1Oxidation reactions1.1Alkene epoxidationDevelopment of “clean” methods for alkene epoxidation using hydrogen peroxide as co-oxidant continues to be a highly active area. Several metal-catalysed methods1–5as well as a kinetic study of activation of hydrogen peroxide in 1,1,1,3,3,3-hexafluoro-2-propanol6have appeared. Stack has studied the influence of ligand and pH on Mn-mediated epoxidation of terminal alkenes with peracetic acid.7For metal-catalysed oxygen transfer reactions, crucial insights into reactivity have emerged from computational studies and recent results on epoxidation by inorganic peroxides have been summarised by Deubel.8Amongst methods for the key asymmetric alkene epoxidation process, Jacobsen/Katsuki Mn(salen) chemistry is synthetically well established, and here again the precise mechanistic details are being further illuminated by theoretical studies.9Biocatalysis is another potentially efficient approach and the use of a cell-free flavin- and NADH-dependent bacterial monooxygenase for the highly enantioselective epoxidation of styrenes in a dodecene/water emulsion has been described.10Exceptional progress continues to be registered in the development of metal-free methods for catalytic asymmetric epoxidation of unfunctionalized alkenes. Activation of Oxone (active constituent KHSO5) has provided the best results to date, and Armstrong has provided an overview of the field.11Chiral ketones (viadioxirane intermediates) continue to receive considerable attention.12Two of the most prevalent workers in the area, Shi13and Yang,14have presented summaries of their achievements. In an application of Yang's binaphthyl-based chiral ketone catalysts, Seki has provided a detailed study of the synthesis of glycidic acids by asymmetric epoxidation of cinnamic acid derivatives.15In continuing detailed structure/selectivity studies to allow rational catalyst improvement, Shi has compared the ketone1to its carbocyclic analogue2.16Carbocycle2gives higher enantioselectivities than1in the asymmetric epoxidation of styrenes (up to 93% ee). Shi suggests that the electron withdrawing oxygen in1lowers the energy of the dioxirane oxygen lone pairs, reducing their overlap with the substrate alkene's π*-orbital in the epoxidation transition state and thus reducing the preference for a spiro-TS relative to a planar one. This is important since it is suggested that the planar and spiro-arrangements lead to opposite product enantiomers. The lengthy synthesis of the more selective catalyst2(13 steps from quinic acid) is a practical disadvantage, however. Shi has also reported a study of the asymmetric epoxidation of severalcis-β-methylstyrenes catalysed byN-aryloxazolidinones3.17In the non-asymmetric dioxirane area, Toy has developed a poly(ethylene glycol)-supported trifluoroacetophenone epoxidation catalyst,18and further computational studies on the dioxirane epoxidation reaction have been performed.19Iminium salts will also promote epoxidation by Oxone,viaoxaziridinium intermediates. As well as a new non-aqueous reaction system (using the tetraphenylphosphonium salt of Oxone),20Page has reported significantly improved levels of asymmetric induction compared to earlier attempts. Catalyst4afforded 95% ee for the asymmetric epoxidation of phenylnaphthalene (Scheme 1).21The dihydroisoquinolinium core has been a commonly studied iminium motif, and Bohé has shown that its catalytic efficiency in achiral epoxidations may be improved by incorporating 7-nitro- and 3,3-dimethyl-substitution.22The aforementioned epoxidation methods are generally electrophilic in nature, and the complementary array of nucleophilic reagent systems provides the methods of choice for electron-poor alkenes (e.g.enones). Catalysis by polyleucine is a fascinating area and saw renewed interest in 2004. The original reaction system was triphasic (inorganic base and H2O2in water; substrate in organic phase; insoluble polyleucine). Geller and co-workers found that the addition of a phase-transfer catalyst (Bu4NBr) allows much faster reactions without the induction period otherwise needed for catalyst activation, and far lower quantities of base and H2O2are required.23They also investigated the effect of the method used for the preparation of polyleucine, and found that material made by high-temperature polymerization gave best results. Importantly, much lower loadings of polyleucine can now be used (0.5 mol% for chalcone epoxidation). These workers have carried out the process on 100 g scale. Roberts and co-workers built upon the finding of the beneficial effect of a phase-transfer catalyst by showing that stirring NaOH, H2O2, Bu4NHSO4and polyleucine in water/toluene followed by removal of the aqueous phase provides a biphasic gel in toluene in which the polyleucine has sequestered the peroxide. This active gel is particularly useful for base-sensitive substrates and was used to prepare epoxides5and6in good yields and excellent enantioselectivities.24Vinyl sulfones are now also viable substrates (e.g. formation of7). Further mechanistic work on the system has been performed.25This includes an interesting discussion of asymmetric amplification: studies using polyleucine derived from non-enantiopure amino acid show highly