The Jacobsen asymmetric epoxidation

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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R. D. Larsen, T. R. Verhoeven, and P. J. Reider, Mechanistic study of the Jacobsen asymmetric epoxidation of indene,/. Org. Chem. 1997, 62, 2222-2229. International Conference on Harmonisation Guidance on Q A Specifications Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products, Chemical Substances. Federal Register 2000, December 29, 65(251), Notices Food and Drug Administration [Docket No. 97D-0448],... 

The premiere method for producing chiral oxiranes from non-functionalized olefins is the Jacobsen asymmetric epoxidation, which utilizes a chiral manganese salen complex as a catalyst. Since Jacobsen s first report in 1990, intensive study in this area has generated a plethora of reaction conditions and catalyst type.s, as well as questions regarding the mechanistic parameters. The course of the oxygen transfer itself remains a matter of much debate. Norrby and Ackermark <97AG(E) 1723> maintain support for the intermediacy of a metallaoxetane species... 

The Jacobsen asymmetric epoxidation reaction was developed at the beginning of the 1990s aiming at filling the existing lack of suitable method for the epoxidation of unfunctionalized alkenes. The catalytic system is particularly selective toward czis-alkenes 61 (Scheme 34.17) and the possible olefin range nicely complements the Sharpless... 

Synthesis of Indinavir An example of the application of the Jacobsen asymmetric epoxidation method is the large... 

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. 

The reaction was also successful for substituted salicylaldehydes. When Jacobsen came to develop his asymmetric epoxidation, which, unlike the Sharpless asymmetric epoxidation, works for simple alkenes and not just for allylic alcohols, he chose salens as his catalysts, partly because they could be made so easily from salicylaldehydes. For example ... 

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 applicability of the Sharpless asymmetric epoxidation is however limited to functionalized alcohols, i.e. allylic alcohols (see Table 4.11). The best method for non-functionalized olefins is the Jacobsen-Kaksuki method. Only a few years after the key publication of Kochi and coworkers on salen-manganese complexes as catalysts for epoxidations, Jacobsen and Kaksuki independently described, in 1990, the use of chiral salen manganese (111) catalysts for the synthesis of optically active epoxides [276, 277] (Fig. 4.99). Epoxidations can be carried out using commercial bleach (NaOCl) or iodosylbenzene as terminal oxidants and as little as 0.5 mol% of catalyst. The active oxidant is an oxomanganese(V) species. 

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). 

Another study compared a Jacobsen asymmetric epoxidation to epoxide formation through an asymmetric dihydroxylation. The latter process (Scheme 3.21) was found to be advantageous as the overall yield was higher and better stereochemical control could be achieved [324]. 

The catalyhc asymmetric epoxidation of alkenes offers a powerful strategy for the synthesis of enantiomerically enriched epoxides. Among the several existing catalyhc methods, the asymmetric epoxidahon of unfunctionalized alkenes catalyzed by chiral Mn(lll)(salen) complexes such as homochiral [( N.N )-bis(3,5-di-tert-butylsalicylidene)-l,2-cyclohexanediamine]manganese(lll) chloride (22) (Figure 7.7), as developed by Jacobsen and coworkers, represents one ofthe most reliable methods [39]. 

Metal complexes of enantiomericaUy pure N,N -ethylenebis(salicylideneaminato) (salen) complexes in combination with stoichiometric oxidants currently provide the most selective method for the catalytic asymmetric epoxidation of unfunctionalised alkenes. The use of C2-symmetric salen complexes of manganese(lll) were reported independently in 1990 by Jacobsen and coworkers and Katsuki and coworkers. The first generation catalysts are represented by the general structure (4.33). The complex with R = Bu is known as Jacobsen s catalyst. All of the first generation catalysts are composed of a enantiopure diamine core and possess large substituents at the 3/3 and 5/5 positions. Subsequently Katsuki and coworkers developed second generation catalysts such as (4.34) with axially chiral groups at the 3/3 positions. 

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. 

The Sharpless asymmetric epoxidation is reliable, but it works only for allylic alcohols. There is an alternative, however, which works with simple alkenes. The method was developed by Eric Jacobsen and employs a manganese catalyst with a chiral ligand built from a simple diamine. The diamine is not a natural compound and has to be made in enantiomeric form by resolution, but at least that means that both enantiomers are readily available. The diamine is condensed with a derivative of salicylaldehyde to make a bis-imine known as a salen. ... 

Take the millions of lives saved by the synthesis of indinavir, for example. This drug would not have been possible had not the Sharpless and Jacobsen asymmetric epoxidations, the catalytic asymmetric reduction, and the stereoselective enolate alkylation, along with many of the methods tried but not used in the final synthesis, been invented and developed by organic chemists in academic and industrial research laboratories. Some of the more famous names involved, like Sharpless, Jacobsen, and Noyori, invented new methods, while others modified and optimized those methods, and still others applied the methods to new types of molecules. Yet all built on the work of other chemists. 

Thornton, J. E., Fritz, A. and Singh, A. K. Development of Jacobsen Asymmetric Epoxidation and Sharpless Asymmetric Dihydroxy lation Methods for the Large-Scale Preparation of a Chiral Dihydrobenzofuran Epoxide. Org Process Res Dev 7,821-827 (2003). 

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