1.Oxidation reactionsGeneral reviews on metal-catalysed aerobic oxidation1and on ruthenium-catalysed oxidations2have appeared.1.1Alkene epoxidationDevelopment of more efficient methods for alkene epoxidation, particularly using “clean” oxidation systems such as air3or H2O24continues to be a very active area. New methods for enantioselective epoxidation are a particularly interesting challenge, and a review of progress so far appeared in 2005.5The Sharpless Ti/tartrate epoxidation of allylic alcohols is an historical landmark in the field, and one of its most attractive features is the high level of confidence with which the epoxide product’s absolute configuration can be predicted. Intriguingly, Janda and co-workers have confirmed that when the tartrate is attached to poly(ethyleneglycol) monomethyl ether (MPEG), the sense of enantioselectivity can be reversed for a particular tartrate enantiomer. Remarkably, the reversal is dependent on the molecular weight of the polymer, and occurs within a relatively small molecular weight range. Thus, epoxidation ofE-2-hexenol in the presence ofl-tartrate-MPEG350gives the expected (2S, 3S)-enantiomer, butl-tartrate-MPEG750gives the (2R, 3R)-epoxide (Scheme 1). It is suggested that the predominant species in the Ti/MPEG mixture is a 2∶1 Ti∶ligand complex, as opposed to the 2∶2 Ti∶ligand complex of traditional Sharpless epoxidations.6Walsh has developed a one-pot procedure in which a vinyl zinc reagent, preparedin situfrom an alkyne, undergoes enantioselective addition to an aldehyde in the presence of a chiral ligand, leading to an allylic zinc alkoxide which is then epoxidised upon addition of Ti(OiPr)4and molecular oxygen (Scheme 2).7Products are obtained in excellent enantioselectivity and moderate diastereoselectivity. As an alternative to Ti-based systems for allylic alcohol epoxidation, Yamamoto has recently focused on V-catalysis using hydroxamic ligands. This chemistry has seen a notable advance with the use of complexes2bearing aC2-symmetrical ligand (Scheme 3).8Yamamoto points out several advantages over the Sharpless epoxidation including low catalyst loading (down to 0.2 mol%) and the possibility of using aqueoustBuOOH rather than an anhydrous solution. High enantioselectivities were observed for epoxidation of trisubstituted- andtrans-1,2-disubstituted alkenes as well as—notably—forcis-1,2-disubstituted substrates.For enantioselective epoxidation of “unfunctionalised” alkenes, the chiral Mn(salen) complexes associated with Jacobsen and Katsuki are the best known catalysts. The chemistry of Mn(salen) complexes—as well as their Cr-counterparts, which can display usefully different selectivities9—is the subject of an excellent review.10Modified11and polymer-supported12salen ligands continue to attract attention. Studies of rate and selectivity in the Mn(salen)-catalysed epoxidation of methyl-substituted styrenes have allowed analysis of several competing modes of approach of the alkene to the intermediate Mn(oxo) species,13while computational and1H NMR studies have related observed epoxide enantioselectivities to the conformation of the salen catalysts.14Katsuki has reported some interesting di-μ-oxotitanium catalysts for alkene epoxidation using hydrogen peroxide. Reaction of the corresponding salen ligand with Ti(OiPr)4leads to reduction of one of the imines through a Meerwein-Pondorff-Verley type process to give3, and the addition of water leads to assembly of4. Interestingly, the homochiral isomer (with regard to the configuration at Ti), as depicted schematically inScheme 4, is formed selectively in this case. This catalyst then effects alkene epoxidation in high ee (Scheme 4); styrene was epoxidised in 93% ee under these conditions.15Other catalysts studied recently for enantioselective alkene epoxidation using H2O2include Ru-based systems16and methyltrioxorhenium (VII) (MTO)17in the presence of chiral pyridines.18The use of chiral metalloporphyrin catalysts has been reviewed.19Amongst metal-free alternatives for asymmetric epoxidation, systems involving Oxone as co-oxidant continue to be prevalent. Shing has reported some novel arabinose-derived ketone catalysts such as5, containing a tuneable butanediacetal motif, which effect alkene epoxidation with up to 90% ee.20Shi reported catalyst6in 2002 which is resistant to Baeyer–Villiger reaction and can be used for the enantioselective epoxidation of α,β-unsaturated