14-Methyl steroids. Part 5. Structural features influencing stereoselectivity of 14-methylation of 15-oxo-19-norsteroids: synthesis of 14α-methyl-19-norprogesterone

Abstract

Methylation of 3-methoxy-I 4P-estra-1,3,5(10),8-tetraen-l5-one (5) in the presence of base affords a ca. 5 : l mixture of the corresponding 1 4~-and 14P-methyl compounds (6) and ( 7 ) respectively, whereas similar treatment of 20,20-ethylenedioxy-3-methoxy-l9-norpregna-1,3,5( 10) -trien-I 5-one (15) results in exclusive formation of the 14~-methyl product (18). The latter compound (18) has been converted into 1 4~-m e t h y l -l 9-norprogesterone (23). The stereoselectivity of 14-methylation of 15ketones is correlated with the propensity of ring D to adopt a quasi-trans or quasi-cis conformation in the derived enolate, leading to preferred 1 &-or 1 4P-methylation respectively.The sterically directing role of unsaturation in rings B or c, and of 17-functionality, upon the course of base-mediated alkylation of steroidal 15-ketones is implied in earlier reports in the l i t e r a t~r e . '~~ We have shown * that highly stereoselective 140-methylation takes place in simple 15-0x0-19-norsteroids, and that this reaction course is retained in 17,17-ethylenedioxyand I7P-acetoxy-1 Sketones, both of which proceed through A16-intermediates. However, it has been reported that only 14%alkylation occurs in cholest-8( 14)-en-15-ones and in pregnan-15-0nes.~ The former result was authenticated through eventual correlation of the derived products with the synthetic target, l a n~s t e r o l ,~ and has, more recently been successfully adapted for a synthesis of methyl 14~-methyl-l5-oxo-5~-chol-8-en-24oate from cholic acid.5It is tempting to conclude that the stereochemical course of the reaction is dictated by the conformation imposed upon ring D by the 14(15)-en-15-olate anion or a derived transition state,

Cycloaddition route to 14,17-ethano- and 14-alkyl-19-norsteroids

“…I D + 100" (c 0.98); v, , , . 1 745,l 318, and 1 149 cm-'; 6,(500 MHz) 0.88 (3 H, s, 13P-Me), 1.11 (1 H, ddd, J 13.5, 4.0, and 2.6 Hz, 12P-H), 1.23 (1 H, dddd, J 13.6, 13.3, 12.3, and 4.0 Hz,1.39 (1 H,ddd,J 12.0,11.6,and 2.6 Hz, 8P-H), 1.64 (3 H, s, 17P-OAc), 1.68 (1 H,dddd,J 12.3,12.0,9.9,and 7.7 Hz,1.85 (1 H,dddd,J 12.3,4.1,3.6,and 2.6 Hz, 7P-H), 1.99 (1 H, dd, J 12.6 and 5.0 Hz, 15a-H), 2.03 (1 H, dd, J 12.6 and 8.6 Hz, 15P-H), 2.21 (1 H, dddd, J 13.3,3.8,3.7, and 2.6 Hz, 1 la-H), 2.3 (1 H,ddd,J 13.6,13.5,and 3.8 Hz,12a-H), 2.51 (1 H,ddd,J 12.3,11.6,and 3.7 Hz,9a 8Hz,2-H),7.15(1 H,d,J8.6HzY 1-H), 7.56 (2 H, m, m-H x 2 of PhSO'), 7.64 (1 H, m, p (b) A mixture of the dienyl acetate (2) (17 g, 52.4 mmol) and phenyl vinyl sulphone (10.58 g, 62.9 mmol) in anhydrous xylene (30 ml) was heated in a sealed tube at 145°C for 72 h. The reaction mixture was cooled to 25 "C, whereupon the product crystallised. Recrystallisation from benzene-hexane gave the product (3) (13.61 g, 52.7%), identical to that obtained in the foregoing experiment.…”