amplified epoxide enantiomeric excess and fit a mathematical model requiring the active catalyst to have five terminal homochiral residues,26as rationalized by molecular modeling studies.27Asymmetric phase-transfer catalysis is another valuable approach for enone epoxidation. The novel “dual function” catalyst8from Maruoka's group has hydroxyl groups which were incorporated to allow hydrogen bonding to the enolate intermediate, and catalyses enone epoxidation with 89–99% ee.28Interestingly, and unlike some other systems, alkyl substitution in the β-position is tolerated (Scheme 2). Lanthanum–BINOL catalysts also represent an important reagent class, and tris(trifluorophenyl)phosphine oxide has been shown to be an effective additive, allowing enone epoxidation with up to 99% ee.291.2Alkene dihydroxylationOsmium-mediated alkene dihydroxylation is an exceptionally powerful synthetic method, but the reagent's cost and toxicity are often cited as a problem. Thus there is much ongoing interest in systems that allow easy reagent separation and recycling.30The use of fluorous-phase diol ligands for osmium31is one recent example. A quaternary solvent mixture (tBuOH/MeCN/hexane/H2O) has been reported which allows homogeneous dihydroxylation, but becomes binary on addition of extra water. In the presence of dendritic ligands, osmium then partitions into the organic phase, but the diol product resides in the aqueous one, allowing separation.32A reusable “biomimetic” system has been reported consisting of a flavin andN-methylmorpholine-N-oxide immobilized in an ionic liquid that can be employed with aqueous H2O2.33Ionic liquids have also been used34to help facilitate purification and recycling in the Sharpless asymmetric dihydroxylation (AD) reaction, one of the best known and most successful methods for asymmetric synthesis. The development of modified co-oxidant systems for this process also continues, with NaClO2being a recent example.35The most commonly used ligands in Sharpless AD chemistry consist of two cinchona alkaloid units linked by a phthalazine (PHAL) spacer. Bradley has developed a new, readily accessed ligand class centred on a triazine core, which when compared to Sharpless ligands gives similar ee values fortrans-alkenes (although lower for other substitution patterns).36New synthetic applications of the Sharpless AD continue to emerge: for example, 1-silyloxy-1,3-dienes can be converted into furanose derivatives through regioselective dihydroxylation, which surprisingly occurs on the alkene furthest from the silyloxy group.37AD of arylallenes proceeds regioselectively and provides an interesting approach to α-hydroxyketones (Scheme 3).38Substrates with electron-rich aryl groups give best results. Finally, in achiral osmium-mediated dihydroxylationen routeto conformationally-locked difluorosugar analogues, Percy and co-workers noted an unexpected relative stereochemical outcome which was attributed to a possible directing effect by coordination to a ketone carbonyl.39Given the aforementioned cost and toxicity disadvantages of osmium tetroxide, the search for efficient alternative dihydroxylation reagents is an important one. Ruthenium tetroxide is one possibility, but this reagent is more usually associated with alkene cleavage. A recent computational study provides insights into why this is the case.40Last year's Report outlined studies by Plietker and co-workers on the development of modified conditions to allow RuO4-mediated dihydroxylation. The alkene cleavage products usually formed from use of this reagent were suggested to arise directly from the intermediate cyclic ruthenate ester rather thanviathe diol product, and the addition of sub-stoichiometric sulfuric acid to promote hydrolysis of the intermediate was indeed found to allow diol formation to predominate. A detailed account of the optimization, scope and limitations of this chemistry has now appeared.41Interestingly, Plietker has also shown that an added co-oxidant (Oxone) can intercept the ruthenate ester intermediate, leading to direct formation of α-hydroxyketones from alkenes (Scheme 4).42The reaction conditions have been optimized, and a non-aqueous work-up procedure developed which allows recovery of the Ru-catalyst by centrifugation or filtration. The process tolerates several common functional groups including chloride, acetate and even acetals. As shown inScheme 4, good levels of regiocontrol can be observed for non-symmetrical substrates, especially when one of the substituents is an electron withdrawing group. For cyclic alkenes, cleavage competes, but can be minimized by performing the reaction at lower temperatures. While there is not yet an asymmetric version of this ketohydroxylation, it can be used to process enantiomerically pure diols obtained from Sharpless asymmetric dihydroxylation, thus yielding enantiomerically pure α-hydroxyketones (Scheme 5).431.3Alkene aminohydroxylationAlkene aminohydroxylation is closely related to dihydroxylation, and potentially as useful. Muniz has provided an account of the chemistry of the imidoosmium(viii) compounds involved.44As with dihydroxylation, procedures to aid catalyst/ligand recovery are attracting attention, with the use of a polyethyleneglycol-bound