Epoxides under acidic conditions

The structure of glabrescol was subsequently revised, and the new structure was synthesized enantioselectively through sequential hydroxy-directed anti-oxidative cyclization of acyclic y-alkenols with VO(acac)2/TBHP to construct the adjacent THF rings via epoxides under acid conditions [35b],... 

Intramolecular cyclization can also occur on treatment of epoxides under acidic conditions, although, when aqueous acids are used, a competing attack by water occurs,61 as in 58 - 59. 

Further studies that demonstrate that hydration of bay-region diol epoxides under acidic conditions can occur by general acid catalysis in addition to proton catalysis have expanded our understanding of their reactivity. General acid catalyzed hydration involves H-bonding of the epoxide O-atom by the acid catalyst, followed by nucleophilic attack of the distal C-atom by H20/H0 [108][109],... 

In 1985, O Malley et al. published the total syntheses of rac-averufin (103) and rac-nidurufin (104) (65). These are both early precursors of the aflatoxins in their biosynthesis. Nidurufin (104) is the direct successor of averufin (103) and the direct precursor of versiconal hemiacetal acetate (12, see Scheme 2.1). Nidurufin (104) and averufin (103) are accessible by the same synthesis route only the two last steps differ firom each other (see Scheme 2.17). The first reaction was a double Diels-Alder reaction with dichloro-p-benzoquinone (97) and two equivalents of diene 98. Then, three of the four alcohol functions were selectively MOM-protected (—> 99). The remaining alcohol was converted into the allyl ether and then subjected to a reductive Claisen rearrangement, followed by MOM-protection of the redundant alcohol ( 100). By addition/elimination of PhSeCl, 101 was formed. Deprotonation of t-butyl 3-oxobutanoate, followed by reaction with 101 yielded the pivotal intermediate 102. This could be converted into rac-averufin (103) by deprotection of the alcohols and decarboxylation at the side chain. The last step was a p-TsOH-catalyzed cyclization to give 103. By treating 102 with /m-CPBA, the double bond is epoxidized. rac-Nidurufin (104) was then formed by cyclization of this epoxide under acidic conditions. 

In summary, never use a Grignard reagent in the presence of an add. The same rule applies to the use of LAH (lithium aluminum hydride), which is both a strong nucleophile and a strong base. Therefore, much like a Grignard reagent, LAH also cannot be used to open an epoxide under acidic conditions ... 

Notice that this example does not violate the principles underlying electronic trends. Specifically, when there is an oxygen atom attached directly to one side of the epoxide, under acidic conditions, ring opening can occur at this site, because it results in a more stable (resonance-stabilized) cation. 

Another synthesis of the cortisol side chain from a C17-keto-steroid is shown in Figure 20. Treatment of a C3-protected steroid 3,3-ethanedyidimercapto-androst-4-ene-ll,17-dione [112743-82-5] (144) with a tnhaloacetate, 2inc, and a Lewis acid produces (145). Addition of a phenol and potassium carbonate to (145) in refluxing butanone yields the aryl vinyl ether (146). Concomitant reduction of the C20-ester and the Cll-ketone of (146) with lithium aluminum hydride forms (147). Deprotection of the C3-thioketal, followed by treatment of (148) with y /(7-chlotopetben2oic acid, produces epoxide (149). Hydrolysis of (149) under acidic conditions yields cortisol (29) (181). 

Epoxides, like other ethers, are cleaved by nucleophiles under acidic conditions. For example, cyclopentene oxide produces a mixture of 1,2-cyclopentanediol stereoisomers when treated with water and sulfuric acid. 

For the formation of substituted THF rings (Route a, Scheme 8.1), Kishi developed a procedure based on the hydroxy-directed epoxidation of a y-alkenol [10]. Epoxidation of bishomoallylic alcohol 3 by TBHP/VO(acac)2 by this approach, followed by treatment of the intermediate epoxide 4 with acetic acid, gave the TH F derivative 5 of isolasalocid A (a 5-exo cydization Scheme 8.2) [11]. Further epoxidation of 5 (a y-alkenol) under the same conditions, followed by acetylation, afforded epoxide 6. For the synthesis of the natural product, the configuration of epoxide 6 had to be inverted before the second cydization reaction. Epoxide 6 was consequently hydrolyzed under acid conditions to the corresponding diol and was then selectively... 

The cyclization of the homologous epoxide 36 under acidic conditions was also investigated (Table 9.5) [110]. As would be expected, compound 36a reacted by a 6-exo cyclization to give tetrahydropyran 38a (Entry 1). The a, 3-unsaturated hydroxy epoxide 36b gave a 1 3.5 mixture of oxepane 37b and tetrahydropyran 38b (Entry 2). Subjection of 36c and 36d, which both contain more electron-rich 71-systems, to the reaction conditions resulted in preferential 7-endo cyclization to give 37c and 37d, thus confirming the powerful regiodirecting effect of the vinyl moiety (Entries 3 and 4). 

