STEHOILKCCX
Xarch, 1963
underwent the Grignard exchange reaction, then reaction with carbon dioxide to afford the corresponding 17a-propiolic acid IT'. Hydrogenation of the acetylenic bond in methanol in the presence of a 5% palladium-on-charcoal catalyst led to the saturated acid V, which in the presence of a trace of acid, cyclized to the y-lactone VIa. The corresponding 3-tosylate VIb smoothly underwent elimination upon heating under reflux in collidine to furnish the A2-androstene-17-spirolactone TTI. Oxidation of the propionic acid lactone VIa with chromic acid in acetone-dilute sulfuric acid" gave the corresponding 3-ketone VIII, the physical constants of which are in good agreement with those published by the Searle group.5 Condensation of this ketolactone TTII with ethyl formate led to attack of the lactone ring as well as at C-2. Exclusive condensation a t C-2 I--CC=O
&Ia, R = CH3 b,R=H
c= c & -
RO
c-
C-COzH
-
H IIIa,R=H b , R = o
IV
U
OH
V
VIa, R = H b, R = TOS
r c = o
y c I= o
r C = O I
H IXa, R = H b. R = CH,,
H
X
(16) (a) H. B. Henbest, E. R . H. Jones, and I. SI. S. Walls, J . Chem. Soc., 3646 (1950); (b) C . W. Greenhalgh, H. €3. Henbest and E. R. H. Jones,
ibid., 1190 (1951); (c) A. C. Ott, M. I . Murray and R. L. Pederson, J . A n . Chen. Soc., 74, 1239 (1952); (d) F. Sondheimer, N. Stjernstrom and D. Rosenthal, J . Org. Chem., 24, 1280 (1959). (17) (a) K. Boaden. I. M. Heilbron. E. R. H. Jones and B. C. L. Weedon, J . Chem. S o c . , 39 (1946); C. Djerassi, R. R. Engle and A. Bowers. J . Org. Chem., 21, 1547 (1956).
1x3
was effected by carrying out the reaction with ethj-1 formate with a suspension of the sodium salt of the steroid-17a-propionic acid in beazene-tetrahydrofuran.'* Treatment of this product with tartaric acid gave the 2-hydroxymethylene analog IXa of the 3 keto-17-spirolactone. Conversion of this substance IXa into the 2-formyl-A2-spirolactoiie X then follo\ved essentially the procedure outlined earlier from our Laboratories.'? Formation of the methyl ether IXh by reaction with methanol containing a trace of perchloric acid was followed by reduction of the 3-keto group with sodium borohydride and treatment of the resulting /3-hydroxy-vinyl ether with acid to effect a concerted hydrolysis and elimination reaction, leading to the 2-formyl-A2-17-spirolactone X.
ExperimentalI9 17~t-Ethynylandrostane-3p,l7fi-diol-3(2'-tetrahydropyrany1)ether (IIIb).-17~tEthynylandrostane-3p,l7p-diol~~ (IIIa) \vas prepared from androstane-3p-ol-17-0ne'~ (11) by a Grignard reaction with ethynylmagnesium bromide, and 1% orking up in the normal manner. 17a-Ethl-nylandrostane-3p,l7p-diol(111%)( 2 5 g.) m.p. 264~ (c, 1.1; CH,OH) were dissolved in 1380 ml. of 266"; [ a ]-41" anhydrous benzene after which about 400 nil. of benzene was distilled o f f under vacuum. The remaining solution was cooled to room temperature. T o this solution was added 56 nil. of redistilled dihydropyran and 1.1 g. of recrystallized p-toluenesulfonic acid monohydrate. After being kept 1 hr. a t room temperature and then 13 hr. a t 5 0 1 6 water was added and the organic layer was washed first with l O c L sodium carbonate solution, and then with water t o neutrality. After being dried over anhydrous sodium sulfate, the organic layer was concentrated under vacuum. The crude product, m.p. 175-176", (28.4 g.) was recrystallized from methylene chloridemethanol to afford an analytical sample of 17a-ethynylandrostane-3/3,l'ij3-dio1-3(2'-tetrahydropyrany1)-ether(IIIb), m.p. 182-184", [ a ] -86" ~ (c, 1); A":, 3.0, 3.13 and 4.36 p . Anal. Calcd. for CssH,,Oa 0.5 C H 3 0 H : C, 76.45; H, 10.16; 0, 13.39. Found: C, 76.8'2; H , 9.87; 0, 13.31. Androstane-3p,17~-diol-l7a-propiolic Acid (IV).