Jacobsen asymmetric epoxidation

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

Asymmetric epoxidation. Jacobsen s salen-based catalyst 1, derived from (R,R)-or (S,S)-diphenyl-l,2-diaminoethane (16,157) can effect asymmetric epoxidation of alkenes with NaOCI, but the enantioselectivity is generally only moderate ( 70% ee) in the case of cu-alkenes. Subsequently, this group has examined salen-based catalysts... 

The asymmetric epoxidation of electron-poor cinnamate ester derivatives was highlighted by Jacobsen in the synthesis of the Taxol side-chain. Asymmetric epoxidation of ethyl cinnamate provided the desired epoxide in 96% ee and in 56% yield. Epoxide ring opening with ammonia followed by saponification and protection provided the Taxol side-chain 46 (Scheme 1.4.12). 

A breakthrough in the area of asymmetric epoxidation came at the beginning of the 1990s, when the groups of Jacobsen and Katsuki more or less simultaneously discovered that chiral Mn-salen complexes (15) catalyzed the enantioselective formation of epoxides [71, 72, 73], The discovery that simple achiral Mn-salen complexes could be used as catalysts for olefin epoxidation had already been made... 

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. 

The past thirty years have witnessed great advances in the selective synthesis of epoxides, and numerous regio-, chemo-, enantio-, and diastereoselective methods have been developed. Discovered in 1980, the Katsuki-Sharpless catalytic asymmetric epoxidation of allylic alcohols, in which a catalyst for the first time demonstrated both high selectivity and substrate promiscuity, was the first practical entry into the world of chiral 2,3-epoxy alcohols [10, 11]. Asymmetric catalysis of the epoxidation of unfunctionalized olefins through the use of Jacobsen s chiral [(sale-i i) Mi iln] [12] or Shi s chiral ketones [13] as oxidants is also well established. Catalytic asymmetric epoxidations have been comprehensively reviewed [14, 15]. 

Jacobsen (1999) has carried out carbomethoxylation of asymmetric epoxides. Thus, the carbomethoxylation of (R)-propylene oxide with CO and methanol yields 92% of (3R)-hydroxybutanoic acid in greater than 99% ee. Similarly, the reaction of (/ )-epichlorohydrin gives 96% of 4-chloro-(3R)-hydroxybutanoic acid in greater than 99% ee. The catalyst consists of dicobalt octacarbonyl and 3-hydroxy pyridine. A continuous process for making enantiomeric 1-chloro-2-propanol has been suggested. With a suitable catalyst propylene reacts with O2, water, cupric and lithium chloride to give 78% of (S)-l-chloro-2-propanol in 94% ee. 

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 is now clear that asymmetric catalytic hydrogenation is rather successful. However, the initial research work of Sharpless [5] in the asymmetric epoxidation, followed by the results of Jacobsen et al. [6] opened large opportunities for liquid-phase asymmetric oxidation. Sharpless epoxidation has been widely applied in bench-scale organic synthesis, and more recently, salene derivatives emerged among the most effective catalysts in this reaction [7,8],... 

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 ... 

From the point of view of efficiency and application to the industrial production of optically pure compounds the chiral catalyst procedure is the methodology of choice. In this context. Sharpless asymmetric epoxidation and dihydroxylation, Noyori-Takaya s second generation asymmetric hydrogenations and Jacobsen s epoxidation [3] have had a tremendous impact in the last few years and they constitute the basis of the newly spawned "chirotechnology" firms, as well as of the pharmaceutical, fine chemical and agriculture industries. 

Ready, J. M. Jacobsen, E. N. (2001) Highly active oligomeric (salen)Co catalysts for asymmetric epoxide ring opening Reaction, J. Am. Chem. Soc., 123 2687-2688. 

Heterogeneous Asymmetric Epoxidation of Olefins over Jacobsen s Catalyst Immobilized in Inorganic Porous Materials... 

In the present work, the Jacobsen s catalyst was immobilized inside highly dealuminated zeolites X and Y, containing mesopores completely surrounded by micropores, and in Al-MCM-41 via ion exchange. Moreover, the complex was immobilized on modified silica MCM-41 via the metal center and through the salen ligand, respectively. cis-Ethyl cinnamate, (-)-a-pinene, styrene, and 1,2-dihydronaphtalene were used as test molecules for asymmetric epoxidation with NaOCl, m-CPBA (m-chloroperoxybenzoic acid), and dimethyldioxirane (DMD) generated in situ as the oxygen sources. 

In 1990, Jacobsen et al. and Katsuki et al. independently reported asymmetric epoxidation of conjugated olefins by using complexes 9 and 10, respectively, as catalysts [29], These Mn-salen complexes were further improved to complexes 11 [30], 12 [31], and 13 [32]. The common features of these first-generation Mn-salen complexes are i) they possess C2-symmetry, ii) two sp3 carbons at the ethylenediamine moiety are replaced with chiral ones, and iii) they have tert-butyl groups or enantiopure 1-phenylpropyl groups at the C3 and C3 positions. 

Chiral (salen)Mn(III)Cl complexes are useful catalysts for the asymmetric epoxidation of isolated bonds. Jacobsen et al. used these catalysts for the asymmetric oxidation of aryl alkyl sulfides with unbuffered 30% hydrogen peroxide in acetonitrile [74]. The catalytic activity of these complexes was high (2-3 mol %), but the maximum enantioselectivity achieved was rather modest (68% ee for methyl o-bromophenyl sulfoxide). The chiral salen ligands used for the catalysts were based on 23 (Scheme 6C.9) bearing substituents at the ortho and meta positions of the phenol moiety. Because the structures of these ligands can easily be modified, substantia] improvements may well be made by changing the steric and electronic properties of the substituents. Katsuki et al. reported that cationic chiral (salen)Mn(III) complexes 24 and 25 were excellent catalysts (1 mol %) for the oxidation of sulfides with iodosylbenzene, which achieved excellent enantioselectivity [75,76]. The best result in this catalyst system was given by complex 24 in the formation of orthonitrophenyl methyl sulfoxide that was isolated in 94% yield and 94% ee [76]. 

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],... 

In the example of the asymmetric epoxidation of olefins, enzymes, synthetic catalysts, and catalytic antibodies have been compared side-by-side with respect to performance in chemical synthesis (Jacobsen, 1994). Epoxidation of olefins is a reaction of considerable industrial interest where, historically, enzymes have not performed extremely well. One reason is the dependence of the enantiomeric purity of the diol and epoxide products on the regiospecificity of the attack on the racemic epoxide by a water molecule (Figure 20.1). 

Literature devoted specifically to asymmetric epoxidation with Jacobsen catalysts a) E. N. Jacobsen, Acc. Chem. Res. 2000, 33, 421-431 b) E. N. Jacobsen,... 

Wu in Comprehensive Asymmetric Catalysis I-III (Eds. Jacobsen, E. N. Pfaltz, A. Yamamoto H.), Springer, Berlin, 1999, p. 649f. (c) For organocatalytic asymmetric epoxidations, see chapter 10. 

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