esters.21An efficient synthesis of6has been described (4 steps from fructose).22Shi has reported further studies of a range of ketones bearing a spirocyclic oxazolidinone in the α-position with the aim of probing the structure-enantioselectivity effects in alkene epoxidation.23The results suggest that an attractive interaction between alkene π-substituents and the oxazolidinone ring in ketones such as7is responsible for the high enantioselectivities observed in the epoxidation of conjugatedcis-alkenes. Further information regarding the reaction transition state has come from a study of kinetic resolution of trisubstituted cyclic alkenes.24Singleton has shown that experimental and calculated kinetic isotope effects for epoxidation by dioxiranes derived from chiral ketones are in good agreement, lending validity to the computational methods and providing new insights into the mode of asymmetric induction.25In particular, this study suggests that asynchronicity with regard to the formation of the two epoxide C–O bonds is a major consideration when developing transition state models.The related epoxidation system in which Oxone is activated by an iminium salt continues to show promise. A paper by Lacour summarises earlier attempts at using chiral iminium salts and provides a detailed account of some diphenylazepinium catalysts such as8with an exocyclic chiral substituent on the nitrogen.26These salts, employed with the TRISPHAT [tris(tetrachlorobenzenediolato)phosphate(v)] counterion, afford up to 80% ee for epoxidation of 1-phenylnaphthalene. Interestingly,1H NMR and CD studies suggested no obvious correlation between the ability of the exocyclic chiral substituent to control the catalyst’s chiral biaryl axis, and product epoxide ee. Having previously developed a non-aqueous oxidation system employing tetraphenylphosphonium monoperoxysulfate as co-oxidant,27Page applied these conditions along with catalyst9to effect highly asymmetric epoxidation of alkene10, allowing enantioselective synthesis of the antihypertensive agent levcromakalim12(Scheme 5).28The non-aqueous reaction conditions have also made it possible to investigate the reaction by1H NMR spectroscopy, with evidence being obtained for the proposed oxaziridinium intermediate.29In a further mechanistic contribution, Biscoe and Breslow have shown that hydrophobic effects are important in oxaziridinum epoxidations, since more hydrophobic alkenes are epoxidised faster in competition experiments in aqueous solvents.30Amines can also catalyse alkene epoxidation by Oxone. Yang has reported a detailed study using fluorinated amines which supports a dual role of the amine as Oxone activator and phase transfer catalyst, with ee’s of up to 61% being obtained.31A mechanistically distinct type of amine catalysis is demonstrated in the work of Jorgensen, who has discovered an impressive system for the asymmetric epoxidation of α-β-unsaturated aldehydes.32Here, the proline-derived catalyst13activates the enal substrate towards conjugate addition of hydrogen peroxide with formation of an intermediate iminium ion. This explains the regioselective epoxidation shown inScheme 6. Excellent enantioselectivities and high diastereoselectivities are observed fortrans-aliphatic and aromatic enals, with a slightly lower ee for a β,β-disubstituted example. Aqueous alcohol solvent mixtures can also be employed.33Amongst methods for the nucleophilic epoxidation of enones, the use of polyleucine as catalyst is one of the most mechanistically intriguing. Recent kinetic studies support the idea that the reaction proceeds by reversible addition of the chalcone substrate to a polyleucine-bound hydroperoxide.34Amongst other developments,35polyleucine has been grafted onto silica to facilitate catalyst recovery.36Another prominent method for enone epoxidation involves asymmetric phase transfer catalysis. Jew and co-workers have screened dimeric cinchona alkaloid-derived chiral quaternary ammonium salts and found that highly enantioselective epoxidation of chalcones can be achieved in the presence of surfactants, with Span 20 (sorbitan monolaurate) proving optimal.37Shibasaki has extended the utility of his Sm(BINOL)/Ph3AsO-catalysed asymmetric epoxidation of α,β-unsaturated amides by demonstratingin situopening of the epoxide product with nucleophiles (e.g.azide, phenylthiolate, cyanide).38Dynamic ligand exchange with the initial catalyst and