cinchona alkaloid ligand providing a recent example.45One complication with aminohydroxylation (which is not an issue with dihydroxylation) is control of regiochemistry. Donohoe has previously demonstrated one strategy for surmounting this by developing intramolecular, “tethered” aminohydroxylation, and has advanced these studies by looking at acyclic stereocontrol in chiral allylic carbamates.46High levels ofsyn-stereoselectivity were observed, even for 1,1-disubstituted substrates where A1,2and A1,3-strain effects are often in competition (Scheme 6). Taylor has provided an application of the tethered aminohydroxylation in an approach to simplified analogues of the natural product scyphostatin.471.4Alcohol oxidationAs one of the most widely employed oxidation reactions in synthesis, conversion of alcohols to carbonyl compounds continues to attract interest, particularly in the quest for cleaner and more selective methods. The 2004 literature contains reviews on biocatalytic alcohol oxidation.48Oxidation using molecular oxygen is especially environmentally attractive, and progress in the field has also recently been reviewed.49,50Marko has further refined his copper-catalysed aerobic oxidation of primary alcohols to aldehydes mediated by dialkyl azodicarboxylates.51A catalytic aerobic system using V2O5has been described which allows selective oxidation of secondary alcohols in the presence of primary ones.52The most spectacular examples of aerobic metal-catalysed alcohol oxidation reactions in recent years have come from the independent studies of Stoltz and Sigman on Pd-catalysed kinetic resolution of secondary alcohols in the presence of sparteine. These workers have provided accounts of their work to date53,54and their most recent contributions include the use of ambient air as the stoichiometric oxidant55as well as further mechanistic studies,56models to rationalize the enantioselectivity,57,58and applications of the methodology to the synthesis of pharmaceutical building blocks.59The 2,2,6,6-tetramethylpiperidinyloxy radical (TEMPO) is by now a well established catalyst for alcohol oxidation,60particularly for selective alcohol oxidation in carbohydrates,61and an aerobic, metal free catalytic system has now been reported (Scheme 7),62as well as a further example of a polymer-supported variant of TEMPO.63Hypervalent iodine reagents are another important class of oxidant for alcohols.64IBX9is one such reagent, the chemistry of which has been extensively developed in recent years. Its uses in ionic liquids65and under solvent-free conditions66have been described. Recent alcohol oxidations to be reported using9include oxidations of lactols to lactones,67and Iwabuchi has shown that it will effect oxidative rearrangement of cyclic (5- and 6-membered ring) tertiary allylic alcohols, providing an alternative to classical chromium reagents for this enone transposition tactic.68The strategy of one-pot alcohol oxidation and subsequentin situfunctionalization of the generated carbonyl compound continues to be explored in Taylor's laboratories, with recent examples including MnO2oxidation/trapping with 1,2-diamines to give quinoxalines or dihydropyrazines,69conversion of alcohols to 1,1-dibromoalkenes70and tandem oxidation/cyclopropanation.711.5Other oxidationsWacker oxidation of alkenes is a well established transformation, and normally converts terminal alkenes to ketones. In an interesting application of Ru-chemistry, Che has described direct conversion of styrenes and aromatic 1,3-dienes to aldehydes (Scheme 8).72The process proceeds by initial epoxidation followed by rearrangement. Since the Ru-catalyst will also promote formation of ylides from diazo compounds, the oxidation can be combined with an olefination step in a one-pot procedure (Scheme 9).IBX9will effect other useful oxidations besides conversion of alcohols to carbonyl compounds. For example, it can effect aromatization through dehydrogenation,73and Nicolaou has provided a detailed account of its use for oxidation of amines and dithianes (leading to deprotection in the case of the latter functionality).74IBX will also effect α-oxidation of acetophenones.75For this type of transformation, however, the most exciting recent findings have been the use of proline as catalyst along with nitrosobenzene as oxidant, effecting α-oxidation of carbonyl compounds.76Reported earlier for aldehydes, 2004 saw this chemistry extended to ketones (Scheme 10),77,78affording products which are highly versatile synthetically. The reaction is mechanistically intriguing,79since Blackmond has shown that the reaction rate rises with time, and that there is a positive non-linear effect in ee of product relative to that of proline catalyst.80Formation of an enamine intermediate between proline and the substrate, along with hydrogen bonding between product and proline, are now believed to be involved.81Synthetic developments have included modified proline catalysts82andin situfunctionalization of the α-oxygenated aldehyde products by olefination83and allylation.84Cordova has also reported that molecular oxygen can be used in place of nitrosobenzene in these proline-catalysed α-oxidations of aldehydes, but the enantioselectivities are currently moderate.85