Dihydroxylation, of alkenes

If we want a ds-diol, then both of the OH groups must be added from the same face of the molecule, and this is ideally achieved by a synchronous process. When osmium tetroxide 

This is the Upjohn reagent for cw-dihydroxylation of alkenes. We need to consider which face of the molecule will react one is significantly less hindered than the other, and this is the face that reacts, so the product is 11.33. 

The development of RuO as a aT-dihydroxylation catalyst is a relatively new and potentially important area. Until recently OsO has been the reagent of choice for this, but use of the cheaper RuO may well become competitive, though stringent reaction conditions need to be used because RuO is so much more powerful an oxidant than OsO. Reactions are much faster than for OsO, but so-called flash dihydroxylations in which low temperatures are used have been developed, and are the subject of much current research. There are several reviews including mechanistic aspects [7-9] and one on the synthesis of poly oxygenated steroids [6]. The scope and limitations of the procedure have been discussed [155, 156]. 

The first observation that RuO is usable for the reaction was made by Sharpless et al. in 1976 in a footnote to a paper on osmylation of alkenes. It was found that E- and Z-cyclododecene with stoich. RuO /EtOAc at -78°C gave the threo and erythro diols, but the procedure was not deemed viable owing to the low yields obtained and the necessity for working at low temperatures [157], 

The system RuCl3/aq. Na(IO )/CeCl3.7H3O/EtOAc-CH3CN/0°C was used to cw-dihydroxylate 3-benzyloxy-2,2-difluoro-cyclo-oct-4Z-en-l-one to 3R -benzyloxy-2,2-difluoro-9-oxa-15, 5R -bicyclo[3.3.1]nona-15, 45 -diol and the 

Acetic acid 2-hydroxy-3-oxo-3-phenylpropyl ester 3 - Acetoxy-1 -cyclohexene 17)3-Acetoxy-estr-5(10)-ene-3-one rrara-Cyclohexenyl diacetate 4-Acetyl- 1-Methylcyclohexene 3-(Azidopropenyl)benzene 

3-Cyanocyclohexene 2-Cyclohexen-1 -one Allyl acetate Stilbene Styrene 

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Catalytic asymmetric dihydroxylation of alkenes with participation of insoluble polymer-bound cinchonine alkaloids 99SLI181. 

Another important reaction associated with the name of Sharpless is the so-called Sharpless dihydroxylation i.e. the asymmetric dihydroxylation of alkenes upon treatment with osmium tetroxide in the presence of a cinchona alkaloid, such as dihydroquinine, dihydroquinidine or derivatives thereof, as the chiral ligand. This reaction is of wide applicability for the enantioselective dihydroxylation of alkenes, since it does not require additional functional groups in the substrate molecule ... 

With this reaction, two new asymmetric centers can be generated in one step from an achiral precursor in moderate to good enantiomeric purity by using a chiral catalyst for oxidation. The Sharpless dihydroxylation has been developed from the earlier y -dihydroxylation of alkenes with osmium tetroxide, which usually led to a racemic mixture. 

Scheme 12.7. Enantioselective Osmium-Catalyzed Dihydroxylation of Alkenes...

Syn-Dihydroxylation. When the reaction was first discovered, the syn-dihydroxylation of alkenes was carried out by using a stoichiometric amount of osmium tetroxide in dry organic solvent.56 Hoffman made the observation that alkenes could react with chlorate salts as the primary oxidants together with a catalytic quantity of osmium tetroxide, yielding syn-vicinal diols (Eq. 3.11). This catalytic reaction is usually carried out in an aqueous and tetrahydrofuran solvent mixture, and silver or barium chlorate generally give better yields.57... 

A very effective way of carrying out syn-dihydroxylation of alkenes is by using an osmium tetroxide-tertiary amine N-oxide system. This dihydroxylation is usually carried out in aqueous acetone in either one-or two-phase systems, but other solvents may be required to overcome problems of substrate solubility.61... 

Since Sharpless discovery of asymmetric dihydroxylation reactions of al-kenes mediated by osmium tetroxide-cinchona alkaloid complexes, continuous efforts have been made to improve the reaction. It has been accepted that the tighter binding of the ligand with osmium tetroxide will result in better stability for the complex and improved ee in the products, and a number of chiral auxiliaries have been examined in this effort. Table 4 11 (below) lists the chiral auxiliaries thus far used in asymmetric dihydroxylation of alkenes. In most cases, diamine auxiliaries provide moderate to good results (up to 90% ee). 

However, for the dihydroxylation of alkenes the microbiological method is not so effective and the biocatalytic methodology pales into insignificance compared with the powerful chemical technique introduced by Sharpless. 