-To a boiling solution of 72 ml. of methylmagnesium bromide in ether (3 -21) in 190 ml. of anhydrous tetrahydrofuran there nas added a solution of 12 g. of the above ether I I b in 60 nil l 4 of anhydrous tetrahydrofuran. When the addition was complete, a further 24 ml. of ethereal methylmagnesium bromide was added. The mixture was allowed t o reflux for 16 hr. A further 24 ml. of Grignard reagent then was added and reflux continued for 24 hours The reaction mixture was cooled to room temperature and then poured into a dewar flask where it was mixed with Dry Ice and allowed t o stand for 65 hr. The mixture was then poured into 1.5 1. of 2 S sulfuric acid and extracted with ethyl acetate. The organic layer was washed several times mith a Yaturated aqueous solution of sodium bicarbonate To the bicarbonate extracts 30% aqueous hydrochloric acid was added carefully until acidity was achieved. The acid IV which precipitated was filtered o f f , vcashed with water and dried under vacuum, to give the crude product: m.p. 240-250" (7.5 g,). Further recrystallizations from methanol -water afforded the pure sample of androstane-3@,l7p-diol17~-propiolicacid (IV), m.p. 248-250' (dec.): [ Q ] D -46" (c, 2.81, 5.85 p . 0.4; CHBOHj; ' : :X 209 nipz0(log t 3 74), (IS) L. H. Knox. R. Villotti, I . A . Kincl and H. J. Ringold, i b i d . , 26, 501 (1961). (19) Microanalyses were carried out by Dr. A. Bernhardt, M a x Planck Institut, Mlilheirn. Germany, or by X i d u e s t hIicrolab. Inc.. Forest Lane, Indianapolis 20, Ind., U.S.A. Except where otherwise stated rotations were taken in chloroform solution. Melting points uere determined in capillary tubes with a "hlel-Temp" apparatus and are uncorrected. Infrared spectra were taken with a Perkin-Elmer l l o d e l 21. equipped Tvith a S a c 1 prism. Ultraviolet absorption spectra are for 95% ethanol solutions and were measw e d with a Beckman Spectrophotometer, Model D.U. Alumina was prepared as described in ret. 1 1 , footnote 42. ( 2 0 ) This ultraviolet spectrum was obtained with a Beckman spectrophotometer, Model D . K . 2.
.-lr~al. Calcd. for C22HY&: C, 73.80; H, 8.95: 0, 17.75. Found: C, 73.24; H, 8.86; 0, 17.90. Androstane-3p,l7p-diol-l7~-propionic Acid (V) and Androstane-3@,17@-diol-l7~propignicAcid Lactone (Via).-A s o h tion of 500 mg. of the propiolic arid I V in 20 nil. of methanol--was stirred under a hydrogen atmosphere in the presence of 0.3 g . of 57, palladium on carbon until two equivalents of hydrogen had been absorbed. Stirring was discontinued and the catalyst filtered off. Methanol was removed by vacuum distillation to afford the crude acid T', 1n.p. 195-196" (450 mg.). Further recrystallization from et,hanol-water gave a pure sample of androstane-3b,17p-diol-17a-propionic acid (V): 1n.p. 198-2OOD; 1 , ~1 1 , -2' (c, 0.6; CHaOH); X ~ ~ C : 3 . 