Asymmetric Epoxidation and Dihydroxylation

Asymmetric oxidation of alkenes is a useful reaction in organic synthesis. Sharpless and coworkers made an outstanding contribution in this field. The first practical method of asymmetric epoxidation of ally lie alcohols was reported by Sharpless in 1980. The epoxidation agent was tert-butylhydroperoxide, and the asymmetric catalyst was composed of diethyl tartrate (DET) D-(—) or L-(+) and titanium tetraisopropoxide. 

The great value of the asymmetric Sharpless epoxidation lies in both the variety of applications for the products of the reaction and the variety of allylic alcohols that will give a product in good yield and high enantiomeric excess, as well as the simplicity of the reagents used to carry out the above reaction. 

---

It is now clear that pure pheromones can be synthesized in quantity. The problem is how to prepare them simply and efficiently. New synthetic methodologies are always welcome to improve the existing syntheses. Organoborane reactions and organotransition metal chemistry contributed much to improve the efficiency of carbon-carbon bond formation, while asymmetric epoxidations and dihydroxylations as well as enzymatic reactions greatly improved the enantiomeric purity of synthetic pheromones. 

The oxidation of enol ethers and their derivatives is a useful method for the synthesis of a-hydroxy-ketones or their derivatives, which are versatile building blocks for organic synthesis. Since enol ethers and esters are types of olefin, some asymmetric epoxidation and dihydroxylation reactions have been applied to their oxidation. 

H ASYMMETRIC EPOXIDATION AND DIHYDROXYLATION OF OLEFINIC DOUBLE BONDS... 

Since the first two approaches are very well known and exploited, and excellent reviews and books on the topic are available [1], we will deal only with some of the most recent findings in chemical catalysis -excluding the Sharpless asymmetric epoxidation and dihydroxylation, to which the whole of Chapter 10 is devoted. Synthetic catalysts which mimic the catalytic action of enzymes, known as chemzymes, will be also considered. 

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. 

The chapter on alicyclic stereoselection has been splitted in two chapters (9 and 10). Chapter 10, which is exclusively devoted to Sharpless asymmetric epoxidation and dihydroxylation, has been rewritten de novo. The most recent advances in catalytic and stereoselective aldol reactions are incorporated in Chapter 9. 

R. Noyori shared the Nobel Prize in Chemistry in 2001 with W. S. Knowles, who pioneered the use of Rh-catalyzed asymmetric hydrogenation, and K. B. Sharpless, who is known for fundamental work on asymmetric epoxidation and dihydroxylation of alkenes involving transition metal catalysis. 

Some of the most pertinent virtues of asymmetric epoxidations and dihydroxylations were already present in their classical versions. Both reactions are highly chemo-selective and can be carried out in the presence of many other functional groups. More important with respect to stereochemistry, each reaction is stereospecific in that the product faithfully reflects the E or Z configuration of the starting olefin (the nucleophilic epoxidation of a,P-unsaturated carbonyl compounds is an important exception). And one should not underestimate the importance of experimental simplicity in most cases, one can carry out these reactions by simply adding the often commercially available reagents to a substrate in solvent, without extravagant precautions to avoid moisture or air. 

More recently, research concerning catalytic oxidation reactions has emerged on one side from bioinorganic chemistry with cytochrome P450 models and non-por-phyrinic methane mono-oxygenase models, and on the other side, from organic chemistry with asymmetric epoxidation and dihydroxylation. 

Olefins are abundant and chemically stable points of departure for the generation of a wide variety of functionalities. Consequently, their chemo- and stereoselective elaboration continues to be of immense importance in the field of organic synthesis. Oxidative transformations of olefins include a wide variety of efficient and stereoselective synthetic reactions to access highly functionalized, chiral building blocks. In particular, the catalytic asymmetric epoxidation and dihydroxylation reactions constitute two of the most reliable and general enantioselective processes developed to date. 

Posticlure [(6Z,9Z,llS,12S)-ll,12-epoxy-6,9-henicosadiene, 14] is the female sex pheromone of the tussock moth, Orgyia postica. Wakamura s first synthesis of 14 was achieved by employing Sharpless asymmetric epoxidation, and the final product was of 59% ee [38]. Mori prepared 14 of high purity as shown in Scheme 25 basing on asymmetric dihydroxylation (AD) [39]. Kumar also published an AD-based synthesis of 14 [40], which was more lengthy and less efficient than Mori s [39]. 

