SYNTHESIS OF 1 KETO STEROIDS
July 20, 1953
well with water, and dried i n vacuo over PZOSa t 100'; yield 0.26 g. (91%), m.p. 255260" (dec.). Calcd. for CziHm09NIz: C, 36.70: H. 3.40: N. 2.04: I. 36.94. Found:.C,36.41; H , 3.60; N, 2.05; I , 36.27. Fluorine analysis on the free glucoside was carried out as described for VI1 and X I . Again, the results indicated that not more than 1% of the trifluoroacetyl groups could have resisted the hydrolytic treatment. N-Trifluoroacetyl-Dh-thyroxine Methyl Ester.-m-Thyroxine (Hoffmann-La Roche)32was esterified according to Ashley and H a r i n g t ~ n . ~0.73 ~ g. of thyroxine methyl ester (m.p. 148-151" dec.) was suspended in 30 cc. of 1:l ethyl acetate-chloroform, treated with 0.4 cc. of trifluoroacetic anhydride, and worked up as described for V; yield 0.76 g . (93%), m.p. 203-206". Anal. Calcd. for C18H120SNF314: C, 24.37; H, 1.35; N, 1.58; I, 57.24. Found: C, 24.46; H , 1.54; N, 1.55; 1 , 5 7 3 . This derivative of thyroxine failed to couple with either acetobromoglucose or acetobromoglucuronic acid methyl ester by the methods described here. N-Benzoyl-I,-thyroxine Methyl Ester.-~-Thyroxine30 was esterified in the same manner as the DL-isomer (treatment of a methanol suspension of the amino acid with dry HCl gas and removal of HCl from the resulting hydrochloride with an equivalent amount of NaOH). The ester prepared by I
,
(32) We are indebted to Dr. A. E. Heming of Smith, Kline and French Laboratories, for a supply of DL-thyroxine.
[CONTRIBUTION FROM
THE
3477
this procedure was not entirely satisfactory. It started t o melt a t approximately IOO", but melted over a range of 1015' to give a sticky, non-flowing melt. Several different preparations all behaved in this manner, differing somewhat in the temperature a t which melting fist started. The preparation used for the N-benzoyl derivative gave the following analysis. Calcd. for C I ~ H I ~ O I N IC, ~ : 24.28; H, 1.66. Found: C, 24.40; H, 1.70. 1.32 g. of L-thyroxine methyl ester (1.67 mmoles) was dissolved in 50 cc. of chloroform in a separatory funnel. Six cc. of 2 N NazCO3 was added, and then in portions, 0.25 cc. of benzoyl chloride (2.1 mmoles) contained in several cc. of chloroform, was added with shaking. The chloroform layer was drawn 08,washed with 10 cc. of 2 N NaZCO3, twice with water, and dried with CaC12. The chloroform solution was concentrated in vacua a t room temperature, and the residue was redissolved in a small volume of warm benzene. After charcoal treatment and concentration in vacuo the benzene solution was treated with several volumes of petroleum ether, whereupon the product started to crystallize. Precipitation was completed by standing in the refrigerator overnight; yield 1.22 g. (82%), m.p. 200-206'. Anal. Calcd. for C23H1706NIn: C , 30.82; H, 1.91. Found: C, 31.44; H, 2.13. An attempt to couple the above thyroxine derivative with acetobromoglucuronic acid methyl ester was not successful. BERKELEY, CALIF.
RESEARCH LABORATORIES OF MERCK& CO., INC.]
Synthesis of 11-Keto Steroids B Y E. hf. CHAMBERLIN,
xr.v. RUYLE,A. E. ERICKSON, J. M. CHEMERDA, L. M. ALIMINOSA,
R.L. ERICKSON, G. E. SITAAND M. TISHLER RECEIVED DECEMBER 9, 1952
A general synthesis of 11-keto steroids is described in which the prerequisite A7~9(11)-alZo-steroid is converted through successive stages to a A7-9a,lla-epoxide, a A8-7~,11a-diol, a A8-7,11-dione,and finally to a 7,11-dione. The latter can be reduced preferentially a t the 7-position to an 11-keto steroid. By means of this procedure ergosterol, stigmasterol and diosgenin can be converted to aZlo-pregnan-3p-ol-l1,20-dione acetate (XV) which can be used for the synthesis of cortical steroids.
