Sharpless process

A particular class of modified electrodes consists of those containing a layer of asymmetric compounds, and such electrodes are termed chiral. If one uses these electrodes in organic synthesis, the compound produced may also be asymmetric and optically active. One of the better-known examples of such phenomena is called the Sharpless process (Finn and Sharpless, 1986 Katsuki, 1996). In such processes, the electrode is modified by asymmetric compounds that lead to epoxidation and dihy-droxylation of olefenic compounds, but in an asymmetric form. An example is shown in Fig. 11.5, in which the hydroxylation occurs either on the top or the bottom of the enantiomorphic surface. 

The emergence of the powerful Sharpless asymmetric epoxida-tion (SAE) reaction in the 1980s has stimulated major advances in both academic and industrial organic synthesis.14 Through the action of an enantiomerically pure titanium/tartrate complex, a myriad of achiral and chiral allylic alcohols can be epoxidized with exceptional stereoselectivities (see Chapter 19 for a more detailed discussion). Interest in the SAE as a tool for industrial organic synthesis grew substantially after Sharpless et al. discovered that the asymmetric epoxidation process can be conducted with catalytic amounts of the enantiomerically pure titanium/tartrate complex simply by adding molecular sieves to the epoxidation reaction mix-... 

Further improvement of this process was accomplished by Yudin and Sharpless by use of the stoichiometric oxidant bis(trimethylsilyl) peroxide (BTSP, Scheme 12.7) [28],... 

Asymmetric epoxidation is another important area of activity, initially pioneered by Sharpless, using catalysts based on titanium tetraisoprop-oxide and either (+) or (—) dialkyl tartrate. The enantiomer formed depends on the tartrate used. Whilst this process has been widely used for the synthesis of complex carbohydrates it is limited to allylic alcohols, the hydroxyl group bonding the substrate to the catalyst. Jacobson catalysts (Formula 4.3) based on manganese complexes with chiral Shiff bases have been shown to be efficient in epoxidation of a wide range of alkenes. 

Catalytic dihydroxylations using the osmium tetroxide-tm-butyl hydroperoxide system are largely due to Sharpless and co-workers. The aqueous 70%-i-butyl hydroperoxide is commercially available and ideal for direct use in this dihydroxylation process.60... 

The second synthesis of crystalline 43 was reported by Mori as summarized in Scheme 62 [93]. The building block (4.R,5S)-A was prepared by an enzymatic process, while another building block C was synthesized via Sharpless asymmetric epoxidation. Coupling of A with C gave D, which was cyclized under Op-polzer s conditions to give crystalline E. When E was oxidized with Dess-Martin periodinane or tetra(n-propyl)ammonium perruthenate or Jones chromic acid, crystalline 43 was obtained. Swern oxidation or oxidation with 2,2,6,6-tetramethylpiperidin-1 -oxyl of E afforded only oily materials. Accordingly, oxidation of E to 43 must be executed extremely carefully. A synthesis of oily 43 was reported by Gil [94]. 

V. V. Rostovtsev, L. G. Green, V. V. Fokin, and K. B. Sharpless, A stepwise Huisgen cycloaddition process Copper(I)-catalysed regioselective ligation of azides and terminal alkynes, Angew. Chem. Int. Ed., 41 (2002) 2596-2599. 

The Sharpless epoxidation is a popular laboratory process that is both enantioselective and catalytic in nature. Not only does it employ inexpensive reagents and involve various important substrates (allylic alcohols) and products (epoxides) in organic synthesis, but it also demonstrates unusually wide applicability because of its insensitivity to many aspects of substrate structure. Selection of the proper chirality in the starting tartrate esters and proper geometry of the allylic alcohols allows one to establish both the chirality and relative configuration of the product (Fig. 4-1). 

Related catalytic enantioselective processes It is worthy of note that the powerful Ti-catalyzed asymmetric epoxidation procedure of Sharpless [27] is often used in the preparation of optically pure acyclic allylic alcohols through the catalytic kinetic resolution of easily accessible racemic mixtures [28]. When the catalytic epoxidation is applied to cyclic allylic substrates, reaction rates are retarded and lower levels of enantioselectivity are observed. Ru-catalyzed asymmetric hydrogenation has been employed by Noyori to effect the resolution of five- and six-membered allylic carbinols [29] in this instance, as with the Ti-catalyzed procedure, the presence of an unprotected hydroxyl function is required. Perhaps the most efficient general procedure for the enantioselective synthesis of this class of cyclic allylic ethers is that recently developed by Trost and co-workers, involving Pd-catalyzed asymmetric additions of alkoxides to allylic esters [30]. 

