Epoxides opening with carbon nucleophiles

Epoxide opening with nucleophiles occurs at the less substituted carbon atom of the oxlrane ting. Cataiytic hydrogenolysis yields the more substituted alcohol. The scheme below contains also an example for trons-dibromination of a C—C double bond followed by dehy-drobromination with strong base for overall conversion into a conjugated diene. The bicycKc tetraene then isomerizes spontaneously to the aromatic l,6-oxido[l0]annulene (E. Vogel, 1964). 

The mechanisms and the regio- and stereo-selectivity of epoxide reactions have been reviewed.39 The review also covers the role of epoxides in biologically important reactions. The achiral and chiral catalysts used in these reactions are discussed. A second review40 discusses the ring-opening reactions of oxiranes with carbon nucleophiles. 

Rough guidelines for the prediction of regioselectivity in epoxide ring openings are summarized in Scheme 4.60. Under neutral or basic reaction conditions alkyl-or aryl-substituted epoxides react with most nucleophiles at the less substituted carbon atom [248-253]. Under acidic reaction conditions, however, product mixtures or preferential attack at the most substituted carbon atom can be observed. Acids can usually be used to enhance the reactivity of epoxides and to promote substitution at the site of an epoxide which forms a carbocation more readily. 

The ring opening of epoxides with carbon nucleophiles represents a Scheme 2.21 useful way of making C-C bonds. Grignard, organolithium and organocopper reagents and alkali metal acetylides have all been used for this purpose. This type of reaction has been used to form carbocyclic systems. 

Since its introduction in carbohydrate chemistry by Hicks and Fraser-Reid in 1975 [22], applications of the opening of epoxide with carbon nucleophiles abound in the literature. Just a few seminal examples will be mentioned here, other examples will be found in combination with other branching-chain methods. 

Nucleophilic Opening at C(2) and C(3). This opening depends on steric and electronic factors. For example, in the presence of camphorsulphonic acid, nucleophilic attack by methanol occurs at the more substituted carbon. However, with epoxy alcohols having the same number of substituents at C(2) and C(3), epoxide opening with nucleophiles occurs preferentially at C(3) because the presence of the electron-withdrawing OH group at C(l) retards 8 2 substitution at C(2). 

A difficult challenge in developing ARO reactions with carbon nucleophiles is identifying a reagent that is sufficiently reactive to open epoxides but at the same time innocuous to chiral metal catalysts. A recent contribution by Crotti clearly illustrates this dehcate reactivity balance. The lithium enolate of acetophenone added in the presence of 20 mol % of the chiral Cr(salen) complex 1 to cyclohexene oxide in very low yield but in 84% ee (Scheme 10) [23]. That less than one turnover of the catalyst was observed strongly suggests that the lithium enolate and the Schiff base catalyst are not compatible under the reaction conditions. 

There is an important difference in the regiochemistry of ring opening reactions of epoxides depending on the reaction conditions Unsymmetncally substituted epoxides tend to react with anionic nucleophiles at the less hindered carbon of the ring Under conditions of acid catalysis however the more highly substituted carbon is attacked... 

The reactions are highly exothermic. Under Uquid-phase conditions at about 200°C, the overall heat of reaction is —83.7 to —104.6 kJ/mol (—20 to —25 kcal/mol) ethylene oxide reacting (324). The opening of the oxide ring is considered to occur by an ionic mechanism with a nucleophilic attack on one of the epoxide carbon atoms (325). Both acidic and basic catalysts accelerate the reactions, as does elevated temperature. The reaction kinetics and product distribution have been studied by a number of workers (326,327). 

Base-catalyzed epoxide opening is a typical S -2 reaction in which attack of the nucleophile takes place at the less hindered epoxide carbon. For example, 1,2-epoxypropane reacts with ethoxide ion exclusively at the less highly substituted, primary, carbon to give l-ethoxy-2-propanol. 

More traditional carbon nucleophiles can also be used for an alkylative ring-opening strategy, as exemplified by the titanium tetrachloride promoted reaction of trimethylsilyl enol ethers (82) with ethylene oxide, a protocol which provides aldol products (84) in moderate to good yields <00TL763>. While typical lithium enolates of esters and ketones do not react directly with epoxides, aluminum ester enolates (e.g., 86) can be used quite effectively. This methodology is the subject of a recent review <00T1149>. 

Epoxides are extremely useful intermediates in organic synthesis since they react with a variety of nucleophiles suffering opening of the epoxide ring with retention or inversion of configuration at the carbon undergoing attack. Thus, the development of highly stereoselective methods for the synthesis of certain chiral epoxides, such as the methods under discussion, has enabled the asymmetric synthesis of a wide variety of 1,2-bifunctional compounds. 

The benzylidene derivative above is used, if both hydroxyl groups on C-2 and C-3 are needed in synthesis. This trans-2,3-diol can be converted to the sterically more hindered a-epoxide by tosylation of both hydroxy groups and subsequent treatment with base (N.R. Williams, 1970 J.G. Buchanan, 1976). An oxide anion is formed and displaces the sulfonyloxy group by a rearside attack. The oxirane may then be re-opened with nucleophiles, e.g. methyl lithium, and the less hindered carbon atom will react selectively. In the following sequence starting with an a-glucoside only the 2-methyl-2-deoxyaltrose is obtained (S. Hanessian, 1977). 

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