When 3-thiolene dioxide is treated with hydrogen peroxide, the corresponding epoxide is obtained313. The 3,4-trans-diols can be obtained by hydrolysis under acidic conditions (equation 120). 

Substitution of the free epoxide, which generally occurs under basic or neutral conditions, usually involves an Sn2 mechanism. Since primary substrates undergo Sn2 attack more readily than secondary, unsymmetrical epoxides are attacked in neutral or basic solution at the less highly substituted carbon, and stereospecifically, with inversion at that carbon. Under acidic conditions, it is the protonated epoxide that undergoes the reaction. Under these conditions the mechanism can be either SnI or Sn2. In S l mechanisms, which favor tertiary carbons, we might expect that attack would be at the more highly substituted carbon, and this is indeed the case. However, even when protonated epoxides react by the 8 2 mechanism, attack is... 

Fig. 10.11. Chemical mechanisms in the hydrolysis ofK-region epoxides. Pathway a characteristic proton-catalyzed hydrolysis under acidic conditions Pathway b nucleophilic hydrolysis by H2C) Pathway c HO"-catalyzed hydrolysis under basic conditions. Pathways b and c form the trans-diol. In the case of Pathway a, partial configurational inversion may occur at the carbonium ion, resulting in a mixture of the trans- and cw-diols. 

In other words, the non-K-region epoxides of phenanthrene react like epoxides of lower arenes (Fig. 10.1). In contrast, the K-region epoxide of phenanthrene, under alkaline conditions, hydrolyzes as does an olefin epoxide (i.e., as in Fig. 10.4), but seemingly faster. Under acidic conditions, however, it exhibits dual behavior, isomerizing mainly like an arene oxide (i.e.,... 

Reaction of epoxides with nitrate anion under acidic conditions... 

Unsymmetrical epoxides (39) can form two isomers, (40) and (41), on reaction with nitrate anion and so raise the issue of regioselectivity. Under acidic conditions terminal epoxides are found to predominantly yield the primary nitrate ester (41) although this is not clear cut and propylene oxide is reported to yield an ill defined mixture of isomers. A comprehensive study on the regioselectivity of epoxide opening with nitrate anion under acidic conditions was conducted on glycidol. ... 

Epoxides, like cyclic halonium ions, undergo ring opening through rearside attack of nucleophiles (see Section 6.3.2). Two mechanisms are shown, for both basic and acidic conditions. Under acidic conditions, protonation of the epoxide oxygen occurs first. The epoxidation-nucleophilic attack sequence also adds substituents to the double bond in an anti sense. 

The 4-amino group of 31 was selectively acetylated under acidic conditions using acetic anhydride (1 equiv.) and methanesulfonic acid (1 equiv.) in acetic acid and f-butylmethyl ether to give 32. Deallylation of 32 using 10% Pd/C in the presence of ethanolamine in refluxing ethanol proceeded as before to afford 1, which was converted to the phosphate salt in 70% yield with high purity (99.7%). The overall yield of 1 from epoxide 23 was 35-38%. 

Berkessel and Andreae reported that the catalytic activity of benzenearsonic acid in the epoxidation of olefins with hydrogen peroxide is potentiated in fluorinated alcohols such as Since Brpnsted acids do not effect epoxidation under these conditions, the... 

Acenaphthene oxide is known to be unstable under acidic conditions and is therefore isolated in low yields when prepared by common methods. The highly strained acenaphthene was smoothly epoxidized in quantitative yield at —30°C in CH3CN by using 51 . C -stilbene was epoxidized with 51 at —35 °C in CH3CN to a mixture of the trans-(70%) and c/3-epoxides (30%) (equation 79). This result shows that the peroxysulfonyl intermediate must be a radical like the acylperoxy radical ArC(0)00 ° and the phenyl nitroso oxide radical PhNOO . ... 

Under non-aqueous conditions the epoxy function in the epoxylactones can be opened only by Lewis acid assistance. Thus, 2-fluoro-2-deoxy-lactones have been prepared from 2,3-epoxylactones by treatment with HF-amine complexes [38,49,50], while 5,6-epoxylactones yield 6-deoxy-6-fluoro-lactones by this treatment [49, 50]. Likewise, BFj-assisted opening of a 2,3- epoxy function with TMSN3 [51] gave a 2-azido-2-deoxy-lactone [52]. In all cases the opening of the epoxide is a frans-opening, and it is noteworthy that under acidic conditions the nucleophile attacks at C-2 or at the primary position, similar to the opening of acetoxonium ions by bromide ions in the... 

Conversion of bromohydrins to alkenes. The 14,15-epoxide (1) of arachidonic acid methyl ester has been converted into the 11,12-epoxide (5) in two steps. The first is conversion of 1 into a mixture of isomeric bromohydrins (2 and 3) with KBr. The mixture is then epoxidized under the conditions of Sharplcss (5, 75 76) to give, after chromatographic purification, 4, the epoxide of 2. Conversion of 4 into 5 presented a problem, but was eventually achieved by treatment of the w c-bromo Inflate with P[N(CHj)2]j as a Br acceptor. 

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