These cinchona esters also effect asymmetric dihydroxylation of alkenes in reactions with an amine N-oxide as the stoichiometric oxidant and 0s04 as the catalyst. Reactions catalyzed by 1 direct attack to the re-face and those catalyzed by 2 direct attack with almost equal preference for the 5i-face. 

Polymer-supported [e.g. 8, 9] and silica-supported [10] cinchona alkaloids have been used in the asymmetric dihydroxylation of alkenes using osmium tetroxide. Enantiomeric excesses >90% have been achieved for diols derived from styrene derivatives. 

About a decade after the discovery of the asymmetric epoxidation described in Chapter 14.2, another exciting discovery was reported from the laboratories of Sharpless, namely the asymmetric dihydroxylation of alkenes using osmium tetroxide. Osmium tetroxide in water by itself will slowly convert alkenes into 1,2-diols, but as discovered by Criegee [15] and pointed out by Sharpless, an amine ligand accelerates the reaction (Ligand-Accelerated Catalysis [16]), and if the amine is chiral an enantioselectivity may be brought about. 

Figure 14.13. Schematic dihydroxylation of alkenes by metal oxo complexes...

Sharpless stoichiometric asymmetric dihydroxylation of alkenes (AD) was converted into a catalytic reaction several years later when it was combined with the procedure of Upjohn involving reoxidation of the metal catalyst with the use of N-oxides [24] (N-methylmorpholine N-oxide). Reported turnover numbers were in the order of 200 (but can be raised to 50,000) and the e.e. for /rara-stilbene exceeded 95% (after isolation 88%). When dihydriquinidine (vide infra) was used the opposite enantiomer was obtained, again showing that quinine and quinidine react like a pair of enantiomers, rather than diastereomers. 

Air or dioxygen can be used as an oxidant with non-chiral DABCO to give a low cost catalyst for dihydroxylation of alkenes into racemic mixtures dihydroquinidine modified catalysts with the air variant give lower e.e. s than the AD-mix catalysts [26],... 

Scheme 55 Electrochemical enantioselective Sharpless dihydroxylation of alkenes.

Asymmetric dihydroxylation of alkenes using osmium tetroxide... 

After the "asymmetric epoxidation" of allylic alcohols at the very beginning of the 80 s, at the end of the same decade (1988) Sharpless again surprised the chemical community with a new procedure for the "asymmetric dihydroxylation" of alkenes [30]. The procedure involves the dihydroxylation of simple alkenes with N-methylmorpholine A -oxide and catalytic amounts of osmium tetroxide in acetone-water as solvent at 0 to 4 °C, in the presence of either dihydroquinine or dihydroquinidine p-chlorobenzoate (DHQ-pClBz or DHQD-pClBz) as the chiral ligands (Scheme 10.3). 

The work by E.J. Corey [37], M. Hirama [38] and K. Tomioka [39], and their associates, on asymmetric dihydroxylation of alkenes with chiral diamine-osmium tetroxide complexes also deserves to be mentioned. 

Scheme 4.13 Solid-phase attached catalysts for the asymmetric dihydroxylation of alkenes.

Other functionalized supports that are able to serve in the asymmetric dihydroxylation of alkenes were reported by the groups of Sharpless (catalyst 25) [88], Sal-vadori (catalyst 26) [89-91] and Cmdden (catalyst 27) (Scheme 4.13) [92]. Commonly, the oxidations were carried out using K3Fe(CN)g as secondary oxidant in acetone/water or tert-butyl alcohol/water as solvents. For reasons of comparison, the dihydroxylation of trons-stilbene is depicted in Scheme 4.13. The polymeric catalysts could be reused but had to be regenerated after each experiment by treatment with small amounts of osmium tetroxide. A systematic study on the role of the polymeric support and the influence of the alkoxy or aryloxy group in the C-9 position of the immobilized cinchona alkaloids was conducted by Salvadori and coworkers [89-91]. Co-polymerization of a dihydroquinidine phthalazine derivative with hydroxyethylmethacrylate and ethylene glycol dimethacrylate afforded a functionalized polymer (26) with better swelling properties in polar solvents and hence improved performance in the dihydroxylation process [90]. 

The dihydroxylation of alkenes is a useful sttategy for the synthesis of polyols and these can be nitrated to the corresponding nitrate esters. Evans and Gallaghan " synthesized both the mono- (74) and di- (70) allyl ethers of pentaerythritol and used these for the synthesis of some novel nitrate ester explosives. 

The Sbarpless asymmetric dihydroxylation of alkenes usually employs a stoichiometric amount of iodine or potassium ferricyanide to re-oxidisc the osmium centred intermediates in the catalytic cycle [73]. Either reagent can also be used in catalytic amounts and re-oxidised electrochemically at an anode [74, 75]. 

Osmium-catalyzed oxidation is one of the most useful routes to dihydroxylation of alkenes to give the corresponding diols. This oxidation proceeds in the presence... 

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