QufMICA DE LA UNIVERSIDAD NACIONAL RESEARCH LABORATORIES OF SYNTEX,S. A]
[ J O I N T CONTRIBUTION FROM THE INSTITUTO DE
AUT~NOMA DE MOXICO
AND THE
STEROIDAL SAPOGENINS. XVIII.1 EXPERIMENTS I N T H E 5,6-DIHYDROKRYPTOGENIN SERIES A. L. NUSSBAUM,* A. SANDOVAL, G. ROSENKRANZ,
AND
CARL DJERASSI*
Received November 8 , 1961
A5-Cholestene-3P,26-di01-16~22-dione (kryptogenin)z occurs rather abundantly in a number of species of Dioscoreae, but the only feasible method (2) up to the present time for the utilization of this sapogenin for the manufacture ,26-diol of steroid hormones consists of conversion to A5Js,20(zz)-furostatriene-3P 26-diol ($-kryptogenin) folloa-ed by hydrogenation to A5~20(22)-furostadiene-3P, ($-diosgenin), which has already been degraded by Marker (3) to A5rI6-pregnadien-3P-ol-20-one. It appeared of interest to prepare sapogenin derivatives with a 17,2Q-double bond, since they might lend themselves to oxidative degradation to 17-keto steriods; as demonstrated in an earlier communication (4), A5-cho1estene-3p,26-dio1-16,22-dione (kryptogenin) represents a particularly suitable starting material for such purposes since it can be transformed into A6Ji(20)-22-isospirostadien-3~-ol (17-dehydrodiosgenin) through intermediates such as 11, 111, and IV (with a double bond in the 5,6-position). I n order to study satisfactorily methods for the side chain degradation of such A1’@O)unsaturated sapogenins, it was desirable to prepare model compounds which contain no additional double bond in the nucleus as do the earlier described (4) A5J7-dienesand the present paper is concerned with the synthesis of such nuclear saturated derivatives from cholestane-3P,26-diol-16,22-dione(5,6-dihydrokryptogenin) (Ia). Marker and collaborators (5) have synthesized cholestane-3P, 26-diol-16,22dione diacetate (Ib) by catalytic hydrogenation of “kryptogenin diacetate” with platinum oxide catalyst. For large preparations, it was found advantageous t o carry out the hydrogenation with palladized charcoal in ethyl acetate solution to avoid any reduction of the diketone system. The diacetate I b was con26-diol diacetate (5,6-dihydro-$-kryptoverted to A16~20(22)-allofurostadiene-3P, genin diacetate) (IIb) by the recently described (4) acetic anhydride-p-toluenesulfonic acid method; Marker, et al. ( 5 ) had synthesized this diacetate I I b by heating in a bomb tube with acetic anhydride, but reported only a m.p. and analysis. For further characterization, the free furostadiene I I a was prepared and the previously unreported rotations were determined of the various intermediates. The dextrorotatory shift, typical (1,4) for the conversion to a furostene derivative, was observed in this instance also and serves as further confirmation for structure 11. Chromium trioxide oxidation of the furostadiene diacetate I I b afforded an oil with an ultraviolet absorption spectrum a t 246 mp, which was shown t o have the constitution of A17(20)-cholestene-3/3, 26-dio1-16,22-dione
* Present address : Department of Chemistry, Wayne University, Detroit 1, Michigan. Paper XVII, Mancera, Barton, Rosenkranz, and Djerassi, J . Chem. Soc., in press. For nomenclature of steroidal sapogenins see Rosenkranz and Djerassi, N a t u r e , 166, 104 (1950).
426
427
STEROIDAL SAPOGENINS. XVIII
diacetate (111), since just as in the case of the A5-unsaturated analog (4), reaction with hydrazine hydrate in ethanol solution produced the pyridazine derivative V of cholestane-3/3,26-diol-16,22-dione. The formation of 111 from the furan derivative I1 was postulated (4) to proceed through an intermediate 16 ,17-oxide. Some support for this supposition is now furnished by the observaI11 can be obtained in good yield when I1 is tion that the A17(20)-16,22-dione treated with perphthalic acid. Saponification of the oily acetate 111 produced 22-diol-16-one (IV) (ultraviolet the crystalline 22,26-0xido-A~~(~~)-cholestene-3p,
ti
&-
Ro
Pm
I a R = H
b R=Ac
c
R=
ma^=^ b R=Ac
C&CO
absorption maximum a t 237 mp) which upon refluxing with hydrazine hydrate in ethylene glycol was transformed into the identical pyridazine V. Finally lithium aluminum hydride reduction of IV led to A17(20)-22-isoallospirosten-3/3-ol (VIa) (no selective absorption in the ultraviolet), which formed a monoacetate VIb. The structure assignments of 111, IV, and VI appear secure on the basis of analogy to the previously described A5-unsaturated derivatives as well as of the analytical and spectroscopic results. As an alternate and hitherto undescribed route to A17(20)-unsaturated sapogenin derivatives, there was examined the Diels-Alder condensation of Ale,20(22)-
428
A. L. NUSSBAUM, A . SANDOVAL, G . R. ROSENKRANZ, AND
c.
