Intramolecular hydrogen bonding in hydroxy-keto-steroids

摘要

1972 171Intramolecular Hydrogen Bonding in Hydroxy-keto-steroidsBy T. Suga," T. Shishibori, and T. Matsuura, Department of Chemistry, Faculty of Science, Hiroshima Univer-The i.r. spectra of hydroxy-keto-steroids with an equatorial-hydroxy-group u to the ketone show a band due tohydrogen bonding (OH . * 0 type) ; those with an axial hydroxy-group 0: or @to the ketone exhibit two absorptionbands, due to a free and a bonded hydroxy-group (OH - . r type). The mode of multiple hydrogen bonding inepimeric pairs of monohydroxy-diketo-steroids and dihydroxy-monoketo-steroids is discussed. Hydrogen bond-ing in dihydroxy-keto-steroids is more extensive than in monohydroxy-keto-steroids.sity, Higashisenda-machi, Hiroshima, JapanIKTRAMOLECULAR hydrogen bonding in diols and hydr-oxy-ketones has been studied extensively by means ofi.r.spectroscopy.l-5 However, there is little informationon the hydrogen bonding of polyfunctional compoundssuch as monohydroxy-diketo-steroids and dihydroxy-monoketo-steroids. This paper deals with the correla-tion between conformation and intramolecular inter-action in polyfunctional steroids as revealed by hydroxy-stretching frequencies in the i.r. spectrum.RESULTS AND DISCUSSIONThe a-eq-hydroxy-ketone (2) showed a single bandwith a large shift of 130 cm-l relative to the free hydr-oxy-stretching frequency, indicating the presence of anOH - - - 0 hydrogen bond.7 The a-ax-hydroxy-ketones(1) and (3) and the p-ax-hydroxy-ketone (4) exhibited twobands, one due to a free hydroxy-group and the othershifted 10-20 cm-l due to an OH - - - x interaction, inaccord with the data in ref.4.Hydroxy- and carbonyl stretching absorptions ofhydroxy-keto-steroidsVItl8=(0-H) /cm-l361436023482361536033620361035993487362 13599353234533575346834963498+mar. *22708420661265548910414410710010892hl,(c=O) /cm-117171705172117211727171417101723+Inax. *509603485525656754601710* Apparent molecular extinction coefficient (1 mol-I cm-l).5-Hydroxy-5a-cholestane-3,6-dione (5), in which theaxial hydroxy-group is a to one keto-group and p to thef When the free hydroxy-stretching absorption was notobserved, values of 3627 and 3618 cm-l were used for secondaryand tertiary hydroxy-groups, respectively, as generally recog-nized absorption frequencies.OH - - - 0 Refers to an inter-action between the hydroxy-group and the lone-pair electronsof the carbonyl oxygen atom and OH - * n to that between thehydroxy-group and the rr-electrons of the carbonyl group.M. Tichp, in ' Advances in Organic Chemistry: Methodsand Results,' eds. R. A. Raphael, E. C. Tayler, and H. Wynberg,Wiley, New York, 1965, vol. 5, p. 115; T. Suga and T. Shishibori,Kugakzt 1.20 Ryoiki, 1968, 22, 995, 1079.other, showed a slightly shifted band due to the OH * * xinteraction (Figure 1). It is not clear whether the a- orthe @-interaction gives rise to the OH - 0 - x induced shift,since both would exhibit similar hydroxy-absorption.The absence of a free hydroxy-absorption in this com-pound indicates an increased OH - a - x interaction.5-Hydroxy-5p-cholestane-3,6-dione (6), whose hydr-oxy-group is a-eq to one keto-group and p-ax to theother affords the best opportunity for competition be-tween the OH - * - x interaction and OH - - - 0 hydrogenFIGURE 1 The i.r.spectra of 5-hydroxy-6u-cholestan-3,6-dione(6) (full line) and B-hydroxy-5/3-cholestan-3,6-dione (6) (brokenline)bonding cf. (2) and (a). The isomer (6) exhibited aband due to an OH - 0 hydrogen bond only (Figure 1)indicating that it has the conformation