746
steroids 7 1 ( 2 0 0 6 ) 745–750
2.2.
Chemistry
2.2.1. Acidic treatment of gestodene (1)
Gestodene (1.90 g, 6.13 mmol), was suspended in 1 M
hydrochloric acid (380 mL) at 80 ◦C. After 2 h gestodene
was almost completely converted in one more polar com-
pound as resulted by TLC analysis (ethyl acetate–petroleum
ether 1:1). The mixture was cooled and, after adding 1 M NaOH
(380 mL), extracted with two volumes of dichloromethane
(190 mL). The organic layers were dried over sodium sulphate,
and the organic solvent was removed under reduced pressure
affording a yellow solid residue (1.80 g). Flash chromatogra-
phy (ethyl acetate–petroleum ether 3:7) of the crude reaction
product yielded 13-ˇ-ethyl-18,19-dinorpregna-4,14,16-trien-3,20-
dione 3 (1.55 g, 5.00 mmol) that showed: mp 206–207 ◦C (dec)
(from dichloromethane–hexane); [␣]D = +580.5◦ (c = 1); 1H NMR
(CDCl3): ı = 0.28 (t, J = 7.0 Hz, 3 H, CH3), 0.86–0.94 (m, 2 H, H9
and H12␣), 1.48 (m, 1 H, H11), 1.54 (m, 1 H, H1␣), 1.62 (m, 1
H, H7␣), 1.78–1.86 (m, 2 H, H11␣ and CHaH18), 2.11–2.70 (m,
3 H, H7, H8 and CHHb18), 2.23–2.33 (m, 6 H, H1, H2␣ or ,
H10 and CH321), 2.36–2.45 (m, 2 H, H2␣ or  and H6), 2.53
(m, 1 H, H12), 2.58 (m, 1 H, H6␣), 5.86 (br s, 1 H, H4), 6.04
(br dd, J = 2.0 and 2.5 Hz, 1 H, H15), 7.25 ppm (dd, J = 2.5 Hz, 1
H, H16); 13C NMR (CDCl3): ı = 7.43 (CH3CH2), 25.24 (CH3CH2),
25.96 (C11), 26.53 (C21), 26.80 (C1), 28.53 (C7), 34.97 (C6), 36.38
(C2), 36.78 (C12), 40.78 (C8), 42.75 (C10), 53.37 (C9), 58.07 (C13),
119.91 (C15), 125.02 (C4), 143.36 (C16), 152.68 (C ), 165.12 (C ),
169.21 (C ), 192.77 (C20), 199.56 ppm (C3); EI-MS: m/z 310 [M]+;
Anal. calcd. for C21
H 8.48.
H26O2: C 81.25, H 8.44; found: C 80.97,
2.2.2. Acidic treatment of drospirenone (2)
2.
Experimental
Drospirenone (2.00 g, 5.46 mmol), was treated with acetone
(30 mL) and 36% hydrochloric acid (0.75 mL) under reflux for
2 h. This treatment caused complete disappearing of the start-
ing material and formation of two main compounds (TLC,
ethyl acetate 100%) together with tars not further identified.
After cooling the mixture was neutralized with a saturated
NaHCO3 solution, water was added and acetone was removed
under reduced pressure. The residue was extracted twice with
ethyl acetate, and the organic layers were washed with brine
and dried over sodium sulphate. The solvent was removed
under reduced pressure affording a semi-solid residue (1.50 g).
Flash chromatography (hexane–ethyl acetate from 50:50 to
30:70) of the crude reaction product yielded compound 4
(0.70 g, 1.74 mmol), and compound 5 (0.10 g, 0.25 mmol) in the
order.
7-Chloromethyl-15,16-methylene-3-oxo-17-pregn-4-
ene-21,17-carbolactone 4 showed: mp 198 ◦C (from methanol),
[␣]D = +19.0◦ (c = 1); 1H NMR (CDCl3): ı = 0.56 (m, 1 H, H15ꢀ␣),
0.87 (s, 3 H, H18), 0.95 (m, 1 H, H15ꢀ), 1.12 (m, 1 H, H9), 1.16 (s,
3 H, H19), 1.25 (m, 1 H, H12 ), 1.38 (m, 1 H, H11), 1.45 (m, 1
H, H16), 1.49 (m, 1 H, H15), 1.62–1.74 (m, 3 H, H12␣, H11␣ and
H1␣), 1.86–2.00 (m, 3 H, H8, H7 and 1), 2.10 (m, 1 H, H14), 2.16
(m, 1 H, H20), 2.23 (m, 1 H, H20␣), 2.28–2.42 (m, 3 H, H2␣, H2
and H6␣), 2.51 (m, 1 H, H21), 2.61 (m, 1 H, H6), 2.69 (m, 1
2.1.
General
Uncorrected melting points were determined on a Bu¨ chi appa-
ratus. Optical rotations were determined on a Perkin-Elmer
241 polarimeter in a 1 dm cell at 20 ◦C using chloroform solu-
tions. Gestodene [5] and drospirenone [6] were a generous gift
of Industriale Chimica s.r.l. Saronno, Italy and all reagents
were purchased from Aldrich. Reactions were monitored by
TLC on Silica Gel 60 F-254 plates (Merck) with detection by
spraying with cerium based reagent solution and heating to
110 ◦C. Column chromatography was performed on Silica Gel
60 (70-230 mesh, Merck). Mass spectrometry was performed
on a Thermo Electron TRACE DSQTM spectrometer through
the rapid heating filament Direct-Exposure Probe (DEP) inser-
tion mode. The mass spectrometric analyses were performed
in electron impact (EI-MS) ionization at an electron energy
of 70 eV with a source temperature of 250 ◦C. All NMR spec-
tra were recorded at 298 K with a Bruker FT-NMR AVANCETM
DRX500 spectrometer operating at 500.13 and 125.76 MHz for
1H and 13C respectively, in CDCl3 solutions at 298 K. Chem-
ical shifts are reported as ı (ppm) relative to CHCl3 fixed at
7.24 ppm for 1H NMR spectra and relative to CDCl3 fixed at
76.95 ppm (central line) for 13C NMR spectra. A combination of
1D and 2D COSY, HMQC and NOESY experiments, using stan-
dard Bruker pulse programs, was used for the assignment of
compounds 3–5 resonances.
H, H21␣), 3.80 (dd, J7 a,7 = 1.70 and J7 a,7 b = 11.2 Hz, 1 H, H7ꢀa),
ꢀ
ꢀ
ꢀ
4.10 (dd, J7 b,7 = 4.5 Hz, 1 H, H7ꢀb), 5.76 ppm (d, J = 2.1 Hz, 1 H,
H4); 13C NMR (CDCl3): ı = 9.71 (C15ꢀ), 17.23 (C19), 19.52 (C15),
ꢀ
20.26 (C18), 20.83 (C11), 25.48 (C16), 26.87 (C20), 29.46 (C21),