DJERASSI
allofurostadiene-3p, 26-diol diacetate (IIb) and of the corresponding Ab,16,20(22)triene ($-kryptogenin diacetate) with maleic anhydride. In each instance there was obtained in excellent yield an adduct of type VIII. Compound VI11 was reduced with lithium aluminum hydride to the tetrol IX. The successful DielsAlder condensation of I1 thus furnishes additional proof for the presence of a furan ring in the $-derivative of "kryptogenin." Incidental to the above described experiments, there was also examined the catalytic hydrogenation of A16~20(22)-all~f~r~~tadiene-3~, 26-diol diacetate (IIb) which proceeded in the expected manner (2) to yield the previously undescribed (cf. 6) crystalline A20(22)-allofurostene-3p, 26-diol diacetate ($-tigogenin diacetate) (VII) . EXPERIMENTAL3
ChoEestane-SP,86-diol,l~,88-dionediacetate (Ib). A solution of 250 g. of A6-cholestene-3P,26diol-16,22-dione diacetate (kryptogenin diacetate) in 3.6 1. of ethyl acetate was hydrogenated with 25 g. of 10% palladized characoal catalyst a t 40" and 50 p.s.i. for about 16 hours a t which time a sample gave a completely negative test with tetranitromethane. Filtration of the catalyst, evaporation of the filtrate to dryness, and recrystallization from chloroform-methanol gave 90-95% of the desired dihydro acetate Zb with m.p. 121-123", [a]: -133"; lit. (5), m.p. 121-123". The free genin Za showed m.p. 171-172", [a]: -139"; lit. (5), m.p. 169-171". The dibenzoate I C , m.p. 171-173", [CY]: -103" does not appear to have been described. A n a l . Calc'd for C ~ I H S ~C, O 76.84; ~: H , 8.18. Found: C, 76.96; H , 8.21. A~~~zo(~z)-AZlofurostadiene-Sp,b6-diol (11). The isomerization of I b with refluxing acetic anhydride containing a small amount of p-toluenesulfonic acid proceeded exactly as described for the A5-unsaturated analog (4). The resulting diacetate I I b exhibited m.p. 97-98', [CY]: +IO", kE\:H 226 mp, log E 4.05; lit. (5), m.p. 96-98", The previously undescribed free diol ZZa possessed m.p. 189-191", [CY]: +31", X HE :: 227 mp, log e 4.03. A n a l . Calc'd for C27H420a: C, 78.21; H, 10.21. Found: C, 78.41; H , 10.35. 8 ~ , ~ 6 - 0 ~ i d o - A ~ ~ ~ ~ ~ ~ - c h o l e s t e n e - ~ ~ , b 8(-IdVi )ofZr o- 1m6A1e~zo~zz~-allofurostadiene-S8,ds-one diol diacetate (IIb). ( a ) By perphthalic acid oxidation. An ethereal solution of 2.0 g. of the diacetate I I b consumed approximately one mole of peracid in 96 hours, when allowed t o stand a t room temperature with an excess of monoperphthalic acid. The ether solution was washed with dilute sodium carbonate solution and water, dried, and evaporated leaving a colorless oil (111), which exhibited an ultraviolet absorption maximum a t 246 mp, log e 4.11, and could not be crystallized even after extensive chromatography. It was, therefore, saponified directly by refluxing for 1 hour with 2% ethanolic potassium hydroxide and the product extracted with ether. Evaporation t o dryness and recrystallization from hexaneacetone afforded 1.2 g. of colorless crystals with m.p. 205-206", [CY]: -105", 237 mp, log e 4.19. A n a l . Calc'd for C27H4204: C, 75.30; H, 9.83. Found: C, 75.37; H , 9.76. ( b ) By chromium trioxide oxidation. Although proceeding in poorer yield, the following procedure is preferable for large scale work. A solution of 40 g. of the diacetate I I b in 320 cc. of glacial acetic acid was treated a t 15" dropwise with stirring over a period of 30 minutes with a solution of 5.4 g. of chromium trioxide in 150 cc. of 90% acetic acid and the 3 Melting points are uncorrected. Rotations were determined in chloroform and ultraviolet absorption spectrain 95% ethanol solution. Weareindebted toSrta. Paquita Revaque f o r these measurements and t o Srta. Amparo Barba for the microanalyses.