the added nucleophile is believed to form a new catalystin situto promote the ring opening step. The scope of the epoxidation has been extended to α,β-unsaturated esters, for which an yttrium catalyst and a novel ligand14was employed (Scheme 7).39Alkyl substituents are also tolerated in the β-position, although higher catalyst loadings are required and enantioselectivities are slightly lower. A supported La(BINOL) catalyst for enone epoxidation has been developed.401.2Alkene dihydroxylationOsmium tetroxide-mediated alkene dihydroxylation and the Sharpless asymmetric variant are well established synthetic methods. The development of recyclable ligands41and osmium sources42and study of new reaction media43continue to attract much attention from the viewpoint of reducing cost and quantities of the toxic reagent. For the Sharpless AD, a computational study of the effect of chain length on enantioselectivity in the dihydroxylation of terminal alkenes has been reported, with the calculations matching the observed trends.44Muniz has shown that the presence of phenylboronic acid in the AD reaction leads to formation of the cyclic boronate ester product; this is shown to arise by electrophilic cleavage of the intermediate osmate ester rather than from functionalisation of an initially formed diol, and the process sometimes gives higher ee than the standard AD.45The development of alternative metal catalysts for alkene dihydroxylation is an important goal. Feringa has previously shown that the complex [MnIVO2(tmtacn)2]2+(tmtacn =N,N′,N″-trimethyl-1,4,7-triazacyclononane) acts as a catalyst for alkene oxidation with hydrogen peroxide, giving mixtures of diol and epoxide product. The same group has now shown that carboxylic acid additives can give improved efficiencies and selectivities, believed to be due to formation of carboxylate-bridged dimeric Mn complexes.46Interestingly, use of 2,6-dichlorobenzoic acid leads to higher selectivity for diol formation, while epoxide is the major product when salicylic acid is employed. Que’s work on Fe-catalysed systems has been another highlight in recent years. DFT calculations have provided insight into the factors balancing alkene dihydroxylationversusepoxidation by the intermediate oxidant, HO–FeV&z.dbd;O.47A new bio-inspired ligand15has been reported that allows the most efficient Fe-mediated alkene dihydroxylations to date, with hydrogen peroxide as co-oxidant.48Ruthenium chemistry, traditionally associated with alkene cleavage, continues to see further interest for controlled alkene functionalisation.49Che and co-workers have reported synthetic and kinetic studies using acis-dioxoruthenium(vi) complex that effects alkene dihydroxylation intBuOH, but cleavage when acetonitrile is used as solvent.50Plietker has reported a dihydroxylation system that is effective for relatively unreactive, electron poor alkenes, employing catalytic ruthenium trichloride and cerium trichloride along with sodium periodate.51Over the last few years, Plietker has also developed the direct conversion of alkenes to α-hydroxyketones using RuCl3as catalyst along with Oxone.52Studies on the diastereoselectivity of the process when an allylic oxygen substituent is present and on the relative rate of reactivity of various alkenes have now been described.53Finally, progress in some metal-free, indirect methods for alkene dihydroxylation has been reported. The Prevost oxidation (iodine/silver benzoate) and its Woodward modification (with addition of water) are classic methods for theanti- andsyn-1,2-dihydroxylation of alkenes, respectively. Catalytic versions have recently been described (Scheme 8) mediated by bromide ion in the presence of an oxidant.54Use of sodium periodate leads predominantly tosyn-1,2-dihydroxylation, because water is formedin situfrom acetic acid and periodate, whilst PhI(OAc)2affords largely theanti-1,2-diol. Davies has shown that epoxidation ofN,N-dibenzylcyclohex-2-ene with mCPBA in the presence of trichloroacetic acid gives thesyn-epoxyamine, presumably due to hydrogen bonding of the intermediate ammonium salt to the incoming peracid.55The resulting epoxide can then be manipulated to give either thesyn- oranti-1,2-diol.1.3Alkene aminohydroxylation and diaminationOsmium-catalysed alkene aminohydroxylation, closely related to Sharpless dihydroxylation, is potentially useful provided that the regioselectivity of the process can be