3304
V m . 29
CHINN
Conformational Analysis of Steroidal 16,17-Diketones LELAND J. CHINN Division of Chemical Research, G . D. Searle & Company, Chicago 80, Illinois Received June 4, 1964 I n the presence of oxygen and potassium t-butoxide, 17-keto-13a-androst-5-en-3P-01 ( I ) is oxidized to 17-keto13aY-androsta-5,15-diene-38,16-diol(IIa). The presence of an enolic system in ring D of the latter substance is contrasted with a lG,l'i-diketo-C/D-trans steroid, which does not enolize a t all. An explanation based upon conformationd malysis is proposed.
I n any synthesis of 17-keto steroids, a niethod which would permit the ready determination of whether rings C and D are fused trans or cis should be of considerable value. The marked difference in strain of C/D-transand -cis-17-keto steroids suggests a nieans by which a chemical method may be developed. Molecular models show that the cis-hydrindanone system is considerably more flexible than the trans.2 As a result, the former can be more like cyclopentanone in structure and properties than can the latter. It is known that l12-cyclopentanedione exists exclusively in the enol form3 while 16-ketoestrone methyl ether does not enolize a t alL4 To determine whether a 16,17-diketo-C/D-cis steroid exhibits enolization, we subjected 17-keto-1 3 a-androst-5-en-3P-01 (13 a-dehydroisoandrosterone, I)5 to oxidation in the presence of potassium t-butoxide. Doering and Haines have shown that ketones and aldehydes having a-hydrogen atoms are readily oxidized by a combination of oxygen and potassium and Camerino, Patelli, and Sciaky have employed this procedure for the preparation of diosphenols froin saturated 3-keto steroids.' The product, which we obtained from I in 42% yield, melts a t 226-229' and displays a broad absorption maximum at 255-260 inp (log E 3.79) in methanol. A bathochromic shift to 290.5-294 mp (log E 3.69) occurs when the spectrum is determined in dilute alkali. The two diosphenols of 2,3-cholestanedione absorb in the region of 270 nip (log E 3.70 and 3.93), and the maxima are shifted 48 mp toward the longer wave length in basic solution with little change in intensity.8 Since the absorption maximum increases by approximately 11 mp in going from a five-membered ring to the (1) N.m.r. studies offer a n alternative physical method for steroids with a methyl group attached t o C-13. T h e signals of the C-18 and C-19 methyl groups of dehydroisoandrosterone occur a t 52.2 and 62.4 c.P.s., respectively, with reference to internal tetramethylsilane a t 60 Mc./sec. [W. R. Nes and U. H. Kim, Steroids, 1, 594 (1963)l. With androst-4-ene-3,17dione, the C-18 and C - l a m e t h y l s resonateat 56 and 73.8 c.p.8.. respectively [Y. Kawazoe, Y. Sato. M. Natsume, H. Haaegawa;T. Okamoto. and K. Tsuda, Chem. Pharm. Bull. (Tokyo), 10, 338 (1962)l. I n contrast, we find t h a t 13a-dehydroisoandrosterone (I)&shows signals a t 59 and 51 c.p.8. for the C-18 and (2-19 methyl groups, respectively. and for 13a-androst-4ene-3,li-dionel the '2-18 and (2-19 methyl signals appear a t 60 and 64 c.P.s., respectively. T h e assignment of these signals t o the two methyl groups is based on the assumption t h a t t h e additive constants established for the 3-keto-A4 and t h e 3p-hydroxy-As groupings [R.Zurcher. Helu. Chim. Acta, 44, 1380 (196l)l are applicable t o 13a,14a aa well as t o 138,14u and 138,148 steroids. Thus, inversion a t C-13 of a 17-keto-C/D-trane steroid results in a surprisingly large shift of about 9 c.p.8. upfield for the C-19 methyl group and a s h i f t of ea. 5 c.p.8. downfield for the C-18 methyl group. (2) See also A. S. Dreiding, Chem. Ind. (London), 992 (1954). (3) G. Schwarzenbach and C. Wittwer, Helu. Chim. Acta, 80, 663 (1947). (4) M. N. Huffman, J . B i d . Chem., 167, 273 (1947). (5) J. P. L. Bots, Rec. trau. chim., 77, 1010 (1958). (6) W. von E. Doering and R. M. Haines, J . Am. Chem. Soc., 76, -482 (1954). (7) B. Camerino, B. Patelli, and R. Sciaky, Tetrahedron Letters. 554 (1961); see also R. Hanna and G. Ourisson, Bull. soc. chim. France. 1945 (1961). ( 8 ) E. T. Stiller and 0. Rosenheim, J . Chem. Soc., 353 (1938).
