Enantioselective oxidations requirements

The reaction occurs with some enantioselectivity and requires the presence of pivaldehyde (which is also oxidized)29,30. The reaction occurs for many other alkenes using transition metals coordinated to 1,3-diketone type ligands31-34. Use of a cobalt(II) complex and aldoacetal in place of the Mn(III) compound and pivaldehyde gives a novel method for the synthesis of acid-sensitive epoxides35. 

Problem 1 emphasizes reagents for oxidation and reduction. Problems 2-4, stress the selectivity of oxidations and reductions in reaction sequences. Syntheses of Problem 5 TMs require choosing specific reagents to achieve chemo-, stereo-, or enantioselective oxidations or reductions. 

In many cases enantiospecific or enantioselective oxidation of acyclic hydrocarbons or their derivatives is possible using microorganisms, although in few cases has the extent of optical induction been accurately quantified. This is clearly an area where more work is required. In those cases studied so far hydroxylation has been found to occur with retention of configuration at the reacting carbon. 

Asymmetric epoxidation The catalytic asymmetric epoxidation of alkenes has been the focus of many research efforts over the past two decades. The non-racemic epoxides are prepared either by enantioselective oxidation of a prochiral carbon-carbon double bond or by enantioselective alkylidenation of a prochiral C=0 bond (e.g. via a ylide, carbene or the Darzen reaction). The Sharpless asymmetric epoxidation (SAE) requires allylic alcohols. The Jacobsen epoxidation (using manganese-salen complex and NaOCl) works well with ds-alkenes and dioxirane method is good for some trans-alkenes (see Chapter 1, section 1.5.3). 

In the former case, almost complete stereoselective oxidation to the chiral selenoxides has been accomplished quite recently. The Davis oxidant, 3,3-di-chloro-l,7,7-trimethyl-2 -(phenylsulfonyl)spirobicyclol2.2.11heptane-2,3 -oxa-ziridine, was found to be the most efficient reagent for the enantioselective oxidation of a variety of prochiral alkyl aryl selenides [81. Asymmetric oxidation was accomplished by the treatment of the selenides with 1 molar equivalent of the Davis oxidant at 0°C to afford the corresponding chiral alkyl aryl selenoxides in quantitative yields with 91-95% ee (Scheme 1). The oxidation of methyl phenyl selenide was complete within 1 min, whereas that of triiso-propyl(a bulkier alkyl) phenyl selenide required a few hours. Typical results are... 

Davies and Reider (1996) have given some details of the HIV protease inhibitor CRDCIVAN (INDINAVIR) for which (lS,2R)-c -amino indanol is required. Indene is epoxidized enantioselectively, using the lacobsen strategy (SS-salen Mn catalyst, aqueous NaOH and PiNO), to (lS,2/ )-indene oxide in a two-phase system, in which the OH concentration is controlled. Indene oxide was subjected to the Ritter reaction with MeCN, in the presence of oleum, and subsequent hydrolysis and crystallization in the presence of tartaric acid gives the desired amino indanol. 

The highest enantioselectivity in the dialkyl-substituted olefines has been obtained with the aryl ethers of DHQD 94a and DHQ 94b. With potassium ferri-cyanide as secondary oxidant, it is possible to carry out the reaction at room temperature, and slow addition of the olefins is not required. Under these conditions, the diols can be obtained in 85-90% yield and excellent enantioselectivity. 

Enantioselective a-hydroxylotion of carbonyl compounds. The lithium enolates of the SAMP-hydrazones of ketones undergo facile and diastereoselective oxidation with 2-phenylsulfonyl-3-phenyloxaziridine (13, 23-24) to provide, after ozonolysis, (R)-a-hydroxy ketones in about 95% ee. High enantioselectivity in hydroxylation of aldehydes requires a more demanding side chain on the pyrrolidine ring such as —QCjHOjOCH, which also results in reversal of the configuration. 

The allylic acyloxylation of alkenes, the Kharasch-Sosnovsky reaction, Eq. 81, would be an effective route to nonracemic allylic alcohol derivatives, if efficient, enantioselective catalysts were available. The reaction is mediated by a variety of copper salts, and as such, has been the target of considerable research in an attempt to render the process enantioselective. The original reaction conditions described by Kharasch require high temperatures when CuBr is used as the catalyst (93). However, the use of CuOTf (PhH)0 5 allows the reaction to proceed at temperatures as low as -20°C. Unfortunately, long reaction times are endemic in these processes and the use of excess alkene (2-100 equiv) is conventional. Most yields reported in this field are based on the oxidant. 

Clark et al. (113) extended this chemistry to the propargylic oxidation of al-kynes. These substrates proved to be less reactive than the corresponding alkenes, and generally require an excess of the oxidant to achieve satisfactory yields, Eq. 97. Enantioselectivities are modest, at best. 

Camell and co-workers have recently applied lipase-catalysed resolution to formally desymmetrize prochiral ketones that would not normally be considered as candidates for enzyme resolution, through enantioselective hydrolysis of the chemically prepared racemic enol acetate. " For example, an NK-2 antagonist was formally desymmetrized by this approach using Pseudomonas fluorescens hpase (PFL) (Scheme 1.40). By recychng the prochiral ketone product, up to 82 % yields of the desired (5)-enol acetate (99 % ee) could be realized. This method offers a mild alternative to methodologies such as base-catalysed asymmetric deprotonation, which requires low temperature, and biocatalytic Baeyer-Villiger oxidation, which is difficult to scale up. 

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