Sharpless, Jacobsen and

Together, the epoxidations of Sharpless, Jacobsen, and Katsuki, plus others we do not have space to cover, provide valuable solutions to many synthetic problems—in particular because... 

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. 

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. 

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]). 

Optically active epoxides are important building blocks in asymmetric synthesis of natural products and biologically active compounds. Therefore, enantio-selective epoxidation of olefins has been a subject of intensive research in the last years. The Sharpless [56] and Jacobsen [129] epoxidations are, to date, the most efficient metal-catalyzed asymmetric oxidation of olefins with broad synthetic scope. Oxidative enzymes have also been successfully utilized for the synthesis of optically active epoxides. Among the peroxidases, only CPO accepts a broad spectrum of olefinic substrates for enantioselective epoxidation (Eq. 6), as shown in Table 8. 

In a comparison study for the synthesis of the arrhythmia and hypertension drug candidate 7, the intermediate epoxide 8 was prepared by a Sharpless dihydroxylation and a Jacobsen HKR. The latter HKR method gave the highest ee s.116... 

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 (Jacobsen) and dihydroxylation (Sharpless) are other potentially viable approach to epoxides, diols, and aminodiols. 

Catalytic reactions look like the best bet for the future of asymmetric synthesis. In the next chapter you will see how C- H and C-C bonds can also be made by catalytic asymmetric reactions. The only limitation at the moment is the relatively small number of reactions that have been developed. Some of those you have met in this chapter - Sharpless AE and AD and Jacobsen epoxidation - are among the best. 

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. ... 

In summary, the broad application of the Shi epoxidation in the total synthesis of natural products and in drug discovery is a good indication that the reaction will receive more attention and find extended use in the future. Together with the Sharpless epoxidation and the Jacobsen epoxidation, Shi epoxidation has been considered one of the three major catalytic enantioselective epoxidations useful for the synthesis of ehiral epoxides. 

While Table 4 describes the situation in 2001 and many additional processes have been reported. The following analysis is still valid. A look at the processes listed in Table 4 shows that hydrogenation of C=C and C=0 is by far the most predominant transformation applied for industrial processes, followed by epoxidation and dihydroxylation reactions. On the one hand, this is due to the broad scope of cataljrtic hydrogenation and on the other hand it could be attributed to the early success of Knowles with the L-dopa process, because for many years, most academic and industrial research was focused on this transformation. The success with epoxidation and dihydroxylation can essentially be attributed to the efforts of Sharpless, Katsuki, and Jacobsen. If one analyzes the structures of the starting materials, it is quite obvious that many of these compounds are often complex and multifunctional, that is, the successful catalytic systems are not only enantioselective but tolerate many functional groups. 

Jacobsen Epoxidation, Sharpless Dihydroxyiation (Bristol-Myers Squibb). Both, Jacobsen and Sharpless methodology were applied for making multikilogram amounts of benzofuran epoxide, an intermediate for a melatonin antagonist (82). Both reactions required extensive optimization of reagents and reaction conditions. 

In this chapter, we mainly discussed, selective industrial scale organic synthetic applications on C-C and C-0 bond forming ractions involving transition metal catalysis and asymmetric catalysis. It focused on recent advancements of catalytic reactions developed by Nobel laureates, viz., cross-coupling reactions (Heck, Suzuki and Negishi), asymmetric oxidation (Sharpless), metathesis (Grubbs ) and two other noteworthy reactions, Jacobsen and Shi ep-oxidations. 

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. 

---