Epoxide-opening

Although considerable effort has been expended on asymmetric routes to the structural motif within a number of beta-blocker drugs, there has been little h-nancial reward. Through the use of a chiral equivalent of epichlorohydrin (X = Cl), a substitution reaction at the sp center followed by epoxide opening allows 

A considerable amount of work was required to optimize the leaving group and avoid racemization through a Payne rearrangement mechanism [7]. Of course, the Sharpless epoxidation of allyl alcohols is well known to access these 3-functionalized epoxides. 

The regioselective control for the nucleophilic opening of an epoxide in an acyclic system is well known [1,16]. Under basic conditions, the nucleophile usually attacks the sterically less encumbered site, whereas under acidic conditions, the sterically more hindered site is favored [16-20]. The product invariably contains the functional groups in an a ca/-disposition, when an S.,2 pathway is followed [1,16]. Epoxides react with a wide variety of nucleophiles [21]. 

Human immunodeficiency virus (HIV) protease inhibitors have provided the pharmaceutical and fine chemical industry with a number of difficult problems 

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Analysis This is the substitution pattern for a base-catalysed epoxide opening PhCHjO-J- OH... 

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 9 — 15 fragment was prepared by a similar route. Once again Sharpless kinetic resolution method was applied, but in the opposite sense, i.e., at 29% conversion a mixture of the racemic olefin educt with the virtually pure epoxide stereoisomer was obtained. On acid-catalysed epoxide opening and lactonization the stereocentre C-12 was inverted, and the pure dihydroxy lactone was isolated. This was methylated, protected as the acetonide, reduced to the lactol, protected by Wittig olefination and silylation, and finally ozonolysed to give the desired aldehyde. 

Epoxide-opening iatramolecular cycli2ations, in light of their importance in natural product chemistry, have received much attention (62). 

The low position selectivity in the epoxide opening step of this early synthesis was improved in a later study (Ref. 2). 

HETE was also obtained together with ( )-ll-HETE via the epoxide opening reaction of 11,12-epoxyarachidonic acid (Ref. 4). 

Epoxide Opening with Hydrogen Fluoride in Chloroform-Ethanoi... 

Epoxide Opening with 70% Aqueous Hydrogen Fiuoride ... 

Fluorohydrin formation by epoxide opening with hydrogen fluoride in chloroform-ethanol, 433... 

Ester functions are not saponified under these ring opening conditions. However, a trans-a-acetoxy function hinders the epoxide opening reaction and a noticeable decrease in yield is observed in comparison to the cw-a-acetoxy isomer. The ring opening reaction is also dependent on the concentration of sulfuric acid. Polymer formation results when the acid concentration is too low and the reaction is markedly slower with excessive concentrations of acid. A 0.5% (vol./vol.) concentration of acid in DMSO is satisfactory. Ring opening does not occur when ethanol, acetone, or dioxane are used as solvent. 

The configurations assigned to (8) and (9) were established by comparison with the products resulting from epoxidation of 3-methyl-5a-cholest-2-ene followed by reduction with lithium aluminum hydride to the alcohol (9). The usual /ra 5-diaxial epoxide opening requires that the hydroxyl group, formed by reduction, is axial as shown in (9). 

Hie origin of tlie acceleration produced by BF in epoxide alkylation teactions has been examined tlieotetically [124], A plausible patliway for BF patLicipation in tlie epoxide-opening is sliown in Fig. 10.5. An epoxide/BF complex CPI may eti-countet tlie cuprate duster to form a ternary complex CP2, ot siidi a complex may... 

Acid-catalyzed epoxide opening takes place by protonation of the epoxide to increase its reactivity, followed by nucleophilic addition of water. This nucleophilic addition is analogous to the final step of alkene bromination, in which a cyclic bromonium ion is opened by a nucleophile (Section 7.2). That is,... 

Diols can be prepared either by direct hydroxylation of an alkene with 0s04 followed by reduction with NaHSOj or by acid-catalyzed hydrolysis of an epoxide (Section 7.8). The 0s04 reaction occurs with syn stereochemistry to give a cis diol, and epoxide opening occurs with anti stereochemistry to give a trans diol. 

The mechanisms of these acid-catalyzed epoxide openings are more complex than they at first appear. They seem to be neither purely SN1 nor SN2 but instead to be midway between the two extremes and to have characteristics of both. Take the reaction of 1,2-epoxy-l-methylcyclohexane with HBr shown in Figure 18.2, for instance. The reaction yields only a single stereoisomer of 2-bromo-2-methyl-cyclohexanol in which the —Br and —OH groups are trans, an S 2-li.ke result caused by backside displacement of the epoxide oxygen. But the fact that Br attacks the more hindered tertiary side of the epoxide rather than the less hindered secondary side is an SN1 -like result in which the more stable, tertiary carbocation is involved. 

Evidently, the transition state for acid-catalyzed epoxide opening has an Sn2 -like geometry but also has a large amount of S]v-l-like carbocationic character- Since the positive charge in the protonated epoxide is shared by the more highly substituted carbon atom, backside attack of Br- occurs at the more highly substituted site. 

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. 

Steps 1-2 of Figure 27.14 Epoxide Opening and Initial Cyclizations Cyclization is initiated in step 1 by protonation of the epoxide ring by an aspartic acid residue in the enzyme. Nucleophilic opening of the protonated epoxide by the nearby 5,10 double bond (steroid numbering Section 27.6) then yields a tertiary carbo-cation at CIO. Further addition of CIO to the 8,9 double bond in step 2 next gives a bicyclic tertiary cation at C8. 

Scheme 5. Payne rearrangement/epoxide opening reaction hydroxide nucleophile.

A careful analysis of this problem led to the identification of an exceedingly simple solution (see Scheme 10). The Masamune-Sharpless solution to the threo 2,3-diol problem actually takes advantage of the ready availability of the erythro 2,3-diol diastereoisomer. As we have seen in Scheme 9, erythro 2,3-diols such as 20 can be conveniently assembled from trans allylic alcohols via sequential SAE and Payne rearrangement/epoxide opening reac-... 

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