesis. During the development of the first laboratory route into a route usable on a very large scale, many methods were tried and the final choice fell on this relatively new type of asymmetric epoxidation. The Sharpless asymmetric epoxidation works only for allylic alcohols (Chapter 45) and so is no good here. The Sharpless asymmetric dihydroxylation works less well on ris-alkenes than on trans-alkenes, The Jacobsen epoxidation works best on cis-alkenes. The catalyst is the Mn(III) complex easily made from a chiral diamine and an aromatic salicylaldehyde (a 2-hydroxybenzaldehyde). 

The Sharpless asymmetric dihydroxylation works best for tram disubstituted alkenes, while the Jacobsen epoxidation works best for cis disubstituted alkenes. Even in this small area, there is a need for better and more general methods. Organic chemistry has a long way to go. 

Epoxidation of alkenes with complex of a chiral salen ligand and manganese(III), 1.69 or 1.70, is known as Jacobsen epoxidation ... 

Asymmetric epoxidation The catalytic asymmetric epoxidation of alkenes has been the focus of many research efforts over the past two decades. The non-racemic epoxides are prepared either by enantioselective oxidation of a prochiral carbon-carbon double bond or by enantioselective alkylidenation of a prochiral C=0 bond (e.g. via a ylide, carbene or the Darzen reaction). The Sharpless asymmetric epoxidation (SAE) requires allylic alcohols. The Jacobsen epoxidation (using manganese-salen complex and NaOCl) works well with ds-alkenes and dioxirane method is good for some trans-alkenes (see Chapter 1, section 1.5.3). 

The catalytic asymmetric synthesis of (2S,3S)-3-hydroxy-2-phenylpiperidine was developed by J. Lee et al. using an intramolecular epoxide opening 5-exo-tet) followed by ring expansion. The acyclic c/s-epoxide substrate was prepared in good yield and in greater than 94% ee by the Jacobsen epoxidation from the corresponding (Z)-alkene. ... 

Ugly facts, unfortunately, sometimes invalidate a beautiful mechanism. The Jacobsen epoxidation sometimes proceeds with loss of configurational purity of acyclic alkenes. This feature of the reaction can be explained by invoking radicals. Homolysis of the Mn C bond in the manganaoxetane intermediate would give a Mn(III) 1,4-diradical complex, and attack of the alkyl radical on O with displacement of Mn(II) would give the epoxide and regenerate the catalyst. 

A more recent alternative approach, developed by Jacobsen and co-workers, concerns the catalytic asymmetric epoxidation of unfunctionalized olefins using cheap NaOCl as oxidant in the presence of Mn complexes of chiral Schiff bases as catalysts, the so-called salene (Fig. 3-4). Values of 97% e.e. have been achieved using cis-disubstituted or trisubstituted alkenes. Equation 3-15 describes the Jacobsen epoxidation of olefins schematically. 

Mn(III) sits neatly in a tetracoordinate pocket in the ligand, and catalyses the epoxidation of simple alkenes by sodium hypochlorite, NaOCl, ordinary domestic bleach. Best results are obtained when the alkenes are cis (although an alternative range of ligands, developed by Tsutomu Katsuki, work well with trans alkenes), and one of the most significant applications of the Jacobsen epoxidation is with indene, which gives an epoxide in 84% ee with <1% of the catalyst. The mechanism of the reaction is complex and not fully understood, although it probably involves a Mn(V) oxo species and may involve radical intermediates. 

It s no surprise that when chemists from Bristol Myers Squibb needed the epoxide beiow, they turned to asymmetric dihydroxyiation rather than either of the epoxidation methods we have shown you. Sharpless epoxidation works only with allylic alcohols, and Jacobsen epoxidation performs poorly here, giving oniy 70-74% ee (mainly because the substrate is not a cis alkene). However, asymmetric dihydroxyiation saves the day with 98% ee and around 90% yield, and a variant of the reaction we have just shown you gives the epoxide, also in 90% yield—well worth the extra step. 

The epoxide functional group is often an intermediate in organic synthesis sequences because it can be readily opened by a variety of nucleophiles, leading to complex functionalization that starts with just an alkene. Asymmetric variants of epoxidation are important reactions, with the Sharpless and Jacobsen epoxidations being the most well known. Both these reactions involve metal catalysts. 

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]. 

For ffie past several decades, several chemocatalysts and biocatalysts have been used for ffie epoxidation of nonfunctionalized aliphatic alkenes. The Katsuki-Jacobsen epoxidation, which is catalyzed by chiral Mn(III)-salen with NaOCl/PhIO as an oxidant, achieves good yields and high stereoselectivities (84-94%ee) for ffie epoxidation of ds-alkenes [21]. The Shi epoxidation, which is catalyzed by ffie fructose-derived ketone and oxone, has been successfully used in ffie epoxidation of frans-alkenes, yielding ffie corresponding oxides with 93-98% ee [74]. However, for nonfunctionalized terminal aliphatic alkenes, chemocatalysts typically display low stereoselectivity [7]. 

