2006
Org. Chem., Vol. 40, No. 13, 1975
Communications (4) A table of 13C chemical shifts of these compounds is published in the microfilm edition of the journal immediately following these pages. (5) C. Djerassi, Pure Appl. Chern., 21, 205 (1970). (6) T A. Wittstruck and K. I. Williams, J. Org. Chern., 38, 1542 (1973). (7) A table of bond distances and angles averaged over the four molecules is published in the microfilm edition of the journal immediately following these pages. ( 8 ) (a) Worcester Foundation for Experimental Biology, Shrewsbury, Mass. 01545. (b) Medical Foundation of Buffalo Research Laboratories, Buffalo, N.Y. 14203. (c) Extracted in part from the Ph.D. Thesis of J. P.Moreau to be submitted to the University of Orleans, France.
928
P
T h e Worcester Foundation for Experimental Biology Shrewsbury, Massachusetts 01545
Eliahu Caspi*8n William L. Duaxsb Jane F. Griffinsb Jacques P. Moreausa,c Thomas A. Wittstrucksa
Received March 27, 1975 F i g u r e 1.
the carbon and oxygen positions with isotropic thermal pararneters is continuing. The R factor is 11.8% a t the present t h e . The data revealed the presence of four crystallographically independent molecules of 3c in the ceK7 OR'I'EP views (50% probability thermal ellipsoids) of molecule 2 are seen in Figure 1. The structure of 3c is unequivocally 5cu,l7cu-cho~est-14-eii.~3~-01 p - bromobenzoate. Molecules 1, 2, and 4 have the same D ring conformation, 170 envelope, and similar side chain orientation; C-21is anti t o 6-13and gauche to C-16.In molecule 3 tlhe D-ring conformation appears to be a 17a envelope and C-21is gauche to C-13 and C-16.The end of the cholestane side chain, C-25, C-26, 6-27,is probably disordered in a t least two of the molecules. Other interesting conformational details which vary in the four molecules will be discussed in a future paper. The saturated derivative 4 obtained by hydrogenation of 3 could have either the 14cu or 140 stereochemistry. From l3CNMR studies4 of 4c and 4d, it was tentatively concluded that 4 is 5a,l4~,17a-cholestan-3P-ol.
A Ready Synthesis of 17a Steroidu1i2 Summary: Reaction of sterol acetates with a A7, AS(l4), and A14 double bond with hydrogen chloride yields 3P-acetyloxy-14-chloro-5a,l4~,17a-cholestane(structure determined by X-ray analysis), which is easily dehydrohalogenated to 3~-acetyloxy-5a,l7a-cholest-14-ene. Sir: Anhydrous hydrogen chloride in chloroform has been described to promote the isomerization of A7, As, and As(14) double bonds to the 14 position in sterol^.^^^ Compound l a (mp 104-106") was obtained as the single reaction product by bubbling hydrogen chloride for 3 hr a t -60' in a 20-25 m M solution of 3~-acetyloxy-5cu-cholest-7-ene (2) in diethyl ether. The lH NMR spectrum showed signals a t d
Acknowledgments. The work a t the Worcester Foundation for Experimental Biology was supported by National Institutes of Health Grants GM 19882 and GM 16928 and by National Science Foundation Grant BMS72-02440 A01. The work a t the Med.ica1 Foundation of' Buffalo was supported by National Institutes of Health Grants CA 10906 and AM 05619. S u p p l e m e n t a r y M a t e r i a l A v a i l a b l e . Tables o f 13C chemical s h i f i s a n d b o n d distances a n d angles w i l l appear following these pages in t h e m i c r o f i l m edition o f t h i s volume o f the journal, P h o t o copies o f t h e supplementary m a t e r i a l f r o m t h i s paper o n l y or microfiche (105 x 148 mm, 24X reduction, negatives) containing a l l of t h e supplementary m a t e r i a l f o r t h e papers in this issue m a y b e obtained f r o m t h e Journals Department, American Chemical Society, 1155 16th St., N.W., Washington, D.C. 20036. R e m i t check o r money order for $4.50 f o r photocopy or $2.50 for microfiche, referr i n g t o code number JOC-75-2005.