CHARTI
u
u
HO
RO
IIa,R = H b,R=CHaCO
I
IV
I11
4QtCH3 V
corresponding six-membered ring compound, the presence of an enolized a-diketone in ring D of our product is established. Hence, this product is 17-keto13a-androsta-5,15-diene-3p,l6-diol (IIa). Consistent with its enolic structure, IIa readily forms a diacetate (IIb) and imparts a brown color to an alcoholic solution of ferric chloride. This parallels the redbrown enol reaction observed with the Diels-Alder adduct from 2-niethyl-3,4-diketopenteneand l-vinyl-6methoxy-3,4-dihydronaphthalene,1Q which, undoubtedly, has the C/D-cis configuration. I n contrast, 16-ketoestrone methyl ether does not react with ferric chloride.4 I n addition, 16-ketodehydroisoandrosterone acetate prepared in our laboratories by Dr. D. A. Tyner according to the procedure of Huffman14was found to show no ultraviolet absorption in the region characteristic for enols. The presence of two or more trigonal carbon atoms in the five-membered ring of a steroid gives rise to considerable strain in the ring." In a 13a,14a steroid this strain can be relieved by having ring C adopt the Inore flexible boat conformation (111) or the closely akin twist conformation. l 2 The preference at equilibrium of the enolic form IV to the diketo form I11 can be ascribed to the absence in IV of the subtle conformational and (9) A. E. Gillam and T. F. West, ibid., 486 (1942). (10) E. Dane and J. Schmitt, Ann., 686, 196 (1938). (11) Schwarzenbach and Wittwer' have pointed o u t t h a t a five-membered ring u-diketone is considerably strained and t h a t this strain can be relieved through enolization. (12) W. 9. Johnson, V. J. Bauer, J. L. Margrave, M . A. Frisoh, L. J. Dreger, and W. N. Huhbard, J. Am. Chem. Soc., 83, 606 (1961).
NOVEMBER, 1964
STEROIDAL
electrostatic strains produced in I11 by the respective compression of the C-15 hydrogens and the repulsive interaction of the carbonyl dipoles. l3 While the extra trigonal atom (C-15) in I V has a destabilizing effect, the additional energy is offset by the elimination of the aforementioned strain energies present in 111. Thus, in the 13a,14a series, a system possessing three trigonal atoms in ring D, but with ring C in the boat (IV) or twist conformation is more stable than the tautomeric system in which there are only two trigonal atoms in ring D but ring C is in the form of a chair (V).14 As AH of the chair conformation of cyclohexane is 5.5 kcal./mole more favorable than that of the boat,12 it follows (as a first approximation since we are assuming that the effect of the C-18 methyl group cancels the TAS value) that the enolone system of IV is a t least of the same order of magnitude more stable than the tautomeric dione system of the ring C chair conformer (V), and that at equilibrium a five-membered ring adiketone that can undergo enolization is exclusively in the enol form, which is consistent with the determination of Schwarzenbach and Wittwer that the enol content of both 1,2-~yclopentanedioneand 3-methyl-1,2cyclopentanedione is Although the dihedral angle formed by the four carbon atoms, C-15, -14, -13, and -17, of both a C/Dtrans- and -cis steroid is 60' when ring C has the chair conformation, ring C of a CID-trans steroid cannot assume a twist or boat conformation, for, otherwise, this -dihedral angle will increase to 8716 and 120°, respectively. A dihedral angle of these magnitudes cannot accommodate the fusion of a five-membered ring to a six-membered ring. Hence, a 16,17-diketo-C/D-trans steroid is energetically more stable in the arrangement in which there is a minimum number of trigonal carbon atoms in ring D, viz., in the diketo form, in spite of the unfavorable dipole interaction of the two carbonyl groups. 13,16
16,17-DIKETONES
3305
Parenthetically, the inability of the trans-C/D system to relieve its strain through conformational change of ring C helps to explain the readiness with which 15dehydroestrone methyl ether undergoes either polymerization, epimerization a t C-14, or migration of the A16 double bond,17and it provides an explanation for the observation that shifting of the double bond of a A14-17keto-13P steroid into conjugation with the carbonyl group produces the A16-17-keto-13P,14P steroid exclusively. l8
Experimental*s
