Phosphazene-catalyzed desymmetrization of cyclohexadienones by dithiane addition

We report a desymmetrization of cyclohexadienones by intramolecular conjugate addition of a tethered dithiane nucleophile. Mild reaction conditions allow the formation of diversely functionalized fused bicyclic lactones. The products participate in facially selective additions from the convex surface, leading to allylic alcohol derivatives.

ppm). 1 H NMR data are reported as follows: chemical shift, multiplicity (s = singlet, br-s = broad singlet, d = doublet, dd = doublet of doublet, t = triplet, td = triplet of doublet, m = multiplet), coupling constants (Hz), and integration. High resolution mass spectra were obtained with a Thermo Fisher Scientific Exactive or Finnigan TM LTQ-ICR FT TM (all samples prepared in methanol). Melting points were obtained using a Thomas Hoover UniMelt Capillary Melting Point Apparatus. Analytical thin layer chromatography was carried out using Whatman 0.25 mm silica gel 60 plates, Sorbent Technologies 0.20 mm Silica Gel TLC plates. Visualization was allowed by UV light, phosphomolybdic acid in ethanol, or aqueous ceric ammonium nitrate solution. Purification of the reaction products was carried out by using Siliaflash-P60 silica gel (40-63 μm) purchased from Silicycle. Yields refer to isolated yields after flash column chromatography. Since all results are the averages of two trials, the yields listed in the paper may not exactly match those listed below.
Materials: THF and DCM were purified by passing the solvent through a column of aluminum oxide under nitrogen. Dearomatization of phenol derivatives was carried out according to literature procedures. 1 1,3-Dithiane-2-carboxylic acid was prepared according to literature procedure. 2 Phosphazene base P 2 -t-Bu solution (~2.0 M in THF) and DMAP were purchased from Sigma-Aldrich and used as received. (Diacetoxyiodo)benzene, [bis(trifluoroacetoxy)iodo]benzene, and DCC were purchased from Oakwood Chemical and used as received.

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General procedure for substrate synthesis: The substrates were prepared through a two-step synthesis on gram scale.

STEP 1 -Dearomatization of phenols 1
The phenol (1 equiv) was dissolved in MeCN (3 mL for 1 mmol) and H 2 O (1 mL for 1 mmol); the solution was cooled to 0 °C and PhI(OAc) 2 (1.1 equiv) was slowly added as a solid. The reaction mixture was allowed stirred at ambient temperature for 18 h. The mixture was diluted with EtOAc and washed with water and brine. The combined organic phases were dried over Na 2 SO 4 and the solvent was removed under reduced pressure. The crude materials thusly obtained were purified using flash column chromatography on silica gel. STEP 2 -DCC coupling between para-quinols and 1,3-dithiane-2-carboxylic acid The desired p-quinols (1 equiv) and 1,3-dithiane-2-carboxylic acid (1.5 equiv) were dissolved in CH 2 Cl 2 ([quinol] 0 = 1.0 M); 4-dimethylaminopyridine (DMAP) (1 equiv) was then added to the mixture. The reaction mixture was cooled to 0 °C and N,N'-dicyclohexylcarbodiimide (DCC) (1.1 equiv) was added.
The reaction mixture was allowed to warm to rt and stirred for 18 h. After that period, the mixture was filtered through a short plug of silica gel and washed with CH 2 Cl 2 .The solvent was removed under reduced pressure. The crude materials thusly obtained were purified using flash column chromatography on silica gel.
The reaction was stirred at room temperature for 30 min. The reaction was quenched with saturated ammonium chloride, and the layers were separated. The aqueous layer was extracted three times with ethyl acetate, and then the combined organic phases were dried with sodium sulfate, and concentrated in vacuo. The crude materials thusly obtained were purified using flash column chromatography on silica gel using a hexane/EtOAc system (typically EtOAc/hexanes 1:9).