Anti-Selective Epoxidation of Methyl α-Methylene-β-tert-butyldimethylsilyloxycarboxylate Esters. Evidence for Stereospecific Oxygen Atom Transfer in a Nucleophilic Epoxidation Process

Abstract

Methyl α-methylene-β-tert-butyldimethylsilyloxycarboxylate esters are found to undergo diastereoselective epoxidation in the presence of potassium tert-butoxide-tert-butyl hydroperoxide to form anti products. In an effort to better understand mechanistic details of the transformation and the basis of diastereoselectivities observed, we studied the epoxidation of substrates with α-methylene groups containing (trans) deuterium labels and discovered that oxygen-atom transfer proceeds with ≥95% stereospecificity in all cases examined. These and other experiments suggest that the mechanism of epoxidation is not distinguishable from a concerted process.In the context of a problem in target-directed, complex synthesis we were led to explore the epoxidation of methyl α-methylene-β-hydroxycarboxylate esters and their hydroxyl-protected derivatives, and report here that the corresponding tert-butyldimethylsilyl ethers undergo efficient, anti-selective epoxidation with potassium tert-butylperoxide in tetrahydrofuran (THF). While syn-selective epoxidations of α-methylene-β-hydroxy-carboxylate esters have been reported, 1 a method for anti-selective epoxidation of this substrate class had not been described previously. Figure 1 are results of epoxidations of nine methyl α-methylene-β-tertbutyldimethyl-silyloxycarboxylate esters bearing different β-alkyl substituents. All transformations employed stoichiometric amounts of tert-butyl hydroperoxide and catalytic quantities of potassium tert-butoxide (0.1-0.3 equiv) in THF at 0 °C. 2 Substrates with dimethoxymethyl, benzyloxymethyl, or unsaturated β-substituents reacted relatively rapidly, while those with cyclohexyl, ethyl, or 2-benzyloxyethyl β-substituents reacted more slowly, and required distributed addition of as much as 0.3 equiv of potassium tert-butoxide to achieve complete conversion. All reactions were complete within 12 h at 0 °C, provided that care was taken to thoroughly dry all substrates, reagents, and solvents (see Supporting Information). As summarized in Figure 1, anti products were formed selectively in all cases. Substrates with unsaturated β-substituents were epoxidized with somewhat lower selectivities, which evidence suggests may be due in part to a stereoelectronic effect (vide infra). In an important early finding, Tanaka et al. showed that 1,2-disubstituted allylic alcohols undergo syn-selective epoxidation in the presence of vanadium acetylacetonate and tert-butyl hydroperoxide. 3 Later, Baylis-Hillman products were shown to undergo syn-selective epoxidation with both vanadium-and titanium-based reagents. 1 We used the latter method to obtain authentic samples of the syn diastereomers for two of the examples of Figure 1, with the results shown in eqs 1 and 2 below. Interestingly, but not unexpectedly, the rates of epoxidations mediated by potassium tert-butoxide and titanium tetraisopropoxide varied inversely with substrates bearing electron-donating and electron-withdrawing β-substituents. Substrates in Figure 1 with more electron-withdrawin...

A multiply convergent platform for the synthesis of trioxacarcins

“…Hydroxyl protection with tert-butyldimethylsilyl trifluoromethanesulfonate (1.2 eq) and N, N-diisopropylethylamine (1.5 eq) then afforded the tert-butyldimethylsilyl ether 10 (48% over three steps). Nucleophilic epoxidation of 10 at 0°C (4.5 h) in the presence of tert-butylhydroperoxide (2.0 eq) and potassium tert-butoxide (0.1 eq) provided selectively the antiepoxy ester 11 in 81% yield (anti∶syn ¼ 13∶1) (28). Saponification of ester 11 (THF-MeOH-H 2 O, LiOH, 0°C) and activation of the resulting carboxylic acid by treatment with isobutylchloroformate (1.05 eq) in the presence of Et 3 N (1.1 eq) at −20°C with gradual warming to −10°C followed by addition of a solution of diazomethane in ether (∼0.25 M, 2.0 eq) and further warming to 23°C provided, after chromatographic purification on triethylamine-deactivated silica gel, the epoxy diazo ketone 12 as a yellow oil (74% yield, two steps).…”

N‐Methylpyrrolidone Hydroperoxide/Cs2CO3 as an Excellent Reagent System for the Hydroxy‐Directed Diastereoselective Epoxidation of Electron‐Deficient Olefins

“…Alkaline H 2 O 2 , which is generally used for the epoxidation of enones, did not work well with such substrates, and the selectivity was also very low 11c. Švenda and Myers were successful in getting anti ‐epoxides of α‐methylene‐β‐ tert ‐butyldimethyl silyloxycarboxylate esters with a TBHP/KO t Bu system 12. High diastereoselectivity in this case is explained by considering a ‘concerted‐like’ oxygen‐transfer step.…”

“…After understanding the potential of NMPOOH, a comparative assessment of its reactivity was made by studying the formation of epoxides from some selected olefinic precursors under H 2 O 2 /NaOH, TBHP/DBU,23 TBHP/KO t Bu,12 and NMPOOH/Cs 2 CO 3 conditions (Table 1). NMPOOH/Cs 2 CO 3 was found to be the most efficient and required the minimum reaction time for maximum yields.…”

The cyclopropene radical cation: Rovibrational level structure at low energies from high-resolution photoelectron spectra

“…Prop-2ynoic acid methyl ester (5) was deuterated in a mixture of dichloromethane and a solution of potassium carbonate in deuterium oxide by phase-transfer catalysis with tetrabutylammonium iodide to give 3-d-prop-2-ynoic acid methyl ester (6) according to Svenda and Myers. 31 In a second step, 7c was prepared by reduction of 6 with lithium aluminum deuteride and subsequent hydrolysis with deuterium oxide according to Orfanopoulos et al 32 Prop-2-ynoic acid methyl ester (5) was also reduced with lithium aluminum deuteride in tetrahydrofuran and subsequent hydrolysis with water 33…”