controlled. Strategies such as rendering the process intramolecular by having the precursor to the nitrogen source (e.g.a sulfamate ester or sulfonamide)56in the homoallylic position have been adopted. A study of but-3-en-1-ol derivatives has shown that the 4-nitrophenyl ether can be converted selectively into either amino alcohol regioisomer by choice of spacer in the dimeric dihydroquinidine-derived ligand.57Acrylamides are poor substrates for Sharpless asymmetric aminohydroxylation in the presence of cinchona alkaloid ligands, but Muniz has shown that terminal acrylamides bearing anN-α-methylbenzyl substituent undergo aminohydroxylation using K2[OsO2(OH)4] and Chloramine-T (TsNClNa) with high regioselectivity for formation of the β-amino isomer, with a high level of diastereoselectivity.58In the asymmetric aminohydroxylation, the amino alcohol product can potentially act as a ligand for osmium, leading to the possibility of self-replication of chirality. However, a study by Muniz suggests that this is not a feasible process.59In further studies from the same group, it has been shown that carrying out aminohydroxylation under typical Sharpless conditions but with the omission of the chiral ligand can lead to the α-ketoamine, rather than the aminoalcohol, being the major reaction product (Scheme 9).60Enantiomerically enriched aminoalcohols can be converted to enantiomerically enriched α-aminoketones using similar conditions. A related observation comes from Zhu’s attempts to optimise the aminohydroxylation of cinnamate esters, in which the α,α-diaminoarylketone was observed as a by-product,61presumably arising by a second aminohydroxylation reaction on the enol form of the α-aminoketone, itself formed from the initial aminoalcohol by analogy to Muniz’s studies. Muniz has also described the first catalytic enantioselective diamination of alkenes (up to 90% ee) by using a chiral Ti(TADDOL)-based Lewis acid in conjunction with a stoichiometric osmium bisimidocomplex.62Johnston has accomplished a stereochemical outcome which is complementary to osmium-catalysed aminohydroxylation by demonstrating that treatment of unsaturated carbamates such as16with azides in the presence of triflic acid provides the anti-aminoalcohol (Scheme 10).631.4Alcohol oxidationDevelopment of aerobic alcohol oxidations continues to be of great interest. Contributions in 2005 include further studies on palladium catalysis64and the use of copper(ii) catalysis for oxidation of primary alcohols to aldehydes in ionic liquids.65Toste has described the synthesis of α-hydroxyesters of high enantiomeric purity by vanadium-catalysed oxidative kinetic resolution.66o-Iodoxybenzoic acid (IBX) has proved to be a popular oxidant in recent years, and its use in sub-stoichiometric quantities along with Oxone as co-oxidant is a notable recent advance.67A functional ionic liquid bearing a hypervalent iodine reagent for alcohol oxidation has also been reported.68In situfunctionalisation can be a valuable tactic for aldehydes that are unstable or difficult to isolate, and Taylor has provided a summary of his work on tandem MnO2alcohol oxidation/aldehyde transformations.691.5Other oxidationsNicolaou has described some interesting oxidative transformations of amine derivatives mediated by the Dess–Martin periodinane (DMP).70Thus, secondary amides are converted to imides (Scheme 11), with carbamates and benzylic positions being inert to the reaction conditions, while vinylogous amides and carbamates can be prepared by dehydrogenation (Scheme 12). DMP will also convert benzylic amines to nitriles.Higuchi has shown thatN-acyl cyclic amines are converted toN-acylaminoacids by oxidation with a ruthenium porphyrin complex and 2,6-dichloropyridine-N-oxide.71Secondary positions are oxidized selectively (Scheme 13), and the chemistry can be used for conversion ofN-benzoylproline to the corresponding glutamate derivative. Selective C–H oxidation continues to be a highly active area and an intriguing recent addition to the reagents that can effect this is osmium tetroxide.72An aerobic, organocatalytic Baeyer–Villiger reaction of cyclobutanones, mediated by a flavin derivative, has been reported.73Reviews have appeared on the oxidation of sulfides to sulfoxides74and the combination of asymmetric sulfoxidation and subsequent kinetic resolution has allowed highly enantioselective, vanadium-catalysed synthesis of aryl alkyl sulfoxides.75