A Simple Synthesis of Gestodene from 18-Methyl-4-estren-3,17-dione

Abstract

A simple synthesis enables us to obtain the progestin, gestodene, in five steps and satisfactory yields from 18-methyl-4-estren-3,17-dione. This was accomplished through the selective protection of the C-3 carbonyl group as a cyclic ketal and the installation of a phenylsulfoxide group at the C-16 position.

Key words

drugs - steroids - sulfoxides - sulfinylation - progestagen

References

• 1 Hoppe G. Advances in Contraception  1987,  3 (2):  159 
• 2a Hofmeister H, Wiechert R, Annen K, Laurent H, and Steinbeck H. inventors; DE  2546062.  ; Chem. Abstr. 1977, 87, 168265
• 2b Hofmeister H. Annen K. Laurent H. Petzoldt K. Wiechert R. Arzneim.-Forsch.  1986,  36 (I):  781 
• 3 Bohlmann R, Laurent H, Hofmeister H, and Wiechert H. inventors; DE  3710728.  ; Chem. Abstr. 1989, 110, 95633
• 4 Prendin R, and Pirovano S. inventors; EP  700926.  ; Chem. Abstr. 1996, 124, 343797
• 5a Kelly RW. Sykes PJ. J. Chem. Soc. C  1968,  416 
• 5b Liu D. Stuhmiller LM. McMorris TC. J. Chem. Soc., Perkin Trans. 1  1988,  2161 
• 6 A mixture of Δ^{1 5}- and Δ^{1 4}-derivatives was obtained from the dehydrobromination and it is known that the conversion of the unconjugated ketone to the conjugated one, occurring in course of the acidic removal of 17-ketal, leads to an epimerization at C-14. See: Johnson WS. Johns WF. J. Am. Chem. Soc.  1957,  79:  2005 
• 8 Trost BM. Salzmann TN. Hiroi K. J. Am. Chem. Soc.  1976,  98:  4887 
• 9 Sharpless KB. Lauer RF. Teranishi AY. J. Am. Chem. Soc.  1973,  95:  6137 
• 10 The selenation-dehydroselenation procedure has already been reported for the synthesis of a 15-androstene derivative. See: Reeder AY. Joannou GE. Steroids  1996,  61:  74 
• 11 Groszek G. Kabat MM. Kurek A. Masnyk M. Wicha J. Bull. Pol. Acad. Sci., Chem.  1986,  34:  305 
• 18 Gestodene (17α-ethynyl-18-methyl-4,15-estradien-3-one) (1). A solution of 7 in acetone was treated with 6 N HCl (1.2 equiv) for 45 min at r.t. Neutralization with a sat. NaHCO₃ solution, extraction with EtOAc and usual work-up afforded crude product that gave pure 1 (90%) by crystallization (hexane-acetone). DSC (5 °C/min): endothermic peak at 199.75 °C (onset a 198.90 °C). [α]_D ²⁰ -187.8 (c 1, CH₂Cl₂). The other chemical-physical data are in agreement with the reported ones. See: Von Cleve G. Frost E. Hoyer G.-A. Rosenberg D. Seeger A. Arzneim.-Forsch.  1986,  36 (I):  784 

7

18-Methyl-3,3-(2′,2′-dimethyl-1′,3′-propylenedioxy)-5- and 5 (10)-estren-17-one ( 3).
3-Carbonylic group of compound 2 (5 g, Keifeng, Shanghai) was selectively protected by reaction with 2,2-dimethyl-1,3-propanediol (3 equiv), triethyl-ortho-formate (1.7 equiv) and p-TsOH (0.5% w/w), in CH₂Cl₂, at 10 °C (3 h), and the title compound was obtained in 90% yield. Mp 90-110 °C. ¹H NMR (500 MHz, CDCl₃): δ = 0.73 (t, J = 7 Hz, 0.9 H,
18-CH₃), 0.75 (t, J = 7 Hz, 2.1 H, 18-CH₃), 0.85 (s, 0.9 H, CH₃-C), 0.89 (s, 2.1 H, CH₃-C), 1.00 (s, 2.1 H, CH₃-C), 1.06 (s, 0.9 H, CH₃-C), 3.44-3.66 (m, 4 H, CH₂O), 5.50 (m, 0.7 H, CH=). IR (1% KBr): 3449.5, 2952.2, 2866.7, 1732.2. Anal. Calcd for C₂₄H₃₆O₃: C, 77.38; H, 9.74; O, 12.88. Found: C, 77.45; H, 9.69; O, 12.95.

12

Due to the new stereocenters at the C-16 and SO group, four diastereoisomers were obtained, as shown by TLC (toluene-EtOAc 8:2) analysis.

13

3,3-(2′,2′-Dimethyl-1′,3′-propylenedioxy)-18-methyl-16ξ-phenylsulfoxide-5- and 5(10)-estren-17-one (5).
To a solution of 3 in anhyd THF, t-BuOK (4 equiv) was added. The mixture was kept, under N₂ atmosphere, under vigorous stirring at r.t., and after 10 min, methyl benzenesulfinate (Aldrich, 4 equiv) was added; upon disappearance of starting material (2 h), the crude product was recovered by extraction with EtOAc. The combined organic layers were washed with brine and H₂O, dried over Na₂SO₄ and the solvent was removed under reduced pressure. TLC (toluene-EtOAc 8:2) analysis showed a few spots with very similar R_f values (between 0.16 and 0.35). IR (1% KBr): 3449.9, 2954.9, 2868.9, 1735.9, 1129.6, 1106.5, 1093.8, 1048.7 cm^-1. MS: m/z = 497 [M + 1], 496 [M⁺], 371, 370.

