Sharpless asymmetric epoxidation directed epoxidations

As an example of the usefulness of the Sharpless asymmetric epoxidation the enantioselective synthesis of (-)-swainsonine and an early note by Nicolaou on the stereocontrolled synthesis of 1, 3, 5...(2n + 1) polyols, undertaken in connection with a programme directed towards the total synthesis of polyene macrolide antibiotics, such as amphotericin B and nystatin Aj, will be discussed. 

An intramolecular diastereoselective Refor-matsky-type aldol approach was demonstrated by Taylor et al. [47] with an Sm(II)-mediated cy-clization of the chiral bromoacetate 60, resulting in lactone 61, also an intermediate in the synthesis of Schinzer s building block 7. The alcohol oxidation state at C5 in 61 avoided retro-reaction and at the same time was used for induction, with the absolute stereochemistry originating from enzymatic resolution (Scheme II). Direct re.solution of racemic C3 alcohol was also tried with an esterase adapted by directed evolution [48]. In other, somewhat more lengthy routes to CI-C6 building blocks, Shibasaki et al. used a catalytic asymmetric aldol reaction with heterobimetallic asymmetric catalysts [49], and Kalesse et al. used a Sharpless asymmetric epoxidation [50]. 

The oxidation of sulfides to sulfoxides can be made asymmetric by using one of the important reactions we introduced in the last chapter—the Sharpless asymmetric epoxidation. The French chemist Henri Kagan discovered in 1984 that, by treating a sulfide with the oxidant t-butyl hydroperoxide in the presence of Sharpless s chiral catalyst (Ti(0 Pr)3 plus one enantiomer of diethyl tartrate), the oxygen atom could be directed to one of the sulfide s two enantiotopic lone pairs to give a sulfoxide in quite reasonable enantiomeric excess (ee). 

This methodology [94TL3601] was used to construct the optically active erythro-diol 8, which was then stereospecifically converted to (+)- disparlure (9), the sex attractant pheromone of the female gypsy moth. This transformation represents a formal asymmetric epoxidation across a nonfunctionalized olefin, not a direct option with traditional Sharpless asymmetric epoxidation technology. This clever variation using initial Sharpless dihydroxylation (applicable to nonfunctionalized olefins) and subsequent epoxide formation is starting to be recognized as a useful indirect method for asymmetric epoxidation. 

We screened our libraries for the site-selective epoxidation of famesol (120) [182]. Either the peracid reagent /mCPBA, or catalytic n-alkyl acids, provided a benchmark for the intrinsic and poorly selective product distribution of monoepoxides (see Fig. 13b inset for schematic of famesol nomenclature). Hits from the initial libraries, however, showed selectivity toward 2,3-epoxide 121 and 6,7-epoxide 122, inspiring the development of biased combinatorial libraries to select further for these oxidation sites (Fig. 13b). Further optimization of the sequences after additional library sequences yielded peptide 123, which provided 2,3-epoxy famesol 121 with 1 1 >100 site selectivity (10,11 6,7 2,3) in 81% yield and 86% ee. These values are comparable to those provided for this substrate by the venerable Sharpless asymmetric epoxidation [187]. Optimization of the 6,7-biased sequence led to peptide 124, which provided 6,7-epoxy famesol 122 in 1.2 8.0 1.0 site selectivity (10,11 6,7 2,3) in 43% yield and 10% ee. Despite the modest ee of 122, we note that, to our knowledge, no existing catalytic epoxidation method is capable of providing 122 directly in reasonable purity. 

The Sharpless asymmetric epoxidation of allylic alcohols (one of the reactions that helped K. Barry Sharpless earn his part of the 2001 Nobel Prize) offers a good example of an enantioselective technique that can be used to create either enantiomer of an epoxide product. This reaction uses a diester of tartaric acid, such as diethyl tartrate (DET) or diisopropyl tartrate (DIPT), as the source of chirality. The dialkyl tartrate coordinates with the titanium tetraisopropoxide [Ti(Oi-Pr)4] catalyst and t-butyl hydroperoxide (r-BuOOH) to make a chiral oxidizing agent. Since both enantiomers of tartaric acid are commercially available, and each enantiomer will direct the reaction to a different prochiral face of the alkene, both enantiomers of an epoxide can be synthesized. 

The Sharpless asymmetric epoxidations (SAEs) have been used in many cases for the synthesis of enantiopure 5,6-dihydropyrones, both in the direct mode, the conversion of a prochiral olefin into an enantioenriched epoxide, and in the kinetic resolution mode, which involves the selective epoxidation of one of the enantiomers in a racemic olefin. For example, a very recent synthesis of a natural pyrone isolated... 

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. 

The most widely used system in industry for catalytic asymmetric epoxidation is known as Sharpless Asymmetric Epoxidation (SAE) (Figure 14.13). While key mechanistic insights will not be covered here as they have been described in detail in previous reviews, our focus will be on the application of this directed epoxidation in an industrial setting. Notably, SAE has been utilised for process-scale preparation of raw materials and as part of... 

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 ... 

The quinoline portion of the target alkaloids was prepared by condensing p-anisidine 9 with ethyl propiolate, followed by bromination. Coupling of 10 with the boronic ester 8 proceeded to give 11, the intermediate for the synthesis of both 1 and 2. Selective direct epoxidation of 11 using the usual reagents failed, but Sharpless asymmetric dihydroxylation was successful, providing the diol in > 96 4... 

The mechanism of the asymmetric epoxidation of allylic alcohols with the Sharpless-Katsuki catalyst is assumed to be very similar to the one described for the Halcon-ARCO process in Section 2.5. The key point is that the chiral tartrate creates an asymmetric environment about the titanium center (Figure 18). When the allylic alcohol and the t-butyl hydroperoxide bind through displacement of alkoxy groups from the metal, they are disposed in such a way as to direct oxygen transfer to a specific face of the C=C double bond. This point is crucial to maximize enantioselectivity. 

Direct air epoxidation of propylene to propylene oxide suffers from selectivity problems. Epoxidation by alkyl hydroperoxide, as practiced by Arco, is based on the use of Mo(CO)g as a homogeneous catalyst. The most impressive use of homogeneous catalysis in epoxidation, however, is in the Sharpless asymmetric oxidation of allylic alcohols. In view of its importance, this enantioselective reaction is included in Chapter 9 which is devoted mainly to asymmetric catalysis. 

Efaroxan, an a2 adrenoreceptor antagonist, could be used for the treatment of neurodegenerative diseases (Alzheimer and Parkinson), migraine and type II diabetes. Therefore, the total syntheses of ( + )-efaroxan and their derivatives have drawn much attention.The chiral 2,3-dihydrobenzofuran carboxylic acid 135, the direct precursor of (+ )-efaroxan, was obtained mainly from the resolution of racemic 135. Coelho el al. have reported a straightforward enantioselective synthesis of i -( + )-2-ethyl-2,3-dihydrofuran-2-carboxylic acid (135) achieved by a Sharpless-Katsuki asymmetric epoxidation reaction (Scheme 5.22). The dihydrobenzofuran acid 135 was obtained in seven steps from MBH adduct 136 in an overall yield of 17%. 

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