Hydroxylation using Osmium Tetroxide

Osmium tetroxide can undergo reaction with alkenes to form a cyclic osmate, which in the presence of hydrogen peroxide results in a glycol (diol). Hydrogen peroxide oxidizes the osmium back to osmium tetroxide, while hydrolyzing the cyclic osmate to glycol. The predominant product is a syn addition product. 

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The first useful asymmetric synthesis with a-halo boronic esters utilized (S)-pinanediol [1S-(la,2/1.3//,5a)]-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol as the chiral director39,40. This diol is easily prepared from ( + )-a-pinene by a catalytic hydroxylation with osmium tetroxide, and its enantiomer (i )-pinanediol is available from (-)-(a)-pinene41,42. Pinanediol esters remain useful in view of their excellent stability as well as the ease of preparation of the diol. and their stereoselectivity is very high even though it is no longer the state of the art. 

Hydroxylation of an alkene may be carried out using osmium tetroxide in an inert solvent (e.g. ether or dioxane), whereupon a cyclic osmate ester is formed. This undergoes hydrolytic cleavage under reducing conditions (e.g. aqueous sodium sulphite) to give the 1,2-diol resulting from a ds-hydroxylation process.71... 

Syn hydroxylation is most commonly performed using osmium tetroxide or potassium permanganate, and addition usually occurs from the less hindered side of the double bond in the absence of other directing effects. With Aese reagents, the stereospecificity of syn addition results from formation of cyclic ester intermediates. Support for these arises from isolation of solid addition complexes (1) on reaction of... 

Optically active 1,2-diol units are often observed in nature as carbohydrates, macrolides or polyethers, etc. Several excellent asymmetric dihydroxylation reactions of olefins using osmium tetroxide with chiral ligands have been developed to give the optically active 1,2-diol units with high enantioselectivities. However, there still remain some problems, for example, preparation of the optically active anti-1,2-diols and so on. The asymmetric aldol reaction of an enol silyl ether derived from a-benzyloxy thioester with aldehydes was developed in order to introduce two hydroxyl groups simultaneously with stereoselective carbon-carbon bond formation by using the chiral tin(II) Lewis acid. For example, various optically active anti-a,p-dihydroxy thioester derivatives are obtained in good yields with excellent diastereo-... 

The second method uses the pregnane derivative XI as a starting material. This compound, on hydroxylation with osmium tetroxide, afforded the diol Xlla. This diol was then converted to the androstane analogue X. The same approach was independently published also by Hondo and Mori (3). As a by-product of hydroxylation of olefin XI with osmium tetroxide, we obtained 2B,3B-diol XIV and, from this, the lactone XV. However, when we treated XII (a corresponding diacetate, respectively) with trifluoroperacetic acid we found that oxidation of the side chain surprisingly proceeded much faster than oxidation of the B ring. Thus we obtained not only compound X but also an intermediate, compound XHIb, and on hydrolysis compound Xllla, that is the androstane analogue of castasterone ... 

Using osmium tetroxide to add two hydroxyl groups to the second alkene will give the diastereoisomer on the left, because the mechanism ensures both O atoms add to the same side of the alkene (p. 442 of the textbook). To get the trans diol, we can make an epoxide with m-CPBA and then open it with water, an Sn2 reaction that proceeds with inversion of configuration. 

Oxidation. Maleic and fumaric acids are oxidized in aqueous solution by ozone [10028-15-6] (qv) (85). Products of the reaction include glyoxyhc acid [298-12-4], oxalic acid [144-62-7], and formic acid [64-18-6], Catalytic oxidation of aqueous maleic acid occurs with hydrogen peroxide [7722-84-1] in the presence of sodium tungstate(VI) [13472-45-2] (86) and sodium molybdate(VI) [7631-95-0] (87). Both catalyst systems avoid formation of tartaric acid [133-37-9] and produce i j -epoxysuccinic acid [16533-72-5] at pH values above 5. The reaction of maleic anhydride and hydrogen peroxide in an inert solvent (methylene chloride [75-09-2]) gives permaleic acid [4565-24-6], HOOC—CH=CH—CO H (88) which is useful in Baeyer-ViUiger reactions. Both maleate and fumarate [142-42-7] are hydroxylated to tartaric acid using an osmium tetroxide [20816-12-0]/io 2LX.e [15454-31 -6] catalyst system (89). 