Several methods have been developed for the synthesis of the taxol side chain. We present here the asymmetric construction of this molecule via asymmetric epoxidation and asymmetric ring-opening reactions, asymmetric dihydroxylation and asymmetric aminohydroxylation reaction, asymmetric aldol reactions, as well as asymmetric Mannich reactions. 

In 1959, Kharasch et al.43 reported an allylic oxyacylation of olefins. In the presence of f-butyl perbenzoate and a catalytic amount of copper salt in refluxing benzene, olefin was oxidized to allyl benzoate, which could then be converted to an allyl alcohol upon hydrolysis. It is desirable to introduce asymmetric induction into this allylic oxyacylation because allylic oxyacylation holds great potential for nonracemic allyl alcohol synthesis. Furthermore, this reaction can be regarded as a good supplement to other asymmetric olefinic reactions such as epoxidation and dihydroxylation. 

A more versatile method to use organic polymers in enantioselective catalysis is to employ these as catalytic supports for chiral ligands. This approach has been primarily applied in reactions as asymmetric hydrogenation of prochiral alkenes, asymmetric reduction of ketone and 1,2-additions to carbonyl groups. Later work has included additional studies dealing with Lewis acid-catalyzed Diels-Alder reactions, asymmetric epoxidation, and asymmetric dihydroxylation reactions. Enantioselective catalysis using polymer-supported catalysts is covered rather recently in a review by Bergbreiter [257],... 

Enantiomerically pure epoxides and diols, readily available through the asymmetric epoxidation and asymmetric dihydroxylation reactions, are ideal precursors to prepare cis-amino alcohols via the Ritter reaction. " " A Merck group has shown that indene oxide 175a can be converted effectively to c/i-l-amino-2-indanol, a key fragment of the HlV-protease inhibitor Indinavir via the cis-... 

K.B. Sharpless (1941-) studied at Stanford and was first appointed atMIT but is now at the Scripps Institute in California. His undoubted claim to fame rests on the invention of no fewerthan three reactions of immense significance AE (asymmetric epoxidation) and AD (asymmetric dihydroxylation) are discussed in this chapter. The third reaction, AA (asymmetric aminohydroxylation) has still to reach the perfection of the first two. 

The enantioselective total synthesis of the annonacenous acetogenin (+)-parviflorin was accomplished by T.R. Hoye and co-workers." The b/s-tetrahydrofuran backbone of the natural product was constructed using a sequential double Sharpless asymmetric epoxidation and Sharpless asymmetric dihydroxylation. The bis allylic alcohol was epoxidized using L-(+)-DET to give the essentially enantiopure bis epoxide in 87% yield. 

We have spent some time in this chapter looking at the diastereoselectivity of some very important reactions. We shall be returning to the most important of these in chapter 25 where we discuss two of the most important reactions of the century - asymmetric versions of epoxidation and dihydroxylation by osmium. These developments were possible only because of the selectivities already established by the work described in this chapter and the selectivities we have discussed will be important in many syntheses. 

Before the dihydroxylation reaction burst onto the asymmetric scene, asymmetric epoxidation and associated kinetic resolutions were possibly the most popular methods of producing single enantiomers simply because they worked so well. The epoxidation could, for example, be used reliably in undergraduate laboratories. 

We will see Sharpless epoxidation reactions in the Double Methods section towards the end of the chapter. Interestingly, Sharpless other famous asymmetric method - dihydroxylation - has not found widespread use in kinetic resolution. This is probably because the AD is just too powerful or, to be anthropomorphic, too wilful. In other words, it is not sensitive to the chirality of the substrate and charges ahead and reacts with both enantiomers. That is not to say there are not examples of kinetic resolution with dihydroxylation,19 but they are more rare. However, the dihydroxylation is even more useful and much more general than the kinetic resolution of allylic alcohols by asymmetric epoxidation and was discussed in Chapter 25. A slightly complicated case of kinetic resolution of alcohols by asymmetric dihydroxylation is in the Double Methods section. 