STEROIDAL SAPOGENINS. XVIII
429
mixture was allowed to stand a t room temperature for an additional 2 hours. After pouring into water, extracting with ether, washing with carbonate solution and water, drying, and evaporating, the residue was saponified in the above described (a) manner afforded 17 g. of the oxido-diolone IV with m.p. 204-206', [CY]: -107". Pyridazine derivative of cholestane-3p,W-diol-16,22-dione (V). ( a ) From choEestane-3,9,W6diol-l6,2%dzone (I). A solution of 2.0 g. of the diacetate I b in 10 cc. of ethanol was refluxed for 2 hours with 5 cc. of 85% hydrazine hydrate and then cooled. Filtration afforded 1.7 g. of the dihydropyridazine derivative' with m.p. 150-165", [CY]: -210°, 234 mp, log E 3.78,which without purification was refluxed for 2 hours with 25 cc. of nitrobenzene and chilled, whereupon a brownish solid separated. Passage through a column of alumina and recrystallization from hexane-ethyl acetate afforded 1.05 g. of colorless crystals of the pyridazine V with m.p. 209-211", [CY]: +Bo, XzgH 258, 296 mp, log E 3.32,2.60.The same dextrorotatory shift and absorption spectrum was observed previously (4) for the corresponding As-unsaturated analog. Anal. Calc'd for C27H42Nl02: C, 76.01;H, 9.92;pu', 6.57. Found: C, 76.17;H , 10.10;N,6.70. ( b ) From A17~2~~-cholestene-3p,26-diol-16,2Z-dione diacetate (111). Refluxing of an ethanolic solution of 1 g. of the oily diacetate I11 (from the perphthalic acid oxidation of IIb) with 5 cc. of 85% hydrazine hydrate for 2 hours followed by dilution with water and recrystallization from ethyl acetate-hexane led to 0.75 g. of the pyridazine derivative v, identical (mixture m.p., rotation, spectrum, analysis) with the specimen prepared according t o (a). (c) From Z2,Z6-ozido-A*7~20~-choEestene-~~,ZZ-diol-~6-~ne (IV). The crystalline diolone (11') (1.0g.) upon refluxing for 45 minutes with 20 cc. of ethylene glycol and 0.6 cc. of hydrazine hydrate yielded 0.85 g. of the pure pyridazine V, identical in all respects with samples prepared according to (a) and (b) . 4~~(20)-22-Isoallospirosten-Sp-ol (VIa). The saponification product IV (10g.) was refluxed for 30 minutes with 5 g. of lithium aluminum hydride in tetrahydrofuran solution. Decomposition of the excess reagent with acetone, followed by addition of dilute sulfuric acid, filtration of the precipitate, and recrystallization from methanol-chloroform afforded 6.5-7.0g. of colorless crystals with m.p. 226-228",[CY]: -12", no selective absorption in the ultraviolet, free hydroxyl but no carbonyl band in the infrared. A n a l . Calc'd for C27H4203: C, 78.21;H , 10.21. Found: C, 77.91;H, 10.24. iicetylation in the usual manner followed by recrystallization from chloroform-methanol an3 sublimation a t 190-210" and 0.001 mm. led t o colorless crystals of the acetate VIb with m.p. 223-225", [a]: -8", acetate b u t no free hydroxyl band in the infrared. A n a l . Calc'd for C2pHa404:C, 76.27;II, 9.71. Found: C, 76.17;H , 9.59. A2~(~2)-AElofurostene-3p,26-diol diacetate (+tigogenin diacetate) (VII). A solution of 10 g. of A16~zo(~2)-allofurostadiene-3~,26-diol diacetate (IIb) in 75 cc. of ethyl acetate was shaken a t room temperature and atmospheric pressure with 0.8 g. of 5% palladized barium sulfate catalyst (American Platinum Works, riewark, N. J.) in an atmosphere of hydrogen until the up-take corresponding to one mole had stopped (ca. 2 hours). Filtration of the catalyst, evaporation t o dryness, and crystallization from methanol at -10" yielded 9.4 g. of colorless crystals with m.p. 65-68'. The analytical sample showed m.p. 7O-72",[a]: +7". Alkaline saponification produced the known (6) A20(22)-allofurostene-3p,26-diol. A n a l . Calc'd for C81HasOb: C, 74.36;H, 9.66. Found: C , 75.57;H, 9.35. Maleic anhydride adduct ofA16 20(22)-allofurostadiene-Qp,26-diol diacetate (VIII) . A solution of 4.0 g . of the diacetate I I b in 40 cc. of benzene was refluxed with 1.0 g. of maleic anhydride 4 The rotatory and spectral data are analogous t o those found for the dihydropyridazine in the "kryptogenin" series (Ref. 4, footnote 12).