Because osmium tetroxide is expensive, and its vapors are toxic, alternate methods have been explored for effecting vic-glycol formation. In the aliphatic series, olefins can be hydroxylated with hydrogen peroxide with the use of only a catalytic amount of osmium tetroxide. Anhydrous conditions are not necessary 30% hydrogen peroxide in acetone or acetone-ether is satisfactory. The intermediate osmate ester is presumably cleaved by peroxide to the glycol with regeneration of osmium tetroxide. When this reaction was tried on a A -steroid, the product isolated was the 20-ketone ... 

Similar hydroxylation-oxidations can be carried out using a catalytic amount of osmium tetroxide with A-methylmorpholine oxide-hydrogen peroxide or phenyliodosoacetate." A recent patent describes the use of triethylamine oxide peroxide and osmium tetroxide for the same sequence. Since these reactions are of great importance for the preparation of the di-hydroxyacetone side-chain of corticoids, they will be discussed in a later section. 

Problems of acyl anion equivalents met above in the synthesis of similar TMs disappear if (25) is made from the alkene (26), A Wittig is the obvious method to make (26) and reaction between (27) and PhgCO will probably give (26), An alternative is the dehydration of (28), made by Grignard addition to ester (20), Osmium tetroxide was used for the hydroxylation. 

Ishikawa s endgame toward of 54 is shown in Scheme 3.12. First, the allylic alcohol function was oxidized by a substrate-directed dihydroxylation reaction, as developed by Donohoue and coworkers (66 % yield) [36]. This reaction is conducted using 1 equiv each of osmium tetroxide and tetramethylethylene diamine (TMEDA) and provides a method to obtain the syn-A i hydroxylation product in the... 

Exercise 16-37 An elegant modification of the two-step procedure to prepare ketones from alkenes by hydroxylation and oxidative cleavage of the diol formed uses a small amount of potassium permanganate (or osmium tetroxide, 0s04) as the catalyst and sodium periodate as the oxidizing agent ... 

From the practical perspective of laboratory use, the catalytic AD process requires a minimum of concern over stoichiometry. The new osmium tetroxide-chiral ligand complexes are so efficient that for most olefins, 0.2 mol % of osmium will provide a satisfactory rate of reaction at 0°C [291. In the occasional case where hydroxylation is slow under these conditions, the quantity of osmium in the catalyst should be increased to 1 mol % and the reaction temperature kept at 0 °C. In the rare case where hydroxylation is still slow under these conditions, the temperature may be raised to 25°C and, to ensure no loss in enantioselectivity, the ligand concentration may be increased from 1 mol % to 2 mol %. 

The cis- 1,2-glycols, obtainable from the parent aromatic hydrocarbon by osmium tetroxide hydroxylation, can be converted to the corresponding trans-1,2-glycols by oxidation-reduction, using a mixture of dimethyl sulfoxide, sulfur trioxide, and pyridine, followed by lithium aluminum hydride reduction. The trans- 1,2-glycols can be dehydrated to arene oxides using DMF-DMA as mentioned above. Benzo[a]pyrene 4,5-oxide (28) and 7,12-dimethylbenz[a]anthracene 5,6-oxide (30) have been prepared by this method in 68 and 80% yields, respectively.18... 

Alternatively and more conveniently this ds-hydroxylation process can be effected using only catalytic amounts of osmium tetroxide together with hydrogen peroxide, which cleaves the first formed osmate ester to the diol and regenerates the osmium tetroxide. The reaction is carried out in t-butyl alcohol and is illustrated by the conversion of cyclohexene into ds-cyclohexane-l,2-diol (Expt 5.47). 

The classical diene synthesis has been used for building the six-membered ring in the preparation of a/to-inositol by Criegee and Becher.36 trans, trans-Diacetoxybutadiene (XVI) and vinylene carbonate (XVII) condensed at 205-210° to an addition product (XVIII). Hydroxylation of this compound by osmium tetroxide, followed by hydrolysis, gave aWo-inositol the bulky osmium tetroxide approaches from the unhindered side of the molecule and the other possible product of the hydroxylation, m-inositol, is not formed.4 trans-Hydroxy 1 ation of XVIII would give epi-inositol. 

The stereochemistry of the product of a reaction will be influenced by the structures of the reagent and substrate and the mechanisms by which they react. For example, the hydroxylation of but-2-ene by osmium tetroxide and water yields a racemate whilst bromination of the same compound with bromine produces a meso compound (Figure 10.5). Flowever, a stereoselective reaction is most likely to occur when steric hindrance at the reaction centre restricts the approach of the reagent to one direction (Figure 10.6). Furthermore, the action of both enzyme and non-enzyme catalysts may also be used to introduce specific stereochemical centres into a molecule. 

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