Ketones asymmetric 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],... 

Important extensions of proline catalysis in direct aldol reactions were also reported. Pioneering work by List and co-workers demonstrated that hydroxy-acetone (24) effectively serves as a donor substrate to afford anfi-l,2-diol 25 with excellent enantioselectivity (Scheme 11) [24]. The method represents the first catalytic asymmetric synthesis of anf/-l,2-diols and complements the asymmetric dihydroxylation developed by Sharpless and other researchers (described in Chap. 20). Barbas utilized proline to catalyze asymmetric self-aldoli-zation of acetaldehyde [25]. Jorgensen reported the cross aldol reaction of aldehydes and activated ketones like diethyl ketomalonate, in which the aldehyde... 

Deng et al. later found that dimeric cinchona alkaloids such as (DHQ AQN (8, Scheme 6.6) and (DHQD PHAL (9, Scheme 6.7) - both well known as ligands in the Sharpless asymmetric dihydroxylation and commercially available - also catalyze the highly enantioselective cyanosilylation of acetal ketones with TMSCN... 

Stereoselective epoxidation of enoates. The final step in the synthesis of (+)-aphidicolin (4) requires a stereoselective conversion of the cyclic norketone (I) to a Wol,2-diol, >C(0H)-CH20H. Methylcnation of the ketone followed by a Sharpless asymmetric dihydroxylation provides a 1 1 mixture of epimcric 1,2-diols. Reaction with a chiral oxaziridinc also provides a 1 1 mixture of cpimcric epoxides. The transformation is effected successfully by conversion of the ketone to the enol triflate, which is converted to the enoate (2) by Pd-catalyzed carbonylation in methanol (13,234). Epoxidation of 2 with m-CPBA in buffered CH2CI2 with a radical scavenger (4,85-86) results in a single epoxy ester (3) in 90% yield. This product is reduced with lithium aluminum hydride (excess) to aphidicolin (4) in 67% overall yield from the ketone 1. 

Asymmetric dihydroxylation of the side-chain of Z-1-(4-meth-oxyphenyl)-1-(tert-butyldimethylsiloxy)-1-propene to give (R)-l-hydroxyethyl 4-methoxyphenyl ketone in 94% yield (99% e.e.) was effected by addition of the alkene to a stirred mixture of osmium tetroxide, potassium ferricyanide, potassium carbonate, a 9-0-(9 -phenanthryl)ether(PHN) of dihydroquinidine and 1 mole of methanesulphonamide in aqueous tert-butanol (1 1), with reaction during 16 hours at ambient temperature. Then treatment with sodium sulphite prior to work-up to gave the product (ref. 130). Other best ligands were the 9-0-(4 -methyl-2 -quinolyl) ethers (MEQ) of dihydroquinine. 

Hydroxy-ketones have also been obtained very conveniently by epoxidation or dihydroxylation of silyl enol ethers (derived from ketones with either kinetic or thermodynamic control), for example with mCPBA or osmium tetroxide and N-methylmorpholine-A-oxide. Asymmetric dihydroxylation, for example with AD-mix-a or -(3 (see Section 5.3), can provide highly enantioenriched products (6.56). ... 

The Sharpless procedure for effecting osmium-catalyzed ligand-accelerated asymmetric dihydroxylation was utilized successfully the reaction could also be scaled up. Bis(3-methylthien-2-yl) ketone (59) was also a product in these reactions and was accompanied by an impurity whose structure has not been elucidated. Optimum yields of the dihydroxy material were obtained in dioxane-water/t-butanol-water mixtures. Use of osmium tetroxide instead of potassium osmate led to a slower reaction and increased the formation of undesired products. The material derived from synthesis revealed complete identity with the tablet degradates Any diastereomers that formed were not resolved under our chromatographic conditions. Attempted functionalization of the vicinal dihydroxy groups (acetate, acetonide, trflate) was unsuccessful and led to complex mixtures of products. 

Accordingly, the synthesis of phthalide 44 began from methyl ketone 27 (Scheme 18). In order to avoid interference of the olefin moiety with haloge-nation of the aromatic ring, asymmetric dihydroxylation was conducted first. Treatment of alkene 27 with AD-mix a in tcrt-butanol/water (1 1) provided diol 27 in a pleasing 87% yield. Inspection of the and NMR spectra did not indicate the presence of a diastereomeric mixture. However, although alkene 27 is structurally well suited to the Sharpless mnemonic, we thought it... 

In connection with studies on the synthesis of complex cell wall glycans, we have developed effective syntheses of the novel branched sugar aceric acid and its C-2 epimer. Control of asymmetry in the installation of the key tertiary centers was effected by either asymmetric dihydroxylation of an appropriate alkene derivative or by thiazole addition to the corresponding ketone. 

Scheme 5.125 Conversion of silyl enol ethers 506 and 509 into a-hydroxy ketones 508 and 510, respectively, by Sharpless asymmetric dihydroxylation.

The asymmetric oxidation of a variety of differently substituted, acyclic and cyclic enol phosphates using the Sharpless AD (asymmetric dihydroxylation)-reagents, AD-mix-a and AD-mix- 0, and a fructose-derived chiral ketone as a catalyst, with PMS was a terminal oxidant, afforded the corresponding a-hydroxy ketones in good yield and with high enantioselectivity. The influence of substrate steric and electronic factors on the facial stereoselectivity has been studied. Kinetic and activation parameters for copper(II)-catalysed and -uncatalysed oxidation of ornithine with PMS have been determined. Cyclic voltammetric and absorption studies confirmed the formation of a copper-ornithine-PMS complex and ESR spectral studies ruled out the participation of free radical intermediates. Kinetic and activation parameters for the oxidation of aspartic acid and nicotinic acid with PMS have been determined and plausible mechanisms have been proposed. 

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