In an earlier communication, we described Thus, from the reaction between A7*9(11),22-ergobriefly the synthesis of allopregnan-3/3-01-11,20- statrien-3/3-01 acetate (I) (ergosterol-D acetate)4 dione acetate (XV) from ergosterol, stigmasterol and perbenzoic acid in benzene a t 10' a monoand di0sgenin.l Since that time other investiga- epoxide, a di-epoxide, and a tri-epoxide can be isotors have also reported the preparation of ll-oxy- lated by the use of one, two or three moles of the genated steroids from A5s6-steroidsdevoid of func- peracid, respectively. Of these various derivatives, tional groups in ring C.2 Of these publications the mono-epoxide proved most useful for the only two have described the synthesis of the diketo synthesis of 11-keto steroids. Since the mono-epoxide obtained from ergodlopregnane (XV).1r2b We now wish to describe the results presented in our first communication sterol-D acetate exhibits end absorption only in the ultraviolet above 220 mp, it is evident that the :ind additional pertinent data. In the course of research on the introduction of 7,9( 11)-diene system is attacked in preference to 11-oxygen into the above-mentioned steroids, the the side-chain function. In fact the dienic funcoxidation of A7,g('1)-steroid dienes by peracids was tion is attacked with such rapidity that the monostudied. In contradistinction to earlier literature epoxide is obtained almost exclusively from the on the action of perbenzoic acid on conjugated reaction of I with one mole of perbenzoic acid, acetate dienes3 we observed that A7-g(11)-dienes react in an Similarly A7~9(11)-5a,22a-spirostadien-3/3-ol orderly stepwise manner with perbenzoic acid. (XVI) can be selectively oxidized to a monoepoxide and to a di-epoxide. (1) E. M. Chamberlin, W. V. Ruyle, A. E. Erickson, J. M. Chemerda, L. M. Aliminosa, R . L. Erickson, G . E . Sita and M. Tishler, After our initial communication, Jeger and his THISJOURNAL, 73, 2396 (1951). co-workersze reported the conversion of I into the (2) (a) L. F. Fieser, J. E. Herz and Wei-Yuan Huang, ibid., 73, mono-epoxide and ascribed to the latter a A72397 (1951); (b) G. Stork, J. Romo, G . Rosenkranz and C . Djerassi, 9a,l la-epoxide structure (11). Our experience ibid., 73, 3546 (1951); (c) L. F. Fieser, J . C. Babcock, J. Herz, WeiYuan Huang and W. P. Schneider, ibid., 78, 4053 (1951); (d) C. likewise indicates that these mono-epoxides from Djerassi, 0. Mancera. G. Stork and G. Rosenkranz, ibid., '78, 4496 A7~g(11)-alZo-steroids are best described as A7-9a,1l a (1951); (e) H. Heusser, K. Eichenherger, P. Kurath, H. R . DUlenmono-epoxides5 bach and 0. Jeger, Hclu. Chim. A d a , 84, 2106 (1951); (f) R. C. Anderson, R . Budziarek, G. T. Newbold, R . Stevenson and F. S. Spring, Chemistry and Industry, 1035 (1950); J . Chem. SOC.,2892 (1952). (3) A. Windaus and A. Liittringhaus, Ann., 481, 119 (1930); A. Windaus, 0. Linsert and H. J. Eckhardt, ibid., 684, 22 (1938).
(4) An improved method of synthesis of this substance and other A7,@(l%teroidswill be presented later in THISJOURNAL. (5) A report covering additional reactions of the mono-epoxide will be presented later.
