Enantioselective Synthesis Muqubilin and Negombatoperoxides B and C/D

Abstract

Muqubilin, negombatoperoxide B, and negombatoperoxide C/D were synthesized through enantioselective routes, with the quaternary center derived from a peroxy chiral building block of known absolute configuration. The C-2/C-3 stereogenic centers were introduced by asymmetric aldol condensation, and the 1,2-dioxane ring was constructed via an intramolecular alkylation of a hydroperoxide with a mesylate. The synthetic samples showed physical and spectroscopic data consistent with those reported in the literature and thus verified the configurations of the natural products. A potentially more expeditious enantioselective entry to the 1,2-dioxane-aldol moiety (C-1 to C-6) of such cyclic peroxides was also briefly explored, where the C-2/C-3 stereogenic centers were installed through a [2+2] cycloaddition and the 1,2-dioxane ring was closed via an intramolecular alkylation coupled with an alkyl-oxygen cleavage of a β-lactone.

Diastereoselective and Enantioselective Synthesis of α-p-Methoxyphenoxy-β-Lactones: Dependence on the Stereoelectronic Properties of the β-Hydroxy-α-p-Methoxyphenoxycarboxylic Acid Precursors

“…The collected fractions were analyzed by thin layer chromatography with tlc plates coated with fluorescent indicator F 254 and visualized with an ultraviolet light source (λ = 254 nm). All 1 H and 13 C NMR spectra were recorded in deuterated chloroform (CDCl 3 ) using a Bruker Ultra-shield Avance III NMR spectrometer operating at 500 MHz (or 400 MHz) for 1 H NMR spectra and operating at 125 MHz (or 100 MHz) for 13 C NMR spectra. Chemical shifts were reported in parts per million (δ scale), and coupling constants (J values) are listed in Hertz (Hz).…”

“…triplet, J = 8.9 Hz, 1H), 4.50 (dd, J = 8.9 Hz, 7.0 Hz, 1H). 13 General Procedure for the Asymmetric Glycolate Aldol Addition Reaction (22). In a flame-dried, continuously nitrogenpurged 1000 mL round bottom flask equipped with a stir bar were placed the oxazolidine-2-thione (11) (3.00 g, 8.74 mmol, 1.00 equiv, limiting reactant) and anhydrous dichloromethane (300 mL, reaction molarity = 0.029 M).…”

“…1 H NMR (500 MHz, CDCl 3 ): δ 8.46 (s, 1H), 8.19−8.16 (m, 1H), 7.93 (d, J = 7.8 Hz, 1H), 7.55 (t, J = 8.0 Hz, 1H), 7.34−7.30 (m, 3H), 7.22−7.19 (m, 2H), 7.12 (d, J = 3.1 Hz, 1H), 6.59 (d, J = 9.3 Hz, 2H), 6.53 (d, J = 9.3 Hz, 2H), 5.71 (dd, J = 8.4, 2.9 Hz, 1H), 5.55 (s, 1H), 4.79 (dd, J = 9.3, 8.4 Hz, 1H) 4.52 (dd, J = 9.3, 2.9 Hz, 1H), 3.68 (s, 3H) ppm. 13…”

“…In addition to their occurrence in natural products, β-lactones have proven to be effective tools in the synthesis in a variety of natural products including brefeldin, muqubilin, negombatoperoxides, , viridiofungins, vinigrol, and zaragozic acid as key synthetic intermediates (Figure ). These studies have served to increase the interest in the development of methods for synthesizing β-lactone intermediates.…”

“…These diastereomers were separated by chromatography to afford the isomerically pure diastereomers that were then subjected to phenylsulfonyl chloride in the presence of pyridine to yield a series of α-phenoxy-β-lactones (12). In turn, these lactones were thermally decarboxylated for the purpose of obtaining diastereomerically pure enol ethers (13).…”