shown.3p,5-Dihydroxy-5a-cholestan-6-one (7), which has atrms-l,3-diol system and a hydroxy-group a-ax to theketo-group, exhibited two hydroxy-bands (Table 1).Since no hydrogen bonding occurs in a trans-1,3-diolsystem (cj.trans-cyclohexane-l,3-diol 6, the higherfrequency band is due to a free hydroxy-group at C-3and the lower to an OH * * x interaction between theC-5-hydroxy- and the carbonyl group. The 5p-isomer(8) with a cis-1,3-diaxial diol system and a hydroxy-group a-eq to the ketone exhibited a spectrum differentfrom that of the 5a-isomer (7) (Figure 2). The bandsF. Dalton, J. I. McDougall, and G. D. Meakins, J . Chem.SOC., 1963, 4068.C. W. Davey, E. L. McGinnis, J. M. McKeown, G. D.Meakins, M. W. Pemberton, and R. N. Young, J . Chem. SOC.(C), 1968, 2674. * M. oki, H. Iwamura, J. Aihara, and H. Iida, Bull. Chem.SOC. Japan, 1968, 41, 176.L. Joris and P. von R.Schleyer, J . Amer. Chem. SOC., 1968,90, 4599.L. P. Kuhn, J . Amev. Chem. SOC., 1952, 74, 2492172at 3532 and 3453 cm-l are assigned to the OH - * * OHand the OH 6 * 0 hydrogen-bonded hydroxy-absorp-tions, respectively. The absence of a free hydroxy-band implies intramolecular hydrogen bonding. 4a,5-Dihydroxy-5a-cholestan-3-one (9) also exhibited twopeaks (Figure 2). From the Av values of these bands,the higher frequency band was assigned to the hydrogen-bonded hydroxy-absorption of the cis-l,2-diol systemand the lower band to the interaction of the a-eq-hydroxy- and keto-groups. The Av values of the OH -0 band of compounds (8) and (9) were larger thanthat for 3p,5-dihydroxy-5P-cholestane (vmX 3533 cm-lfor bonded OH; Av = 87 cm-1),2 that for 4aJ-dihydr-oxy-5a-cholestane (vmX 3578 cm-I for bonded OH;( 3 1 ' IA-0HO -1 IIO-H (71(11 b)Av = 49 ~ m - l ) , ~ and that for the steroid (2) (Av ca.130cm-1). This indicates that hydrogen bonding is en-hanced by the electronic effect of the formation of two7 P. N. Rao, H. R. Gallberg, and L. R. Axelrod, J . Org.Chem., 1963, 28, 270.8 H. Minato, Bull. Chem. SOC. Japan, 1963, 36, 1020.J.C.S. Perkin Ihydrogen bonds and by the steric effect of the deform-ation of the carbon skeleton giving the shortest oxygen-oxygen distance. For the compound (8), the formationof the O(3)-O(5) hydrogen bond forces the C-5 hydroxy-hydrogen atom into the most favourable orientationfor formation of the O(5)-0(6) hydrogen bond. A similarsituation may also occur for compound (9).1LO a100,w , 0608203600 3400w1crn-lFIGURE 2 The i.r.spectra of 3~,6-dihydroxy-5~-cholestan-6-one(8) (full line) and 4a,6-dihydroxy-5a-cholestan-3-one (9)(broken line)The epimeric pair of 2-hydroxypregn-4-ene-3,20-amp;-ones,' (10) and ( l l ) , afforded an interesting example ofthe influence of hydrogen bonding on conformation.The 2a-epimer (10) showed a band due to O H . . . 0hydrogen bonding, implying an equatorial orientation ofthe hydroxy-group in a half-chair conformation. Com-pound (11) also exhibited an OH * - - 0 hydrogen-bonded band at almost the same frequency also indica-tive of an equatorial hydroxy-group. In the energetic-ally favourable half-chair conformation (1 lb), thehydroxy-group should be axial.However, an un-favourable 1,3-diaxial interaction between the 2-hydr-oxy- and the 10-methyl groups forces the compound intothe half-boat conformation (1 la), which is furtherstabilized by hydrogen bonding between the hydroxy-and the carbonyl groups.Carbonyl stretching bands were also examined foralmost all the compounds. However, the effect ofhydrogen bonding on these bands was not clear, as hasbeen previously pointed out.8EXPERIMENTALI.r. Spectral Measurements.