Epoxidations and dihydroxylations catalyzed by soluble PEG-bound catalysts are well-established reactions and this chemistry has been discussed in recent reviews [5,83,84]. In a recent report [85], tartrate esters 44 prepared with a PEG750 or PEG2000 shown to be effective in the asymmetric epoxidation of (E)-hex-2-en-l-ol using Ti(0(CH(CH3)2))4 and (CH3)3COOH in CH2CI2 at -20 °C. Yields of 85% were obtained with e.e. values of the epoxide of 93% - a... 

In spite of the tremendous progress in catalytic asymmetric synthesis [36,177] its use in the syntheses of anthracyclinones is limited, apart from Baker s yeast reduction and Sharpless epoxidation and dihydroxylation. In the recent anthracyclinone literature two contributions have appeared on the application of catalytic enantioselective synthesis. Both are based on the desym-metrization of a meso compoimd, but in entirely different chemical contexts. 

Chiral nonracemic a-hydoxylated ketones are commonly accessed by asymmetric epoxidation or dihydroxylation of enol ethers and this methodology is discussed in the relevant sections of this book. Another general method for the enantioselective a-oxygenation of ketones and aldehydes is by reaction of an electrophilic source of oxygen with chiral nonracemic enamines or enolates or in the presence of Lewis acids. 

Besides the more common reactions such as hydrogenation, isomerization, alkylation, and the Diels-Alder reaction. Sharpless epoxidation and dihydroxylation by asymmetrical catalysis are rapidly emerging as reactions with immense industrial potential. Table 9.7 lists some important syntheses based on asymmetric catalysis. These include processes for the pharmaceutical drugs (S)-naproxen, (S)-ibuprofen, (,S)-propranolol, L-dopa, and cilastatin, a fragrance chemical, L-menthol, and an insecticide (/ )-disparlure. Deltamethrin, an insecticide, is another very good example of industrial asymmetric synthesis. The total synthetic scheme is also given for each product. In general, the asymmetric step is the key step in the total synthesis, but this is not always so, as in the production of ibuprofen. Many of the processes listed in the table are in industrial production. 

Cerl996 Cemerud, M., Reina, J.A., Tegenfeldt, J. and Moberg, C., Chiral Polymers via Asymmetric Epoxidation and Asymmetric Dihydroxylation, Tetrahedron Asymmetry, 7 (1996) 2863-2870. 

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. 

Synthesis of Naproxen Naproxen 102 (5)-2-(6-methoxy-2-naphthyl)propanoic acid) is a well-known nonsteroidal anti-inflammatory dmg (NSAID), and the physiological activity resides in the S enantiomer. The stereogenic center in the structure can be implemented via Sharpless asymmetric epoxidation or dihydroxylation. In the latter case, a more simple substrate is required and the synthesis is more straightforward (Scheme 34.28). The dihydroxylation step for the preparation of the 5-enantiomer was conducted with AD-mix-a on substrate 103 obtaining the desired product 104 with 98% ee and yield of ca. 85% that was not isolated but directly converted into the next steps because of intrinsic instability of the species. 

Synthesis of A -9-isofurans As a demonstration of the reliability of the asymmetric Sharpless epoxidation and dihydroxylation reaction, Taber et al. in 2009 reported on the synthesis of a series of 32 possible enantio-merically pure diastereoisomers of A -9-isofurans 105 known as product by human metabolism of arachidonic... 

Alternatively, epoxides can be formed with concomitant formation of a C-C bond. Reactions between aldehydes and various carbon nucleophiles are an efficient route to epoxides, although the cis. trans selectivity can be problematic (see Section 9.1.4). Kinetic resolution (see Section 9.1.5.2) or dihydroxylation with sequential ring-closure to epoxides (see Section 9.1.1.3) can be employed when asymmetric epoxidation methods are unsatisfactory. 

When asymmetric epoxidation of a diene is not feasible, an indirect route based on asymmetric dihydroxylation can be employed. The alkene is converted into the corresponding syn-diol with high enantioselectivity, and the diol is subsequently transformed into the corresponding trans-epoxide in a high-yielding one-pot procedure (Scheme 9.5) [20]. No cpirricrizalion occurs, and the procedure has successfully been applied to natural product syntheses when direct epoxidation strategies have failed [21]. Alternative methods for conversion of vicinal diols into epoxides have also been reported [22, 23]. 

---