Asymmetric Alkene Dihydroxylations

Osmium-mediated dihydroxylation of carbon-carbon double bonds with OsO is a classic reaction that can be made catalytic by using cooxidants such as r-butyl hydroperoxide or 8.30. For asymmetric dihydroxylation (ADH) reactions, the co-oxidant of choice is water-soluble potassium ferricyanide. 

Base-catalyzed hydrolysis of 8.37 at the water-organic interface produces the optically active diol and the Os -containing complex [Os02(OH)J . Oxidation of the latter to Os -containing [OsO COH) ] by ferricyanide takes place in the aqueous layer. Both [OsO COH) and 

When organic solvent-soluble co-oxidants such as 8.28 are used, additional catalytically active intermediates are formed in the organic phase. Such intermediates lower the enantioselectivity of the reaction. The advantage of using [Fe(CN)g] as the co-oxidant is that these enantiose-lectivity-lowering pathways are avoided. 

The enantioselectivity of the ADH reaction obviously depends on the coordination properties of the chiral ligand L. Many such ligands have been screened. The most effective ones are those with chiral alkaloid units of the cinchona family. The ligand 8.38 has been shown to be especially effective. It has symmetry with a suitable spacer group coupling the two alkaloid units. 

This ligand coordinates to the OsO molecule through the sp -hybrid-ized nitrogen atom of one of the alkaloid units. Although two alkaloid units are present, coordination to only one OsO molecule takes place. The presence of two alkaloid units increases the scope and enantiose-lectivity of the reaction. 

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Figure 9.10 Catalytic cycle for Os04-catalyzed asymmetric alkene dihydroxylation. The dashed line represents the phase boundary between the organic and the aqueous phase. L is the chiral ligand, e.g., 9.44.

Structures 2.51 and 2.52 show ligands used in enantioselective epoxidation of allylic alcohols and asymmetric alkene dihydroxylation (ADH) reactions, respectively (see Section 8.5). 

Figure 8.6 Asymmetric alkene dihydroxylation in a biphasic system using cMrally modified OsO as the catalyst.

Although a large number of asymmetric catalytic reactions with impressive catalytic activities and enantioselectivities have been reported, the mechanistic details at a molecular level have been firmly established for only a few. Asymmetric isomerization, hydrogenation, epoxidation, and alkene dihydroxylation are some of the reactions where the proposed catalytic cycles could be backed with kinetic, spectroscopic, and other evidence. In all these systems kinetic factors are responsible for the observed enantioselectivities. In other words, the rate of formation of one of the enantiomers of the organic product is much faster than that of its mirror image. 

Draw structures of ligands derived from the chiral framework of glucose, tartaric acid, binaphthol, and cinchona alkaloids that are used for efficient asymmetric hydrocyanation, epoxidation, hydroformylation, and alkene dihydroxylation reactions respectively. 

Quite recently it was reported that in addition to hydrogen peroxide, periodate or hexacyanoferrat(III), molecular oxygen21,31-34 can be used to reoxidize these metal-oxo compounds. New chiral centers in the products can be created with high enantioselectivity in the dihydroxylation reactions of prochiral alkenes. The development of the catalytic asymmetric version of the alkene dihydroxylation was recognized by Sharpless receipt of the 2001 Nobel prize in Chemistry. 

The asymmetric cis dihydroxylation of alkenes covalently bound to chiral fragments, which can be cleaved after the osmylation step, has been the subject of several reports2-5. The subsequent removal of the chiral auxiliary can be effected by various methods and allows the preparation of enantiomerically pure hydroxylated compounds. 

Table 6. Asymmetric Catalytic Dihydroxylation of Alkenes in the Presence of Cinchona Derived Ligands"...

Given the high synthetic potential of this transformation, the last few years have witnessed the use of this method for the asymmetric cis dihydroxylation of more elaborate alkenes and/or the preparation of interesting synthetic targets. A selection is shown in Table 7. 

The classical and asymmetric catalytic dihydroxylation of alkenes by osmium compounds (Scheme 29) can be... 

A highly convergent synthesis of fostriecin (60) via sequential Pd-catalyzed Negishi cross-couplings and regioselective, asymmetric Os-dihydroxylation of the corresponding alkene, has been described by McDonald and Robles. ... 

Manganese An asymmetric c -dihydroxylation of electron-deficient alkenes with oxone, catalysed by a manganese complex bearing a chiral tetradentate N4-donor ligand (2-5 mol%), has been developed the resulting diols were of <96% ee. Analysis of the reaction mixture by high-resolution ESI-MS revealed the formation of a cis-dioxomanganese(V) intermediate. ... 

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. 

When asymmetric epoxidation of a diene is not feasible, an indirect route based on asymmetric dihydroxylation can be employed. The alkene is converted into the corresponding syn-diol with high enantioselectivity, and the diol is subsequently transformed into the corresponding trans-epoxide in a high-yielding one-pot procedure (Scheme 9.5) [20]. No cpirricrizalion occurs, and the procedure has successfully been applied to natural product syntheses when direct epoxidation strategies have failed [21]. Alternative methods for conversion of vicinal diols into epoxides have also been reported [22, 23]. 

Mehrmann SJ, Abdel-MagidAF, Maryanoff CA, Medaer BP (2004) Non-Salen Metal-Catalyzed Asymmetric Dihydroxylation and Asymmetric Aminohydroxylation of Alkenes. Practical Applications and Recent Advances. 6 153-180 De Meijere, see Wu YT (2004) 13 21-58 Manage S, see Fontecave M (2005) 15 271-288... 

Dihydroxylation and asymmetric dihydroxylation of electronically deficient conjugate alkenes have been developed in aqueous media. These reactions were discussed in Chapter 3. 

The history of asymmetric dihydroxylation51 dates back 1912 when Hoffmann showed, for the first time, that osmium tetroxide could be used catalytically in the presence of a secondary oxygen donor such as sodium or potassium chlorate for the cA-dihydroxylation of olefins.52 About 30 years later, Criegee et al.53 discovered a dramatic rate enhancement in the osmylation of alkene induced by tertiary amines, and this finding paved the way for asymmetric dihydroxylation of olefins. 

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). 

Also fifteen years of painstaking work and the gradual improvement of the system, the Sharpless team announced that asymmetric dihydroxylation (AD) of nearly every type of alkene can be accomplished using osmium tetraoxide, a co-oxidant such as potassium ferricyanide, the crucial chiral ligand based on a dihydroquinidine (DHQD) (21) or dihydroquinine (DHQ) (22) and metha-nesulfonamide to increase the rate of hydrolysis of intermediate osmate esters 1811. 

Asymmetric osmylation of alkenes.3 In the presence of 1 equiv. each of 1 and 0s04, alkenes undergo highly enantioselective ris-dihydroxylation. Highest enantiofacial selectivity (90-99%) is shown in osmylation of trans-di- and trisub-... 

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. 

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],... 

In the case of prochiral alkenes the dihydroxylation reaction creates new chiral centers in the products and the development of the asymmetric version of the reaction by Sharpless was one of the very important accomplishments of the last years. He received the Nobel Price in Chemistry 2001 for the development of catalytic oxidation reactions to alkenes. 

Table 4. Calculated and experimental enantioselectivities in the asymmetric dihydroxylation with different alkenes and bases (adapted from Ref. 28).

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. 

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. 

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