Asymmetric oxidation methods

Regarded by many as one of the most important advances of the 1980s, the Katsuki-Sharpless asymmetric epoxidation is apowerful fourth-generation method of synthesising epoxylalcohols, which are versatile intermediates, with predictable absolute conriguration and very high enantiomeric excess. 

The reaction is normally performed at low temperatures (-30 to 0°) in methylene chloride, and is catalytic in the chiral component diethyl or diisopropyl tartrate (DET or DIPT), and in titanium tetra-isopropoxide, provided water is rigorously excluded 4 A molecular sieves may be added to ensure this. Both enantiomers of tartaric acid are commercially available, allowing the synthesis of either enantiomer of the epoxylalcohol. The key to the remarkable enzyme-like enantioselectivity lies in the complex formed from the 

A typical example of the conditions used is provided by the reaction of undec-2-en-l-ol to afford epoxide (60) in 96% yield with an e.e. of 95%. 

There are often problems encountered in the isolation of low molecular weight epoxy-alcohols such as the parent compound glycidol, due to their water solubility. Such difficulties can be avoided by derivatisation in situ as the p-toluenesulphonate or p-nitrobenzenesulphonate ester and this procedure is illustrated in the application of the Sharpless oxidation to prepare (-)-propranolol described in section 7.4.2. 

An interesting variant on this scheme involves kinetic resolution (see section 4.2.4) aracemic secondary allyl alcohol (61) is epoxidised with the Sharpless reagent. Only one enantiomer reacts. It is then a simple matter to separate the enantiomerically enriched starting material (62) from the epoxylalcohol (63). 

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Allylic alcohols are specific substrates for a particular asymmetric oxidation method. 

Similar to the evolution of omeprazole (Prilosec) to esomeprazole (Nexium), the switch from racemic modafinil to enantioenriched armodafinil utilized asymmetric oxidation of sulfide.35 Although several asymmetric oxidation methods to provide enantiopure sulfoxides have been developed, the modified Kagan system [(Ti(Oi-Pr)4/(5,5)-DET] was selected due to superior yields and optical purities (% ee).36b The Kagan method is very useful, but it is substrate dependant (Table 3). Several sulfide derivatives of modafinil were screened to determine a direction for optimization. It was found the sulfide amide 11 provided excellent optical purity and further optimization. 

There are several efficient methods available for the synthesis of homochiral sulfoxides [3], such as asymmetric oxidation, optical resolution (chemical or bio-catalytic) and nucleophilic substitution on chiral sulfinates (the Andersen synthesis). The asymmetric oxidation process, in particular, has received much attention recently. The first practical example of asymmetric oxidation based on a modified Sharpless epoxidation reagent was first reported by Kagan [4] and Modena [5] independently. With further improvement on the oxidant and the chiral ligand, chiral sulfoxides of >95% ee can be routinely prepared by these asymmetric oxidation methods. Nonetheless, of these methods, the Andersen synthesis [6] is still one of the most widely used and reliable synthetic route to homochiral sulfoxides. Clean inversion takes place at the stereogenic sulfur center of the sulfinate in the Andersen synthesis. Therefore, the key advantage of the Andersen approach is that the absolute configuration of the resulting sulfoxide is well defined provided the absolute stereochemistry of the sulfinate is known. 

Sharpless shared the 2001 Nobel Prize in Chemistry for his development of asymmetric oxidation methods. 

In 1980, K. B. Sharpless (then at the Massachusetts Institute of Technology, presently at The Scripps Research Institute) and co-workers reported a method that has since become one of the most valuable tools for ohiral synthesis. The Sharpless asymmetric epoxidation is a method for converting allylic alcohols (Section 11.1) to chiral epoxy alcohols with very high enantioselectivity (I. e., with preference for one enantiomer rather than formation of a racemic mixture). In recognition of this and other work in asymmetric oxidation methods (see Section 8.16A), Sharpless received half of the 2001 Nobel Prize in Chemistry (the other half was awarded to W. S. Knowles and R. Noyori see Section 7.14). The Sharpless asymmetric ep-... 

Bartoli recently discovered that by switching from azide to p-anisidine as nucleophile, the ARO of racemic trans- 3-substituted styrene oxides could be catalyzed by the (salen)Cr-Cl complex 2 with complete regioselectivity and moderate selectivity factors (Scheme 7.36) [14]. The ability to access anti-P-amino alcohols nicely complements the existing methods for the preparation of syn-aryl isoserines and related compounds [67] by asymmetric oxidation of trans-cinnamate derivatives [68]. 

The oxidation method can also be applied to asymmetrically substituted 1,3-diaryltriazenes. The oxygen attacks the nitrogen atom nearest to an electron-releasing... 