2
R, = CH,CO; R2 = CY-H b, R, = C,H,CO RL = a-11 c, R, = CH3C0 R2 = 8 - H d, R, = p-BrC,H,CO: R, = 0-I-I
3a,
References and Notes (1) Professor A. Fiecchi and his associates at the University of Miiano have obtained similar results. It was agreed to publish the results of both groups simultaneously. ( 2 ) J. W. Cornfovth, I. Y. Gore, and G. Popjak. Biochem. J., 85, 94 (1957). These authors have carried out the referred to transformation on the 48(i4)-benzoate. We have carried out the reactions described in this communication on both A8(I4)-acerate and the benzoate. In both instances analogous products were obtained which were interrelated as the free C-3 alcohol. At present we report the results for the acetate. (3) All new compounds were fully characterized. 'H NMR spectra were recorded on a Vavian DA-60 instrument, % NMR spectra were obtained on a Varian HA 100-15 instrument equipped with a Varian time-averaging computer (C-1024) and were recorded at 25.1 MHz. Mass spectra were obtained on a Du Pont 21-491 instrument.
Rz = (5')-H C,HjCO; R2 = (R)-H
5a, R, = CH,CO;
R1 = CHJCO b. R1 = C,H,CO
4a,
b, R,
C,H,TCH=CHCHO 6
=
J. Org. Chem., Vol. 40, No. 13, 1975 2007
Communications
Scheme I
Figure 1. ORTEP p l o t o f 3@-acetoxy-14-chloro-5a,14@,1'7a-choles-
a
tane.
0.81 ((219 CH3, s) and 1.18 (CIS CH3, s). The molecular ion was absent in the mass spectrum which differed from that of 3a only in the relative intensity of fragmentation peaks. b By X-ray diffraction analysis the compound was shown to give orthoronibic crystals with cell dimensions: a = 34.148 (lo), b = 12.538 (21, c = 6.641 (2) A; space group P212121,Z ranic olefin b with hydrogen chloride formally reverses the rearrangement starting from the attack of a proton at 17p = 4. A total of 1371 reflections was measured up to 8 = 45'. position and with the final introduction of chloride ion at The structure was solved by direct methods employing the position 14/3.9 program MULTAN.5 The final R index was 0.091 for the 1125 reflections with Int. > 2 0 Int. The crystal structure Supplementary Material Available. A table of atomic coordianalysis showed that the examined compound is 3P-acetylnates a n d equivalent temperature factors w i l l appear following oxy-14-chlora-5a,l4~,17a-cholestane (la). The ORTEP plot these pages in t h e m i c r o f i l m edition of t h i s volume o f the journal. of the molecule is reported in Figure 1.'j Photocopies o f the supplementary m a t e r i a l f r o m t h i s paper only or microfiche (105 X 148 mm, 24X reduction, negatives) containing Formation of l b in the reaction of 3P-benzoyloxy-5aa l l of t h e supplementary m a t e r i a l f o r t h e papers in t h i s issue m a y cholest-8(14)-ene (4b) with hydrogen chloride has been reb e obtained f r o m t h e Journals Department, American Chemical ported by Cornforth et aL4 According to these authors the Society, 1155 1 6 t h St., N.W., Washington, D.C. 20036. R e m i t compound is transformed into 3~-benzoyloxy-5a-cholest- check or money order for $4.00 for photocopy or $2.50 for micro14-ene (3b) by shaking the reaction mixture with a saturatfiche, referring t o code n u m b e r JOC-75-2006. ed solution of sodium hydrogen carbonate. Treatment of la References and Notes under these conditions failed to transform the compound into 3a, whereas l a with excess triethylamine in methanol (1) This investigation was supported by the Italian National Research Council. (2) Dr. E. Caspi and his associates at the Worcester Foundation have oba t 50' gave the acetate 3c, which showed 'H NMR signals tained similar results. It was agreed to publish the results of both groups at 6 0.87 (C19 CH3, s), 1.09 (CIS CH3, s), and 5.08 (HIS,m). simultaneously. (3) L. F. Fieser and M. Fieser, "Steroids", Reinhold, New York, N.Y., 1959, The mass spectrum showed differences only in the relative pp 113, 260, 354, 400, and references cited therein. intensity of the peaks when compared with that of com(4) J. W. Cornforth. I. Y. Gore, and G. Popjak. Biochem. J., 65, 84 (1957). pound 3a. Compound 3c failed to crystallize but a crystal(5) G. Germain, P. Main, and M. M. Woolfson, Acta Crystallogr., A27, 368 (1971). line 