“…Treatment of compound ( 9) with toluene-p-sulphonic acid (5 mg) in acetic anhydride ( 2 3H, s, 13P-Me), 1.1 and 1.33 (each 1 H,ddd,J6.2,1.5,and 1.2 Hz,[16][17]1.12 (1 H,dddd,J 12.7,12.2,11.8,and 5.9 Hz,1.75 and 1.89 (each 1 H,dt,J 10.2,and 2 x 1.5 Hz,1.83 (1 H,dt,J 2 x 11.4,and 2.3 Hz,8P-H), 2.01(3H,s,17~-OAc),2.15and2.16(each1H,dd,J10.2and1.2 Hz,2.28 (1 H,ddd,J 11.8,11.4,and 3.9 Hz,2.36 (1 H,dddd,12.7,3.9,3.5,and 2.7 Hz,2.8 (2 H,m,3.76 (3 H,s,6.61 (1 H,d,J2.8 Hz,6.71 (1 H,dd,J8.6 and 2.8 Hz,and 7.23 (1 H,d,J 8.6 Hz,; 6c(125 MHz), 170.7 (s, 17P-OCOCH3), 157.45 (s, C-3), 137.9 (s, C-5), 132.4 (s, C-lo), 126.7 (d, C-1), 113.8 (d, C-4), 111.7 (d, C-2), 85.2 (s, 55.2 (9,44.8 (s,42.9 and 35.0 (each d,…”

“…J2.6 Hz,4-H of (26)], 6.87 r0.6 H', d, J2.6 Hz,4-H of (27)], 7.01 14-Acetoxymethyl-3-methoxyestra-1, 3,5( 10)-trien-1 7-one (28).-A solution of the 14a-hydroxymethyl-17-ketone (26) (94.3 mg, 0.3 mmol) and acetic anhydride (2.84 ml, 30 mmol) in dry pyridine (3 ml) was stirred at 25 "C for 2 h. Ice and solid sodium hydrogen carbonate were added, and the product was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate (3 x 10 ml), dried (Na, SO,), and evaporated to give 14-acetoxymethyl-3-methoxyestra-1, 3,5( 10) 14'),55.1 (q,51.8 and 45.95 (each s,41.8 and 37.3 (each d,33.9,30.9,26.1,25.5,24.9,and 24.4 (each t,[2][3][4][5][6]20.8 (q,and 18.3 (q, (Found: C, 74.2; H, 7.8%; M + ,356. Cz2Hz8O4 requires C,74.1;H,7.9%;M,356).…”

“…-0.715 (310 nm); 6H(500 MHz) 0.99 (3 H, s, 13P-Me), 1.56 (1 H, s, exch. by D20, 17P-OH), 1.73 (1 H, ddt, J 13.1,2 x 13.0, and 5.0 Hz,1.96 (1 H, dt, J 2 x 12.3, and 2.5 Hz, 8P-H), 2.2 (1 H, dt, J 2 x 13. 1,and4.7 Hz,2.52 (1 H,ddt,J 13.0,2 x 4.7, and 2.2 Hz, lla-H), 2.83 (3H,m,6a-,6P-,and9a-H),3.76(3H,s,3-OMe),3.87(1H,t,J7.8 Hz,6.59 (1 H,d,J2.7 Hz,6.71 (1 H,dd,J8.6 and 2.7 Hz,7.2 (1 H,d,J8.6 Hz,and 10.15 (1 H, s, 14a-CHO) (Found: C, 76.3; H, 8.4%; M ', 314. C20H2603 requires C, 76.4; H, 8.3%; M, 314), and the 14-hydroxymethyl-17-one (b) To a stirred solution of oxalyl chloride (18.3 pl, 0.21 mmol) in anhydrous THF (1 ml) at -78 "C, was added dimethyl sulphoxide (15.5 p1, 0.22 mmol).…”

“…In the first phase of the work, estrone 3-methyl ether (1) was readily converted into the dienyl acetate (2), using a three-step sequence without purification of intermediates. Treatment of (2) with phenyl vinyl sulphone in benzene at 145OC for 90 h resulted in formation of a single cycloadduct (3) (92%), the structure of which was assigned by analogy ' and by subsequent transformations. Although a 500 MHz 'H n.m.r.…”