3478
CHAMBERLIN,
RUYLE,ERICKSON, CfIEMEKD.%, ALIMINOSA, ERICKSON, SITA
AND 'rISFI1,ER
XI
IS
VOl. 75
SI1
Y O o M e
Although the epoxide ring of the mono-epoxides is stable toward alcoholic alkali under ordinary conditions, it is extremely labile toward acidic reagents. When the levorotatory mono-epoxide (11) from A7~g(11)~zz-ergostatrien-3/3-01 acetate' is subjected to prolonged chromatography over acidwashed alumina cleavage of the oxide ring occurs and a strongly adsorbed dextrorotatory substance is formed. Analysis of the cleavage product indicates hydration of the mono-epoxide 11. The active hydrogen determination together with the formation of a tri-acetate by the action of acetic anhydride-pyridine a t room temperature suggested that the dextrorotatory hydration product of I1 is a
derivative of a tri-secondary triol, namely, A s , n 2 ergostadien - 3/3,75,11a - triol 3 -monoacetate (111). The formulation of the hydrolysis rearrangement product as 111 was confirmed further by the oxidation of I11 to A8~22-ergostadien-3P-01-7, 1I-dione acetate (IV) by chromic acid. As expected, IV exhibits an absorption maximum a t 270 mp (alcohol) or 266 mp (isooctane) which can only be explained in terms of a lJ4-diketoneconjugated through a 2,3double bond. The observed shift of 15 mp from the absorption maximum of A4-cholestene-3,6dione6 is not unexpected in view of the presence of an additional substituent in I V except for the fact (6) W. ROSS,J
C'hem S o r , 737 (1946).
July 20, 1953
SYNTHESIS OF 1 KETO STEROIDS
3479
that a similarly constituted 1,4-enedione,A8(14)-ergo- In accordance with the postulated structures sten-3P-ol-7,15-dione has been reported to absorb both the reduced 7,ll-dione (V) and the parent a t 255 mp.' However, A9-octalin-l,5-dione,sa more As-7,ll-dione (IV) form only mono derivatives precise counterpart of the absorbing entity in IV, with 2,4-dinitrophenylhydrazine or ethylenebishas been reported to possess an absorption maxi- thiol. The difference in reactivities of the carbonyl 1-dione acetate mum at 263 mp. Subsequent transformations of functions of A22-ergostene-3/3-ol-7Jl IV and similar products described in this paper pro- is in fact so great that we were able to effect its vide rigorous proof of the structure of the cleavage selective reduction by the Huang-Minlon modification12 of the WOE-Kishner reduction to AZ2product of I11 and its oxidation product IV. The hydrolytic rearrangement of I1 catalyzed by ergostene-3/3-ol-ll-one which was also characteracidic alumina is also readily applicable to the ized as the acetate (VI). Degradation of the side chain of VI finally proconversion of the monoepoxides prepared from methyl A7~9~11~-3~-acetoxy-uZZobisnorcholadienate vided indisputable proof that a method for the (XII) and A7~9(11)-50r,22a-spirostadiene-3P-ol ace- preparation of 11-keto steroids had been achieved. tate (XVI) into the respective triol monoacetates. Ozonization of VI, decomposition of the ozonide As might be expected from the reactions of buta- with zinc dust-acetic acid, oxidation of the interdiene mono-ep~xide,~ these As-7,11-hydroxylated mediate aldehyde and esterification of the acetoxy derivatives can be obtained also by the action of acid yielded methyl 3P-acetoxy-1l-ketobisnoralloaqueous acids. The Swiss investigators, Jeger cholanate (VII). The latter was transformed into and his co-workers,2ehave described the hydrolytic methyl 3,ll-diketobisnorulZocholanate (VIII) by rearrangement of the mono-epoxide (11) by the hydrolysis followed by oxidation. By an unequivaction of dilute aqueous sulfuric acid in dioxane ocal synthesis, methyl 3a-hydroxy-1 l-ketobisnorfor a short period of time a t a low temperature. cholanate (IX)13was also converted to VI11 which We have likewise observed that the rearrangement proved to be identical with the derivative syntheof these epoxides can be carried out in homogeneous sized from ergosterol. Briefly, the synthesis inmedia.s From the standpoint of efficiency of oper- volved oxidation of IX to the 3-keto compound ation, the alumina-catalyzed