-The hydroxy- and thecarbonyl i.r. spectra were recorded for solutions in dry carbontetrachloride on a Perkin-Elmer 62 1 grating spectrometerat a spectral slit width of ( 2 cm-1 at 25". Sharp andbroad peaks were measured with an accuracy of rfII2 andf 4 cm-l, respectively.The concentrations of sampleswere 0 . 0 0 5 ~ ; sodium chloride cells of 20 mm and 4 mm pat1972lengths were used for the measurements of the hydroxy-and the carbonyl stretching frequencies, respectively.5-H~ydroxy-5a-choEestan-6-one (1) and 5-Hydroxy-5p-cholestan-8one (2) .-3-Chlorocholest-5-ene was prepared bytreating cholesterol with thionyl chloride in pyridine.OThe chlorocholestene was converted into cholest-5-ene bytreatment with metallic sodium in isopentyl alcohol.1deg; Thecholestene was then hydroxylated with performic acid l1to give 5,6p-dihydroxy-5a-cholestane (double m.p. 60 and125'). Oxidation of the diol with N-bromosuccinimideafforded 5-hydroxy-5a-cholestan-6-one (1), m.p. 153-154",a,25 + 44.5' (c 1 in ethanol).5-Hydroxy-5P-cholestan-6-one (2), m.p. 103-104', -16.5" (G 1 in chloroform),l*was prepared from the steroid (1) by isomerization withmethanolic potassium hydroxide.5-Hydroxy-5a-clzoZestan-4-one (3) .-4p, 5-Dihydroxy-5~-cholestane, prepared from cholest-4-ene by oxidation withperformic acid, was further oxidized with N-bromosuccin-imide to give compound (3), m.p. 158-159', olD25 t37.4"(c 1 in chloroform).135-Hydroxy-5P-cholestan-3-one (4) .-Reduction of 413,5-epoxy-5~-cholestan-3-one with lithium aluminium hydride,followed by oxidation with chromic acid, afforded the ketone(4), m.p. 151-152", aID25 + 63.0" (G 2 in CHC1,).143$5-Dilzydroxy-5a-choZestan-6-one (7) and 3p, 5-Dihydroxy-5P-choZestnn-6-one (8) .-Cholesterol was hydroxylated withP.J. Daughenbaugh and J. B. Allison, J . Amer. Chem.SOC., 1929, 51, 3665.lo H. Kwart and L. B. Weisfeld, J . Amer. Chem. SOC., 1956,78, 635.l1 H. Reich, F. E. Walker, and R. W. Collins, J . Org. Chem.,1951, 16, 1753.D. N. Jones, J. R. Lewis, C. W. Shoppee, and G. H. R.Summers, J . Chem. SOC., 1955, 2876.173performic acid l6 to give 3P,5,6@-trihydroxy-5a-cholestane,m.p. 235-238'. Oxidation of the trio1 with N-bromosuc-cinimide afforded the ketone (7), m.p. 232-233" (decomp.).Isomerization of the ketone (7) with methanolic potas-sium hydroxide, followed by chromatography, gave theisomer (8), a viscous oil, aID2j -5.5" (c 2 in CHCl,).lG5-Hydroxy-5a-cholestane-3,6-dione (5) .-Oxidation of3p,5,6P-trihydroxy-5a-cholestane with chromic acid inacetic acid afforded the dione (5), m.p. 232-234", aID25- 13-1" (G 2 in CHClJ.1'5-Hydroxy-5~-cholestane-3,6-d2one (6) .-Oxidation ofcompound (8) with chromic acid in acetic acid afforded thedione (6)' m.p. 120-121deg;.1s4a, 5-Dihydroxy-5a-cholestan-3-one (9) .-Cholest-4-en-S-one was hydroxylated with hydrogen peroxide in thepresence of osmium tetroxide l3 to give compound (9),m.p. 208-210", aIDz6 +40.5" (c 2 in CHC1,).We thank Professor P. Narasinha Rao of SouthwestFoundation for Research and Education, San Antonio,Texas, U.S.A. for samples of 2a- and 2P-hydroxy-4-pregnene-3,20-dione and Dr. M. C. Wani and Dr. J. A. Kepler ofResearch Triangle Institute, North Carolina for advice onpresentation.I1816 Received, March 15th, 19711l3 J. F. Eastham, G. B. Miles, and C. A. Krauth, J . Amer.l4 P. A. Plattner, H. Hausser, and A. B. Kilkami, Helv. Chim.l6 L. F. Fieser and S. Rajagopalan, J . Amer. Chem. SOL, 1949,l6 A. T. Rowland, J . Org. Chem., 1962, 27, 1135.l7 V. Prelog and E. Tagmann, Helv. Chim. Acla, 1944, 27,Chem. Soc., 1959, 81, 3114.Acta, 1948, 31, 1822.71, 3938.1867