15.92p. , \Vhen this acid V was recrystallized froiii metharicrl C I I I I tailling traces of hydrochloric acid the corresponding lartonr VI:t was obtained. By further recrystallization from methylene chloride-methanol there was obtained an analytic:tl sample c r f androstane-3p,1'7p-dio~-l7~~-pr~~pionic arid lactone ( VIa): silky m / , -.86, j.68 p . plates, m.p. 201.5-%02": [ L Y ] ~ , - I < ) ' (c, 1 ) : A""' C'ella, at al., reported$: m.p. 1!)9-2Ol .lncrl. Calcd. for CrEH:140:I:C, 7 Found: C, 76.42; H, 9.77; 0, IX.!)i. Androstane-3p,l7p-diol-l7~-propionicAcid 3-Tosglate (VIb). TIJR solution of 1.5 g . of t h e lac%one VI:%in 40 nil. of anhydrous pyridine \vas added 3 g. of rerrystallized p-tcrliienes~ilfirnyl chloride. The mixture then was :tlloned to stand overnight :it, room temperature, after whiiih water I Y ~ Sadded and the mixture vxtractjed with methylene rhloride. The organic layer was first washed with 107, aqueous hydrochlirricn acid, then with 557, sodium bicarbonate solut,ion and finally uith water. Aft,er being dried over anhydrous sodium sulfate, the solvent was evaporated under vacuum, giving 1.5 g. of the rrude tosylate VIh, m.p. 14X--. 145'. Further crystallization from acetonrhex:tne gave pure :tndrostnne-3@,lip-diol-17a-propioiiic acid 8-tosylate (VIbj, as needles, n1.p. 151-152" (dec.): [ a j -~2 2 " (c, 1); 226 nip (log e 4.11), 256 n i p (log e 2.68), 262 m p (log E 2.771, 267 nip (log c 2.72), 274 m p (log e 2.62); 5.65, 7 . 5 and 8.6 ,u. -4nnl. Calcd. for C29H400jS:C, 69.57; H, 8.05; S , 6.40. Found: C, 69.80; H, 8.19; S, 5.77. ~2-Androstene-17p-ol-l7~-propionic Acid Lactone (VII).-Bndrostene-3~,17p-ol-l7~~-propionirarid 3-tosylate (VIb) 1.5 g. was dissolved in 120 i d . of freshly distilled dry rollidine and the mixture refluxed for 2 hr. under nitrogen. -4fter cooling, water was added and then ethyl acetate. The organic phase was washed several times with 10% hydrochloric acid, and with water to neutrality, dried over anhydrous sodium sulfate and concentrated under vacuum t o give an amorphous material. This compound was further purified by chromatography over alumina. Elution of the column with hexane-benzene ( 9 : 1) afforded 950 nig. of crystalline A2-compoundVII, ni.1). 130- 132". Further recrystallization from acetone-hesarie gave pure 12-androstene17@-0l-17a-propionic ncid l:tctone (VIT): long needles, i i i . 1 ~ . 134- 1.76"; [ a ] n+I;" ( r , 0.8). .lnal. Calcd. for C&?Ha.O2: (I, 80.44: H. !).8:3. I~crund: (', 80.42; H, 9.72. Androstane-17@-ol-3-one-l7~-propionic Acid Lactone (VIII). A solution of 1.69 g. of the lactone VIa in 60 ml. of acetone (twice distilled over potassium permanganate) was cooled to 0" nnd 1.5 mi. of 8 N chromic acid-sulfuric arid solut,ion17was added dropnise with stirring. K h e n the addition was i~ompletestirring was continued for two minutes. TO t,his mixture 57; sodium bicarbonate solution was added to pH 8. Ethyl acet,:tte i,str:tctjs were washed with n-ater t80neutrality, and then dried over anhydrous sodiiini sulfate. The ethyl acetate vas removed ~ J Jwtcuum distillation t o yield 1.6 g . of crude keto-lactone VIII 1ii.p. 170-175". Purification of this compound by chromatography followed hy recrystallization from acetone-hexane gave the pure sample of :tndrostane-lia-o1-3-one-17cu-propionic acid lactone (VIII): m.p. 177-178", cy]^) +5" (c, 0.8). Reported by Cella, at nl.5; m.p. 178-179"; [LY]I, f 5 " (CHCI,); A",: 5.67 and 5.8 p.