hydrolysis possesses (X) bromination of X to the 4-bromo derivative considerable advantage over the use of homo- followed by dehydrobromination using the method geneous media particularly if the epoxide prepara- of Koechlin, Kritchevsky and Gallagher.14 The tion is contaminated with the A7-ulZo-steroids.10 resulting methyl A4-3,l1-diketobisnorcholenate (XI) The latter are difficult to remove by crystallization was hydrogenated to a mixture of saturated diols and hence complicate the purification of subse- which was oxidized to the diketones with chromic quent reaction products derived from the epoxides. acid. Both methyl 3,ll-diketobisnorcholanate(X) Since the triol monoacetates are strongly adsorbed and the desired ullo derivative (VIII) were isolated on alumina, the other less polar impurities are easily by chromatography over alumina. and efficiently separated by elution with non-polar By a similar series of transformations A6-3Psolvents. In this manner the epoxide (11) is acetoxybisnorullocholenic acid, derived from stigconverted to pure I11 in yields of 80435% on the masterol and cholesterol, has also been converted basis of the epoxide present. into methyl 3P-acetoxy-11-ketobisnorallocholanate The triol monoacetate (111) was readily oxidized (VII). In this series A6-3/3-acetoxybisnorcholenic by chromic acid in aqueous acetone to the A8-7,ll- acid was first transformed into methyl A7s9(11)dione (IV). Sodium dichromate in acetic acid 3~-acetoxybisnorulZocholadienate4(XII) and the produced the ene-dione in a much lower yield. latter was converted to the epoxide. The epoxide -dione-8,9- derived from XI1 was converted to the triol monoThe epoxide, A22-ergosten-3,B-ol-7,11 epoxide obtained by the Swiss investigatorsze by acetate derivative which upon oxidation and reducthe oxidation of I11 with chromic acid in acetic acid tion yielded methyl 3P-acetoxy-7,ll-diketobisnorwas not isolated from any of our reaction products allocholanate (XIII). WOE-Kishner reduction of despite considerable investigation of the mother XI11 yielded 3~-hydroxy-ll-ketobisnorullocholanic liquors. However, the same diketo epoxide was acid which was converted to VI1 and found to be obtained in low yield by the direct action of chromic identical with the product derived from ergosterol. acid on the epoxide (11) although in this case other Methyl 3P-acetoxy-11-ketobisnoruZZocholanate unidentified products were formed as well. (VII) reacts with phenylmagnesium bromide in NA8*2z-Ergostadien-3P-ol-7, 11-dione acetate reacts ethylmorpholine-benzene to give the diphenylsmoothly with zinc dust-acetic acid to yield Az2- carbinol which is dehydrated to XIV by the action ergosten-3P-ol-7,ll-dioneacetate (V). The re- of refluxing acetic anhydride. As expected the duced dione remains unaltered in the presence of resulting AZ0-3p-acetoxy-11-keto-22,22-diphenyl sulfuric-acetic acid" as one might expect for a bisnorallocholen (XIV) exhibits an absorption normal B/C ring junction. peak in the ultraviolet, A,, 244 mp. Ozonization of XIV and reductive decomposition of the ozonide (7) H. E. Stavely and G. N. Bollenback, THISJOURNAL, 66, 1285 yields allopregnan-3~-ol-l1,20-dione acetate (XV). (1943). (8) W. P. Campbell and G. C. Harris, ibid., 68, 2721 (1941). In a similar fashion, the allodiketopregnan (XV) (9) W. E. Bissinger, R . H. Fredenburg, R. G. Kadesch, F. Kung, was prepared from diosgenin. The latter was J. H. Langston, H. C. Stevens and F. Strain, ibid., 69, 2955 (1947). transformed consecutively into A6s7-22a-spirosta(10) These materials are common contaminants of A7vWlLallosteroid preparations obtained by the action of mercuric acetate on A'-ah-steroids. For a discussion of the preparation of A7*9(*1L steroids and related problems, see THISJOURNAL, 75, 2604 (1953). (11) V. Prelog and E. Tagmann, HcZu. Chim. Acta, 47, 1880 (1944).
(12) Huang-Minlon, THISJOURNAL, 68, 2487 (1948). (13) L. H. Sarett, J . B i d . Chcm., 164, 601 (1946). (14) B. A. Koechlin, T. H. Kritchevsky and T. F. Gallagher, ibid., 184, 393 (1950); THISJOURNAL, 74, 485 (1952).