3p-p-bromobenzoyloxy derivative (3d, mp 101-102') (6) The reflections were measured with a Philips PW 1100 automatic diffracwas obtained (orthorombic with cell dimensions: a = 22.15, tometer (Cu K a radiation monochromatized with a flat graphite crystai; 8 - 2 8 scan mode; scan rate 0.03'/min; scan width 1.2' 8 ) . The posib = 51.87, c = 11.05 A; space group P212121; Z = 16; autotional and anisotropic thermal parameters of nonhydrogen atoms were matic diffractometer data).7 From the above reported specrefined by full matrix least-squares calculations. The hydrogen atoms tral data, the structure of 3~-acetyloxy-5a,l7a-cholest-14could not be discerned on the difference Fourier map; so they were placed at their theoretically expected positions and held fixed during reene was considered the most probable for compound 3c. T o finement. Bond distances and angles are all within the range of the exconfirm this hypothesis, reductive ozonolysis of compound pected values except three C-C distances involving atoms belonging to the side chain in 17; these atoms exhibit very high thermal vibrations. The 3c was performed. The oily ketoaldehyde 5a was obtained average of the absolute values of the torsion angles inside rings A, 8, and from the reaction. It showed IH NMR signals a t 6 0.88 (C19 C are 58.1, 58.4, and 54.2', respectively. The D ring is a slightly distorted CH3, s), 1.2 (CIS CH3, s), and 9.67 (HIS, t, J 1,5 H). The 13@-envelopeconformation. The angle between the least-squares plane of rings C and D is 68'. The only intermolecular distance less than 3.6 A mass spectrum of 5a showed an intense peak a t m/e 292 occurs between C4 and 0 2 8 and is 3.41 A. corresponding to the loss of a CllHzoO fragment from the (7) When the X-ray analysis was in progress Dr. Caspi informed us that he and his associates had already determined the structure oi this commolecular ion. The structure either of aldehyde 6 or of an pound. isomer of this aldehyde might be assigned to this fragment, (8) A transposition of this type has been reported by A. Lardon and T. Reichsince 4,8-dimethylnon-2-en-l-a1 (6), isolated as the semistein, Helv. Chim. Acta, 45, 943 (1962). It is caused by SOClp in pyridine on methyl 56,14@-androstane-36,14-dihydroxy-15-oxo-l7~-carboxylate carbazone, was obtained by pyrolysis of 5a. On the other and similar compounds. hand pyrolysis of 5b was described by Cornforth et aL4 to (9) A carbonium ion formed from 3a or directly from 4a at Ci4 seems unlikely since there is no conformation of the molecule in which the C12-Ci3 give 6, thus confirming the presence of a AI4 double bond bond is aligned with the vacant p orbital at Ci4 as it appears from molecin 3c. ular models. This assumption is supported by the evidence that the transAcetate la was obtained with hydrogen chloride a t low position of the 106-methyl group pf 5a-cholestane-4a,5-diol-4a-acetate occurs owing to the alignment of the ClO-C19 bond with the vachnt p ortemperature also from 3a, 3c, and 4a. On the basis of these bital at C5. Cf. E. T. J. Bathurst, J. M. Coxon, and M. P. Hartshorn, Aust. experimental evidences, the mechanism shown in Scheme I J. Chem., 27, 1505 (1974). may be hypothesized for this reaction. Dilution and low Institute of Chemistry temperature seem to promote the formation of 3a instead Mario Anastasia" of IC which is obtained under the conditions reported by Faculty of Medicine Martino Bolognesi Cornforth et aL4 Trans addition of HC1 to t h e A14 double Uniuersity of Milan Albert0 Fiecchi bond starting with the attack of a proton at carbon 15 from Milan, Italy Giuseppe Rossi the less hindered a side of the molecule would yield 3pCentro Studio Cristallografia Antonio Scala acetyloxy-14-chloro-5a,l4~-cholestane (a). From the mostrutturale C.N.R. and lecular model it is apparent that the 14P-C1, 13P-CH3, and Institute of Crystallography 17p side chains strongly interact and that these interacUniuersity of Pauia tions can be avoided by elimination of chloride ion, folPauia, Italy lowed by ring C contraction and formation of the spiranic olefin b with loss of the 17a hydrogen.8 Reaction of the spiReceiued March 27,1975
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