430
A. L. NUSSBBUM, A. SANDOVAL,
a.
R. ROSENKRANZ, AND C. DJERASSI
for two hours and then evaporated to dryness. Two recrystallizations of the solid residue from methanol-chloroform gave 3.55 g. of the adduct VI11 with m.p. 167-168") [a]: -5", no selective absorption in the ultraviolet, .!::A 1860, 1786 cm.-l (cyclic anhydride) and 1736 cm.-' (acetate). Anal. Calc'd for C U H & ~ :C, 70.44; H, 8.11. Found: C, 70.65; H , 7.96. Lithium aluminum hydride reduction of 1.7 g. of the adduct VI11 in tetrahydrofuran solution (2-hours refluxing) produced 1.3 g. of the tetrol IX with m.p. 261-263', [a]: +76". Anal. Calc'd for C ~ I H S O C, O ~74.06; : H, 10.03. Found: C, 74.53; H , 9.82. Maleic anhydride adduct of ~6,16,20(zz)-furostatriene-~~,Z6-diol diacetate ($-kryptogenin diacetate). The Diels-Alder condensation of 4.0 g. of A5~18~20(z2)-furostatriene-3,9,26-diol diacetate (4) in the above described manner furnished 3.3 g. of the adduct with m.p. 172174", [a]: -56", no selective absorption in the ultraviolet. Anal. Calc'd for C3sH&: c, 70.68; H, 7.81. Found: C, 70.26; H, 7.76.
Acknowledgment: The authors are indebted to Dr. Glibert Stork of Harvard University for helpful discussion. SUMMARY
Cholestane-3P, 26-dio1-16,22-dione (5,6-dihydrokryptogenin) (I) has been 26-diol diacetate (IIb) and A17(20)transformed via A16~zo(2z)-allofurostadiene-3P, cholestene-3,8,26-dio1-16,22-dione diacetate (111) into 22,26-0xido-A~~(~~)-cholestene-3P ,22-diol-16-one (IV). Lithium aluminum hydride reduction of the latter furnished A17(20)-22-isoallospirosten-3~-o~ (VI). The structure of I11 and IV was proved further by conversion into the pyridazine derivative V of cholestane-3Pf 26-di01-16~22-dione. A6J6,zo(z2)-F~rostatriene-3P, 26-diol diacetate (#-kryptogenin diacetate) as well as its 5,6-dihydro analog I I b readily form adducts (VIII) with maleic anhydride, thus providing further support for the presence of a furan ring in those compounds. Selective hydrogenation of A16,zo(zz)allofurostadiene-3pf26-diol diacetate (IIb) afforded in excellent yield AzO(zz)-al lof~rostene-3~~26-diol diacetate (#-tigogenin diacetate) (VII). LAGUNA MAYRAN 413 MEXICOCITY 17, D.F. REFERENCES (1) DJERASSI, MARTINEZ, AND ROSENKRANZ, J . Org, Chem., 16,307 (1951); DJERASSI,ROMO, AND ROSENKRANZ, J . Org. Chem., 16,758 (1951). (2) KAUFMANN AXD ROSENKRANZ, J . Am. Chem. Soc., 70, 3502 (1948). (3) MARKER, J . Am. Chem. Soc., 62, 3350 (1940). (4) SAVDOVAL, ROMO,ROSENKRANZ, KAUFMANX, AND DJERASSI,J . Am. Chem. Soc., 73, 3820 (1951). (5) ~ I A R K E M'AGSER, R, ULSHAFER, WITTBECKER, GOLDSMITH, AND RUOF,J . Am. Chem. floc., 69, 2197 (1947). (6) MARKERAND ROHRMANN, J . Am. Chem. Soc., 62,898 (1940).
