Diastereo–/Enantioselective Diels–Alder Synthesis of 14β-Hydroxysteroid Scaffolds: A Combined Experimental and DFT Study (2019)

Reactions were carried out under argon with magnetic stirring and degassed solvents.Et2O and THF were distilled over alumina on a dry solvent station GT S100.Thin layer chromatography (TLC) was carried out on silica gel plates (Merck 60F254) and the spotswerevisualized under UV lamp (254 or 365 nm) and sprayed with phosphomolybdic acidsolution (25 g phosphomolybdic acid, 10 g cerium sulfate, 60 mL H2SO4, 940 mLH2O)followed by heating on a hot plate.For column chromatography, silica gel (Merck Si60 40-60μm) was used.IR spectra were recorded on Bruker Alpha (ATR) spectrophotomer.1H NMRspectra were recorded at 500 MHz (Bruker AC-500) and 13C NMR spectra at 125 MHz(Bruker AC-500) using the signal of the residual non deuterated solvent as internalreference.Significant 1H NMR data are tabulated in the following order: chemical shift(δ) expressed inppm, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), coupling constantsin hertz, number of protons.Highresolution mass spectra (HRMS) were performed on aAgilent 6520 Accurate Mass Q-TOF.High Pressure reactions have been done with a LV30/16 chamber and a U 101 press coming from the High Pressure Research Control ofthe Polish Academy of Sciences (Warsaw, Poland). II Experimental procedures and spectral tabulationsCompound (+)-33.Methyl (9S,10S,13S,14R)-7,17-bis((tert-butyldimethylsilyl)oxy)-14-hydroxy-13-methyl-1-oxo-2, 3,5,6,9,11,12,13,14,15-decahydrospiro[cyclopenta[a]phenanthrene-4,2'-[1,3]dioxolane]-10(1H)-carboxylate A solution of diene (+)-13 (100 mg, 0.23 mmol) and -ketoester 31 (58 mg, 0.27 mmol) in toluene (1.5 mL) was submitted to high pressure (9 kbar) at 25 °C for 48 h.Solvent was removed under reduced pressure and the crude material was purified by chromatography on silica gel (petroleum ether / ethyl acetate 90/10 to 80/20) to afford (+)-33 (116 mg, 0.18 mmol, 78%).1 H NMR (500 MHz, CDCl3): 0.07 (s, 3H, SiCH3); 0.14 (s, 3H, SiCH3); 0.17 (s, 3H, SiCH3); 0.18 (s, 3H, SiCH3); 0.87 (s, 9H, Si((CH3)2(C(CH3)3)); 0.91 (s, 9H, Si((CH3)2(C(CH3)3)); 1.02 (m, 1H); 1.03 (s, 3H, CH3); 1.33 (m, 1H); 1.63 (m, 2H); 1.82 (m, 1H); 2.02 (m, 1H); 2.22 (m, 2H); 2.53 (m, 2H); 2.66 (m, 2H); 3.00 (t, J = 7.4 Hz, 1H); 3.32 (m, 1H); 3.67 (s, 3H, OCH3); 4.00 (m, 4H,OCH2CH2O, 4H); 4.38 (t, J = 2.4 Hz, 1H, CH=C(OTBS)); 5.24 (s, 1H, COH) ppm. 13C NMR (125 MHz, CDCl3): -5.45 (CH3, SiCH3); -4.28 (CH3, SiCH3); -3.2 (CH3, SiCH3); -2.5 (CH3, SiCH3); 17.7 (CH3); 18.0 (Cq, Si((CH3)2(C(CH3)3)); 18.4 (Cq, Si((CH3)2(C(CH3)3)); 23.2 (CH2); 25.6 (CH3, Si((CH3)2(C(CH3)3)); 26.1 (CH3, Si((CH3)2(C(CH3)3)); 29.5 (CH2); 32.5 (CH2); 33.2 (CH2); 35.2 (CH); 36.6 (CH2); 41.8 (CH); 42.6 (CH2); 50.8 (Cq); 52.1 (CH3, OCH3); 62.3 (Cq); 64.0 (CH2, OCH2); 64.9 (CH2, OCH2); 81.5 (Cq, COH); 94.6 (=CH, CH=C(OTBS)); 108.3 (Cq, C(OCH2)2); 119.3 (=C); 141.4 (=C); 159.9 (=C); 170.6 (COO); 205.6 (CO) ppm.IR (ATR) : ν (OH) : 3502 cm -1 , ν (CO) : 1720, 1646 cm -1 , ν (C=C) : 836 cm -1 .HRMS (ESI) m/z : C34H56O8Si2 [M + K] + calc.687.3151, found.687.3145. Compound (+)-34Ethyl-7,17-bis((tert-Butyldimethylsilyl)oxy)-14-hydroxy-13-methyl-1-oxo-1, 2,5,6,9,11,12,13,14,15-decahydrospiro[cyclopenta[a]phenanthrene-3,2-[1,3]dioxolane