14

The ¹H NMR spectrum of 5 was very complex due to the presence of four diastereoisomers of a mixture of Δ⁵ and
Δ^{5 (10)} isomers. Except for the signals due to the 5,6-double bond (two multiplets at δ = 5.38 and 5.44 ppm in a ratio 4:6, respectively), it was not possible to assign any other signals. For analytical purposes, the 18-methyl-16ξ-phenylsulf-oxide-4-estren-3,17-dione was prepared by removal (6 N HCl in acetone) of the 3-cyclic ketal from 5. ¹H NMR (500 MHz, CDCl₃): δ = 0.63, 0.69, 0.74, 0.75 (4 t, J = 8Hz, in a ratio 0.14:0.11:0.35:0.40, 18-CH₃), 3.20 (dd, J = 8.4 and 10 Hz, 0.34 H, CHSO), 3.41 and 3.43 (two overlapped dd, 0.53 H, CHSO), 3.48 (dd, J = 8.4 and 10 Hz, 0.13 H, CHSO), 5.72, 5.73, 5.75 (three m, in a ratio 0.18:0.32:0.50, CH=), 7.27-7.42 (m, 5 H, Ar).

15

We observed a cleaner reaction by employing Et₃N instead of the N,N-dimethylaniline reported in the original paper (ref. [11] ).

16

3,3-(2′,2′-Dimethyl-1′,3′-propylenedioxy)-18-methyl-5- and 5(10),15-estradien-17-one (6). A solution of 5 in xylene (20 mL/g substrate) and Et₃N (1 mL/g substrate) was kept at 140 °C under N₂ atmosphere and the reaction progress was monitored by TLC (toluene-EtOAc 8:2) until the starting material disappeared (2.5 h). After cooling to r.t. the crude product was recovered after addition of toluene, washing of the organic phase with brine and H₂O and usual work-up. Purification by silica gel column chromatography (1:25, elution with hexane-EtOAc 9:1) afforded pure 6, in 65% yield from 3. Mp 115-125 °C. ¹H NMR (500 MHz, CDCl₃): δ = 0.74 (t, J = 8 Hz, 1.2 H, 18-CH₃), 0.77 (t, J = 8 Hz, 1.8 H, 18-CH₃), 0.86 (s, 1.8 H, CH₃-C), 0.90 (s, 1.2 H, CH₃-C), 1.01 (s, 1.2 H, CH₃-C), 1.08 (s, 1.8 H, CH₃-C), 3.40-3.70 (m, 4 H, CH₂O), 5.50 (m, 0.4 H, CH=), 5.99 (dd, J = 2.8 and 5.6 Hz 1 H, CH=), 7.47 (d, J = 5.6 Hz, 0.6 H, CH=), 7.54 (d, J = 5.6 Hz, 0.4 H, CH=). IR (1% KBr): 3454.0, 2951.3, 2863.7, 1706.0 cm^-1. MS: m/z = 371 [M + 1], 370 [M⁺], 341.

17

3,3-(2′,2′-Dimethyl-1′,3′-propylenedioxy)-17α-ethynyl-17β-hydroxy-18-methyl-5-and 5(10),15-estradiene (7). To a solution of 6 in anhyd THF (25 mL/g of substrate) the commercially available (Fluka) lithium acetylide-ethylene-diamine complex (4 equiv) was added, at 0 °C and under N₂ atmosphere. The mixture was kept at 0 °C (2 h) under stirring. The reaction progress was monitored by TLC (toluene-EtOAc 8:2) until the starting material disappeared. To this mixture, 6 N HCl was added to pH 6 and the mixture was brought to r.t. Extraction with EtOAc and usual work-up afforded 17α-ethynyl derivative 7 (94%). Differential Scanning Calorimetry (DSC, 5 °C/min): two endothermic peaks at 174 °C and 192 °C. ¹H NMR (500 MHz, CDCl₃):
δ = 0.82 (t, J = 8 Hz, 1.35 H, 18-CH₃), 0.85 (s, 1.35 H,
CH₃-C), 0.86 (t, J = 8 Hz, 1.65 H, 18-CH₃), 0.90 (s, 1.65 H, CH₃-C), 1.00 (s, 1.65 H, CH₃-C), 1.06 (s, 1.35 H, CH₃-C), 2.60 (s, 0.45 H, H-21), 2.61 (s, 0.55 H, H-21), 3.40-3.70 (m, 4 H, CH₂O), 5.46 (m, 0.55 H, CH=), 5.67 (dd, J = 3.5 and 5.6 Hz, 1 H, CH=), 5.90 (dd, J = 2.0 and 6.0 Hz, 0.55 H, CH=), 5.99 (dd, J = 2.0 and 6.0 Hz, 0.45 H, CH=).