Sharpless oxidation alkene dihydroxylation

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. 

Sharpless applied the same principle of using a central metal that can hold a chiral directing group proximal to an alkene substrate in an enantloselective version of the OSO4-catalyzed alkene dihydroxylation (Section 12-11). Here, the essence of the chiral auxiliary is an amine derived from the family of natural alkaloids called the cinchona (Section 25-8). One of these amines is dihydroquinine, which is added in the linked dimeric form shown on the right. Instead of H2O2 as the stoichiometric oxidant (Section 12-11), Fe ... 

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. 

The osmium-catalyzed dihydroxylation reaction, that is, the addition of osmium tetr-oxide to alkenes producing a vicinal diol, is one of the most selective and reliable of organic transformations. Work by Sharpless, Fokin, and coworkers has revealed that electron-deficient alkenes can be converted to the corresponding diols much more efficiently when the pH of the reaction medium is maintained on the acidic side [199]. One of the most useful additives in this context has proved to be citric acid (2 equivalents), which, in combination with 4-methylmorpholine N-oxide (NMO) as a reoxidant for osmium(VI) and potassium osmate [K20s02(0H)4] (0.2 mol%) as a stable, non-volatile substitute for osmium tetroxide, allows the conversion of many olefinic substrates to their corresponding diols at ambient temperatures. In specific cases, such as with extremely electron-deficient alkenes (Scheme 6.96), the reaction has to be carried out under microwave irradiation at 120 °C, to produce in the illustrated case an 81% isolated yield of the pure diol [199]. 

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. 

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. 

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). 

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 first observation of the c/x-dihydroxylation reaction with RuO was made by Sharpless et al. in 1976, who noted that E and Z-cyclododecene were oxidised by stoich. RuO /EtOAc/-78 C to the threo and erythro diols [299]. Later RuCyaq. Na(IO )/EtOAc-CH3CN/0 C was used and reaction conditions optimised for many alkenes [300] a useful paper with good practical examples discusses the scope and limitations of the procedure (Table 3.2) [301]. Later oxidations were done with stoich. RuOyaq. acetone/-70 C [302] the same reagent converted A, and A steroids to cw-diols, ketones or acids [303], while RuO /aq. Na(10 )/acetone gave diones and acids [304]. 

Transformation of alkene 9 into diol 30 is a Sharpless asymmetric dihydroxylation.8 Its catalytic cycle with K3Fe(CNV, as co-oxidant is shown below. 

A variation within the osmium-catalysed asymmetric dihydroxylation (AD) of alkenes has been described that yields cyclic boronic esters from alkenes in a straightforward manner. A protocol based on the Sharpless AD conditions (for enantiose-lective oxidation of prochiral olefins) has been developed that gives cyclic boronic esters, rather than free diols, with excellent enantiomeric excesses. Some of the... 

Osmium-catalysed dihydroxylation of olefins is a powerful route towards enantioselective introduction of chiral centers into organic substrates [82]. Its importance is remarkable because of its common use in organic and natural product synthesis, due to its ability to introduce two vicinal functional groups into hydrocarbons with no functional groups [83]. Prof. Sharpless received the 2001 Nobel Prize in chemistry for his development of asymmetric catalytic oxidation reactions of alkenes, including his outstanding achievements in the osmium asymmetric dihydroxylation of olefins. 

Unlike epoxides, these five-membered heterocyclics have received scant attention from organic chemists. But the recent catalytic asymmetric dihydroxylation of alkenes (14, 237-239), which is now widely applicable (this volume), and the ready access to optically active natural 1,2-diols has led to study of these compounds, including a convenient method for synthesis. They are now generally available by reaction of a 1,2-diol with thionyl chloride to form a cyclic sulfite of a 1,2-diol, which is then oxidized in the same flask by the Sharpless catalytic Ru04 system, as shown in equation I.1... 

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... 

An orf/io-directed lithiation allows the conversion of 25 to aryl iodide 40. Reductive ether formation of aldehyde 40 with crotyl alcohol yields compound 41. Intramolecular Heck reaction of 41 affords a mixture of the olefins 42 and 43. The undesired alkene 42 can be isomer-ized quantitatively to the desired enol ether 43 with Wilkinson s catalyst. Sharpless dihydroxylation ee 94 %) of the enol ether 43 provides lactol 44, which is oxidized directly to lactone 45. Finally, the pyridone-O-methyl ester is cleaved under acid conditions (45 — 7). 

Asymmetric dihydroxylation Sharpless developed a catalytic system (AD-mix- 3 or AD-mix-a) that incorporates a chiral ligand into the oxidizing mixture which can be used for the asymmetric dihydroxylation of alkenes. The chiral ligands used in Sharpless asymmetric dihydroxylation are quinoline alkaloids, usually dihydroquinidine (DHQD) or dihydroquinine (DHQ) linked by a variety of heterocyclic rings such as 1,4-phthalhydrazine (PHAL) or pyridazine (PYR) (see section 1.6, reference 32 of Chapter 1). 

The Sharpless asymmetric hydroxylation can take one of two forms, the initially developed asymmetric dihydroxylation (AD)1 or the more recent variation, asymmetric aminohydroxylation (AA).2 In the case of AD, the product is a 1,2-diol, whereas in the AA reaction, a 1,2-amino alcohol is the desired product. These reactions involve the asymmetric transformation of an alkene to a vicinally functionalized alcohol mediated by osmium tetraoxide in the presence of chiral ligands (e.g., (DHQD)2-PHAL or (DHQ)2-PHAL). A mixture of these reagents (ligand, osmium, base, and oxidant) is commercially available and is sold under the name of AD-mix p or AD-mix a (vide infra). 

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. 

Sharpless s work in oxidation also included methods for the enantioselective dihydroxylation of alkenes (see Section 15.5). 

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