Sharpless asymmetric epoxidation dihydroxylation

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]. 

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. 

Salinosporamide synthesis 196 Sharpless asymmetric dihydroxylation (see also Osmylation) 84,89, 141, 189 Sharpless asymmetric epoxidation 32,141 Silane, allylic synthesis 43 Sonogashira coupling (see Pd)... 

Asymmetric epoxidation, dihydroxylation, aminohydroxylation, and aziridination reactions have been reviewed.62 The use of the Sharpless asymmetric epoxidation method for the desymmetrization of mesa compounds has been reviewed.63 The conformational flexibility of nine-membered ring allylic alcohols results in transepoxide stereochemistry from syn epoxidation using VO(acac)2-hydroperoxide systems in which the hydroxyl group still controls the facial stereoselectivity.64 The stereoselectivity of side-chain epoxidation of a series of 22-hydroxy-A23-sterols with C(19) side-chains incorporating allylic alcohols has been investigated, using m-CPBA or /-BuOOH in the presence of VO(acac)2 or Mo(CO)6-65 The erythro-threo distributions of the products were determined and the effect of substituents on the three positions of the double bond (gem to the OH or cis or trans at the remote carbon) partially rationalized by molecular modelling. 

Jacobsen epoxidation turned out to be the best large-scale method for preparing the cis-amino-indanol for the synthesis of Crixivan, This process is very much the cornerstone of the whole synthesis. During the development of the first laboratory route into a route usable on a very large scale, many methods were tried and the final choice fell on this relatively new type of asymmetric epoxidation. The Sharpless asymmetric epoxidation works only for allylic alcohols (Chapter 45) and so is no good here. The Sharpless asymmetric dihydroxylation works less well on ris-alkenes than on trans-alkenes, The Jacobsen epoxidation works best on cis-alkenes. The catalyst is the Mn(III) complex easily made from a chiral diamine and an aromatic salicylaldehyde (a 2-hydroxybenzaldehyde). 

The aminocyclitol moiety was synthesized in a stereocontrolled manner from cis-2-butene-l,4-diol (Scheme 40)112 by conversion into epoxide 321 via Sharpless asymmetric epoxidation in 88% yield.111 Oxidation of 321 with IBX, followed by a Wittig reaction with methyl-triphenylphosphonium bromide and KHMDS, produced alkene 322. Dihydroxylation of the double bond of 322 with OSO4 gave the diol 323, which underwent protection of the primary hydroxyl group as the TBDMS ether to furnish 324. The secondary alcohol of 324 was oxidized with Dess-Martin periodinane to... 

The Sharpless asymmetric epoxidation of allyl alcohol gives the glycidol derivative 61 in 90% ee after in situ tosylation of 60 [63]. This process is working on a multiton-a-year scale (Arco Co., USA), facilitating the synthesis of a variety of /0-blockers. Asymmetric dihydroxylation of the allyl ether 63 catalyzed by a combined system of OSO4 and the cinchona alkaloid-based ligand 65 allows the commercial synthesis of the propranolol intermediate 64 in 91 % (Sepracor Co., USA) [64]. 

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. 

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. 

The asymmetric dihydroxylation is much less fussy about the alkenes it will oxidize than Sharpless asymmetric epoxidation. Osmium tetroxide itself is a remarkable reagent, since it oxidizes more or less any sort of alkene, electron-rich or electron-poor, and the same is true of the asymmetric dihydroxylation reagent. The following example illustrates both this and a synthetic use for the diol product. 

Margarita Brovetto of the Universidad de la RepubUca, Montevideo, Uruguay, prepared (J. Org. Chem. 2008, 73, 5776) the precursor to the enantiomerciaUy triol 6 by fermentation of bromobenzene with Pseudomonas putida 39/D. Cyclization of 6 gave 7 with high diastereocontrol. Petri M. Pihko of the University of Jyvaskyla, Finland, found (Organic Lett. 2008,10, 4179) that cyclization of 8, prepared by Sharpless asymmetric epoxidation followed by Sharpless asymmetric dihydroxylation, also proceeded with high diastereocontrol. 

Sharpless asymmetric epoxidation is one of the most powerful tools in the field of asymmetric oxidation it requires low temperature eonditions to achieve proper epoxide yields and high enantiomeric excess (ee). Large operation costs associated with reaction conditions restricted the applieation to high scale production however. Sharpless asymmetric dihydroxylation has much use in large-scale productions. 

Sharpless asymmetric dihydroxylation Sharpless asymmetric epoxidation Shi epoxidation Suzuki coupling... 

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. 

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