Preparation of 17-Keto-13~-androsta-5,15-diene-3~,16-diol (IIa).-A magnetically stirred solution of 1 .OO g. (0.00335 mole) of 17-keto-13a-androst-5-en-3P-01 (1)s and 1.OO g. (0.0089 mole) of potassium t-butoxide in 50 ml. of t-butyl alcohol was oxygenated' at atmospheric pressure and at room temperature in a set-up normally used for hydrogenation. After 85% of the calculated amount of oxygen was absorbed over a period of 24 hr., no further uptake of oxygen was observed. The turbid reaction mixture was neutralized with dilute hydrochloride acid and then conccntrated under reduced pressure t o remove the t-butyl alcohol. The residue, which contained a solid, was cooled in an ice bath. The solid was collected by filtration and washed well with water, after which it was dissolved in ethyl acetate. The ethyl acetate solution was diluted to approximately ten times its volume with benzene, and the resulting mixture was poured into a column of 50 g. of silica gel. Elution of the column with 10% ethyl acetate in benzene gave 0.065 g. of I (identified by infrared spectroscopy) and 0.625 g. of IIa. 17-Keto-13a-androsta-5,15diene-30,16-diol (IIa) was crystallized from ethyl acetate to aff2;d 0.444 g. (427,) of peach-colored prisms: m.p. 226-229"; 290.5-294 mp (log E Amax 255-260 mp (log E 3.79); Ap:p'Ic'KoH 3.69); AKBr 2.82, 2.92, 5.84, and 6.17 p ; [ C Y ] % -188" (l'?& dioxane). It gave a brown color to a 5 7 , ethanolic solution of ferric chloride. Anal. Calcd. for Cl&&: C, 75.86; H, 8.67. Found: C, 75.48; H, 8.66. Acetylation of 17-Keto-13a-androsta-5,15-diene-3p,16-diol (IIa).-A solution of 0.228 g. of IIa in 2 ml. of pyridine and 2 ml. of acetic anhydride was allowed to stand at room temperature for 18 hr., after which it was poured into ice-water. The resulting solid was collected, washed well with water, and dried. Crystallization from ether-pentane gave 0.175 g. of 17-keto-13a-andros(13) N. J. Leonard and E. R. Blout, J . A m . Chem. Soc., 72,484 (1950); G. ta-5,15-diene-30,16-dioldiacetate (IIb) a8 colorless laths: m.p. S. Hammond, "Steric Effects in Organic Chemistry," M. S. Newman. Ed., 234-235 mp (log E 3.92); XKBr ca. 5.64, 5.77, 148-150"; ": : :A John Wiley and Sons, Inc., New York, N. Y., 1956, p. 450. D (lye CHCl,); n.m.r. (14) T h e n.m.r. spectrum of 17-keto-13u-androsta-5,15-diene-3,16-diol 5.83 (sh), 6.08, and 7.97 p ; [ c Y ] ~ ~-143" diacetate ( I I b ) was determined with tetramethylsilane as a n internal stand(CDC1,) 449.7, 446.3, 323, 135, 122, 71, and 56 c.p.8. downfield ard a t 60 Mc./sec., and i t shows t h a t the signal8 of the '2-18 and the C-19 with reference to internal tetramethyldane at 60 Mc./sec. on a methyl groups of I I b are shifted 12 and 5 c.P.B., respectively, downfield as Varian A-60. compared t o the signals of the corresponding methyl groups of 13a-dehyA n d . Calcd. for Cz~H3005: C, 71.48; H, 7.82. Found: droisoandrosterone (I). The two acetyl methyl groups of I I b display sigC, 71.57; H, 8.18. nals a t 122 (C-3 OAc) and 135 c.p.8. (C-16 OAc). T h e vinyl proton a t C-6 shows a broad band a t 323 c.p.8. while t h e aignal of the C-15 proton in the 450-c.p.8. region is distinctly split into two peaks a s would be expected from t h e coupling of the C-15 proton with the proton a t C-14. Expansion of this region gives a coupling c o n s t a n t p f 3.4 c.p.s., which indicates t h a t the di~ H C d h is greater than 30' hedral angle, m, between the planes H C I L and and perhaps slightly less than 60° (see L. M. Jackman, "Applications of Nuclear Magnetic Resonance Spectroscopy in Organic Chemistry," Pergamon Press, New York. N. Y., 1959, pp. 85, 87). The result is in agreement with t h e assignment of either the boat, twist, or chair conformation to ring C and does not permit a distinction among them. (15) J. B. Hendrickson, J . Org. Chem., 29, 991 (1964).
(16) T h e cisoid carbonyl groups very likely are not coplanar as a result of a twiat about the 1 6 1 7 bond. While such a twist serves t o minimize the repulsion of the dipoles. i t does not eliminate the interaction entirely. (17) W. S. Johnson and W. F. Johns. J . A m . Chem. SOC., 79, 2005 (1957). (18) W. S. Johnson, J. W. Petersen, and C. D. Gutsche, i b i d . . 69, 2942 (1947): D. K. Banerjee, S. Chatterjee, C. N. Pillai, and M. V. Bhatt, i b i d . , 7 8 , 3769 (1956). (19) Melting points were taken on a Fisher-Johna melting block and are corrected.