The [3+2] cycloaddition of azides to double and triple bond systems has found considerable interest over the last couple of years. The reaction can either be performed under thermal conditions or by copper(i) catalysis <2001AG(E)2004, 2002AG(E)2596>. In an attempt to broaden the chemistry of such cycloaddition processes, Sharpless et al. reported the generation of tetrazole derivatives 61 by an intramolecular process (Scheme 12). In... 

The reaction mechanisms of these transition metal mediated oxidations have been the subject of several computational studies, especially in the case of osmium tetraoxide [7-10], where the controversy about the mechanism of the oxidation reaction with olefins could not be solved experimentally [11-20]. Based on the early proposal of Sharpless [12], that metallaoxetanes should be involved in alkene oxidation reactions of metal-oxo compounds like Cr02Cl2, 0s04 and Mn04" the question arose whether the reaction proceeds via a concerted [3+2] route as originally proposed by Criegee [11] or via a stepwise [2+2] process with a metallaoxetane intermediate [12] (Figure 2). 

It is instructive to compare the properties of metal peroxo and alkyl (or hydro) peroxo groups for the case of Ti because experimental structures of both types are known [117, 119-121] and Ti compounds are catalysts for such important processes as Sharpless epoxidation [22] and epoxidation over Ti-silicalites [122], where alkyl and hydro peroxo intermediates, respectively, are assumed to act as oxygen donors. Actually, the known Ti(t 2-02) complexes are not active in epoxidation. [121-124] However, there is evidence [123] that (TPP)Ti(02) (TPP = tetraphenylporphyrin) becomes active in epoxidation of cyclohexene when transformed to the cis-hydroxo(alkyl peroxo) complex (TPP)Ti(OH)(OOR) although the latter has never been isolated. 

ARCO has developed a process for both enantiomers of glycidol based on the Sharpless epoxidation (Figure 14.5) using the more stable and readily available cumylhydroperoxide instead of tert-butylhydroperoxide [7] the process has been considered for commercial application. 

Moreover, looking for more effective ligands, Sharpless and his group prepared and tested a number of cinchona alkaloid derivatives, first in the stoichiometric ADH process [33] and then in the catalytic process. They found that aryl ethers of dihydroquinidine, as 4a and 4b, are excellent ligands for ADH of dialkyl substituted olefins (Table 10.3). 

Other functionalized supports that are able to serve in the asymmetric dihydroxylation of alkenes were reported by the groups of Sharpless (catalyst 25) [88], Sal-vadori (catalyst 26) [89-91] and Cmdden (catalyst 27) (Scheme 4.13) [92]. Commonly, the oxidations were carried out using K3Fe(CN)g as secondary oxidant in acetone/water or tert-butyl alcohol/water as solvents. For reasons of comparison, the dihydroxylation of trons-stilbene is depicted in Scheme 4.13. The polymeric catalysts could be reused but had to be regenerated after each experiment by treatment with small amounts of osmium tetroxide. A systematic study on the role of the polymeric support and the influence of the alkoxy or aryloxy group in the C-9 position of the immobilized cinchona alkaloids was conducted by Salvadori and coworkers [89-91]. Co-polymerization of a dihydroquinidine phthalazine derivative with hydroxyethylmethacrylate and ethylene glycol dimethacrylate afforded a functionalized polymer (26) with better swelling properties in polar solvents and hence improved performance in the dihydroxylation process [90]. 

Another route to a methyl-branched derivative makes use of reductive cleavage of spiro epoxides ( ). The realization of this process was tested in the monosaccharide series. Hittig olefination of was used to form the exocyclic methylene compound 48. This sugar contains an inherent allyl alcohol fragmenC the chiral C-4 alcohol function of which should be idealy suited to determine the chirality of the epoxide to be formed by the Sharpless method. With tert-butvl hydroperoxide, titanium tetraisopropoxide and (-)-tartrate (for a "like mode" process) no reaction occured. After a number of attempts, the Sharpless method was abandoned and extended back to the well-established m-chloroperoxybenzoic acid epoxida-tion. The (3 )-epoxide was obtained stereospecifically in excellent yield (83%rT and this could be readily reduced to give the D-ribo compound 50. The exclusive formation of 49 is unexpected and may be associated with a strong ster chemical induction by the chiral centers at C-1, C-4, and C-5. 

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