Prasad and co-workers at Bristol-Myers Squibb investigated the process-scale preparation of enantioenriched dihydrobenzofuran epoxide in support of their melatonin agonist programme (Scheme 14.56). The authors hoped to access kilogram quantities of 146 using the Jacobsen epoxidation as the key step. " Thus, the process was developed for the epoxidation of alkene 147 to afford 148. The researchers were able to carry this reaction out on kilo-scale successfully and enantioselectivities obtained were consistently 70-79%. While the Jacobsen epoxidation was able to perform where other catalysts could not (SAE), the investigators ultimately opted to use an alternative two-step process for the preparation of this epoxide on production-scale, utilising dihydrojylation and base-promoted 8 2 displacement to afford epoxide 148. 

Chiral epoxides can be prepared (a) by a stereoselective oxidation of prochiral alkenes (e.g. by Sharpless and Jacobsen epoxidation), or (b) by an enantioselective aUcylidenation of prochiral oxo componnds with ylides, carbenes, or through the Darzens reaction. 

Non-functionalized alkenes 6, with an isolated carbon-carbon double bond lacking an additional coordination site, can be epoxidized with high enantiomeric excess by applying the Jacobsen-Katsuki epoxidation procedure using optically active manganese(iii) complexes ... 

The Best results are obtained with cA-alkenes however, the epoxidation of tri-and tetra-substituted double bonds is also possible. Because of its versatility, the Jacobsen-Katsuki epoxidation is an important method in asymmetric synthesis. 

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. 

Conjugated dienes can be epoxidized to provide vinylepoxides. Cyclic substrates react with Katsuki s catalyst to give vinylepoxides with high ees and moderate yields [17], whereas Jacobsen s catalyst gives good yields but moderate enantiose-lectivities [18]. Acyclic substrates were found to isomerize upon epoxidation (Z, )-conjugated dienes reacted selectively at the (Z)-alkene to give trans-vinylepoxides (Scheme 9.4a) [19]. This feature was utilized in the formal synthesis of leuko-triene A4 methyl ester (Scheme 9.4b) [19]. 

Ordinary alkenes (without an allylic OH group) have been enantioselectively epoxidized with sodium hypochlorite (commercial bleach) and an optically active manganese-complex catalyst. Variations of this oxidation use a manganese-salen complex with various oxidizing agents, in what is called the Jacobsen-Katsuki... 

Immobilization of chiral complexes in PDMS membranes offers a method for the generation of new chiral catalytic membranes. The heterogenization of the Jacobsen catalyst is difficult because the catalyst loses its enantioselectivity during immobilization on silica or carbon surfaces whereas the encapsulation in zeolites needs large cages. However, the occlusion of this complex in a PDMS matrix was successful.212 The complex is held sterically within the PDMS chains. The Jacobsen catalyst occluded in the membrane has activity and selectivity for the epoxidation of alkenes similar to that of the homogeneous one, but the immobilized catalyst is recyclable and stable. 

The protocol developed by Jacobsen and Katsuki for the salen-Mn catalyzed asymmetric epoxidation of unfunctionalized alkenes continues to dominate the field. The mechanism of the oxygen transfer has not yet been fully elucidated, although recent molecular orbital calculations based on density functional theory suggest a radical intermediate (2), whose stability and lifetime dictate the degree of cis/trans isomerization during the epoxidation <00AG(E)589>. 

The requirement for the presence of an adjacent alcohol group can be regarded as quite a severe limitation to the substrate range undergoing asymmetric epoxidation using the Katsuki-Sharpless method. To overcome this limitation new chiral metal complexes have been discovered which catalyse the epoxidation of nonfunctionalized alkenes. The work of Katsuki and Jacobsen in this area has been extremely important. Their development of chiral manganese (Ill)-salen complexes for asymmetric epoxidation of unfunctionalized olefins has been reviewed1881. 

It should be added that many other groups have contributed to the predevelopments of these inventions and also to later developments. All four reactions find wide application in organic synthesis. The Sharpless epoxidation of allylic alcohols finds industrial application in Arco s synthesis of glycidol, the epoxidation product of allyl alcohol, and Upjohn s synthesis of disparlure (Figure 14.4), a sex pheromone for the gypsy moth. The synthesis of disparlure starts with a Ci3 allylic alcohol in which, after asymmetric epoxidation, the alcohol is replaced by the other carbon chain. Perhaps today the Jacobsen method can be used directly on a suitable Ci9 alkene, although the steric differences between both ends of the molecules are extremely small ... 

Although the Sharpless catalyst was extremely useful and efficient for allylic alcohols, the results with ordinary alkenes were very poor. Therefore the search for catalysts that would be enantioselective for non-alcoholic substrates continued. In 1990, the groups of Jacobsen and Katsuki reported on the enantioselective epoxidation of simple alkenes both using catalysts based on chiral manganese salen complexes [8,9], Since then the use of chiral salen complexes has been explored in a large number of reactions, which all utilise the Lewis acid character or the capacity of oxene, nitrene, or carbene transfer of the salen complexes (for a review see [10]). 

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