Mikolajczyk and coworkers have summarized other methods which lead to the desired sulfmate esters These are asymmetric oxidation of sulfenamides, kinetic resolution of racemic sulfmates in transesterification with chiral alcohols, kinetic resolution of racemic sulfinates upon treatment with chiral Grignard reagents, optical resolution via cyclodextrin complexes, and esterification of sulfinyl chlorides with chiral alcohols in the presence of optically active amines. None of these methods is very satisfactory since the esters produced are of low enantiomeric purity. However, the reaction of dialkyl sulfites (33) with t-butylmagnesium chloride in the presence of quinine gave the corresponding methyl, ethyl, n-propyl, isopropyl and n-butyl 2,2-dimethylpropane-l-yl sulfinates (34) of 43 to 73% enantiomeric purity in 50 to 84% yield. This made available sulfinate esters for the synthesis of t-butyl sulfoxides (35). 

Other asymmetric sulfide oxidation methods (a) Bolm, C. and Bienewald, F. (1995) Angew. Chem. Int. Ed., 34, 2640 ... 

Another useful method for the asymmetric oxidation of enol derivatives is osmium-mediated dihydroxylation using cinchona alkaloid as the chiral auxiliary. The oxidation of enol ethers and enol silyl ethers proceeds with enantioselectivity as high as that of the corresponding dihydroxylation of olefins (vide infra) (Scheme 30).139 It is noteworthy that the oxidation of E- and Z-enol ethers gives the same product, and the E/Z ratio of the substrates does not strongly affect the... 

Davis et al.111 developed another method for reagent-controlled asymmetric oxidation of enolates to a-hydroxy carbonyl compounds using (+)-camphor-sulfonyl oxaziridine (147) as the oxidant. This method afforded synthetically useful ee (60-95%) for most carbonyl compounds such as acyclic keto esters, amides, and a-oxo ester enolates (Table 4-20). 

Wacker cyclization has proved to be one of the most versatile methods for functionalization of olefins.58,59 However, asymmetric oxidative reaction with palladium(II) species has received only scant attention. Using chiral ligand 1,1 -binaphthyl-2,2 -bis(oxazoline)-coordinated Pd(II) as the catalyst, high enantioselectivity (up to 97% ee) has been attained in the Wacker-type cyclization of o-alkylphenols (66a-f) (Scheme 8-24). 

In addition, a recent report details a very efficient nonenzymatic method for the asymmetric oxidation of sulfides this employs an organo-vanadium species featuring the imine (38) (Scheme 25)[111]. A second, complementary strategy for the preparation of optically active sulfoxides involves the enantioselective oxidation of racemic sulfoxides. ... 

Optically active iV-p-toluenesulfinyl piperidine 75 prepared in low optical purity by oxidation of iV-p-toluenesulfenyl piperidine with (+)-percamphoric acid represents the first example of a chiral sul-flnamide (105). As in the case of asymmetric oxidation of sulfides and sulfenates, the synthetic utility of this method is strongly limited by its low stereoselectivity. 

Hydroperoxides play an important role as oxidants in organic synthesis [56-58]. Although several methods are available for the preparation of racemic hydroperoxides, no convenient method of a broad scope was until recently [59] known for the synthesis of optically active hydroperoxides. Such peroxides have potential as oxidants in the asymmetric oxidation of organic substrates, currently a subject of intensive investigations in synthetic organic chemistry [60, 61]. The application of lipoxygenase [62-65] and lipases [66,67] facilitated the preparation of optically active hydroperoxides by enzymes for the first time. 

In this review, we focus mainly on the preparative utility of organic peroxides, and only few mechanistic investigations are discussed. This review covers synthetic methodologies for the preparation of alkyl hydroperoxides and dialkyl peroxides (Section II) and the synthetic use of these peroxides in organic chemistry (Section III). In Section II, general methods for the synthesis of organic hydroperoxides and dialkyl peroxides are discussed, as well as the preparation of enantiomerically pure chiral hydroperoxides. The latter have attracted considerable interest for asymmetric oxidation reactions during the last years. 

The asymmetric oxidation of prochiral sulfides has become the method of choice for the synthesis of optically active sulfoxides. The first examples of a really efficient asymmetric oxidation of snlfides to sulfoxides were independently reported by Pitchen... 

An asymmetric osmylation method has been developed by Sharpless and coworkers. 0s04 modified by a dihydroquinidine auxiliary (cinchona alkaloid derivatives)449,455 158 or chiral diamines449,457 160 such as 59 and 60 used in stoichiometric oxidation may yield cis diols with excellent optical purity 460... 

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