3480
ClIAhIIlERJ,IN,
RTTYIX,ERICKSON,
CIIEMERD.1,
ALIMINOSA, ERICKSON,
SITA AND
TISMLERVOl. 73
dien-3p-01 acetate,15 A7-5a,22a-spirosten-3&ol ace- residue was crystallized from methanol and a di-epoxide was obtained; m.p. 174-175', [ a ] D -18". tate16 and finally into A7~9(11'-5a,22a-spirostadienCalcd. for C30H4604: C, 76.55; H , 9.90. Found: 3/3-01 acetate4 (XVI). The mono-epoxide prepared C,Anal. 75.86; H , 9.90. from XVI was ultimately converted into the 5a,22a(c) Tri-epoxide.-Upon reaction of 1.0 g. of A7,9(11),22spirostane-30-ol-l l-one acetate (XVII) by the ergostatrien-38-01 acetate with excess perbenzoic acid (30 procedures already described above. Pyrolysis of cc. of 0.39 M perbenzoic acid) for five days a t room temperaXVII with acetic anhydride a t 200' yielded the ture three molar proportions of perbenzoic were ultimately consumed. After work-up of the reaction mixture as depseudo-sapogenin which was oxidized directly with qcribed above, the crude reaction product was crystallized chromic acid. Cleavage of the oxidation product from methanol and tri-epoxide was isolated 1n.p. 197-198", with sodium hydroxide in aqueous tetrahydrofuran [ a ] D $6". yielded A16-aZEopregnen-3P-ol1ll20-dione acetate Anal. Calcd. for C30H4605: C , 74.03; H , 9.53. Found: (XVIII). Hydrogenation of XVIII yielded allo- C, 73.31; H , 9.31. A8jZ2-Ergostadiene-3j3,7[, 1la-triol 3-Acetate (III).pregnan-3p-ol-l1,20-dioneacetate identical with Early experiments indicated that the mono-epoxide (11) the material derived from ergosterol or stigmas- could be purified by chromatography over acid-washed terol. alumina if the epoxide was eluted in a short time (two to Acknowledgment.-We wish to acknowledge three hours). Even under these conditions a small amount of the dextrorotatory triol monoacetate was formed as indithe aid of Mr. Richard Boos and his staff for the cated by a final elution of the column with methanol-chloroanalyses recorded and Dr. N. R. Trenner and Mr. form. Practically, it proved more feasible t o carry out the F. Bacher and their staffs for the physical meas- desired rearrangement by a batch procedure as described urements reported. In addition we wish to thank below. A solution of 150 g. of A7~22-ergostadien-3~-01-9a,1 laDr. J. van de Kamp for the generous supply of epoxide acetate in 1,800 cc. of benzene was thoroughly methyl 3a-hydroxy-1I-ketobisnorcholanate. mixed with 2,400 g. of acid-washed alumina18and the paste maintained a t room temperature for five days. At the end of this period unreacted epoxide (11) and inert impurities All melting points are corrected. Rotations are deter- were removed by filtration of the slurry followed by extraction of the filter-cake with two 750-cc. portions of benzene. mined in 1% chloroform unless otherwise noted. I. Transformations in Ergosterol Series. Reaction of In this case 21 g. of material was obtained and proved suitA7~*(11)~zz-Ergostaten-38-ol Acetate with Perbenzoic Acid. able for recycling on alumina. The alumina residue was ( a ) Formation of Mono-epoxide (II).-To a solution of 17.5 packed into a canvas bag and the triol monoacetate (111) eluted by extraction with a mixture of 2,500 cc. of methanol g. of ,i7,*(11)+!--ergostatrien-3@-01acetate ( I ) in 100 cc. of benzene was added 100 cc. of 0.42 M perbenzoic acid in ben- and 2,000 cc. of chloroform in a Soxhlet extractor for 16 zene'? over a period of one hour while maintaining the tem- hours. Upon concentration of the methanol-chloroform perature of the reaction mixture a t 10'. Shortly after the extract to a thick slurry, the product was filtered off and washed with methanol. In this manner 106 g. of practiaddition of all of the perbenzoic acid solution, the starchiodide test was negative and the reaction mixture was ex- cally pure triol monoacetate was obtained; m.p. 251-254', tracted successively with 5% sodium hydroxide and water. a vield of 86% based on the reacted eooxide. One recrvsUpon concentration of the benzene extract t o dryness in tailization of 'chis material from acetone afforded pure A8YZ2vacuo, a semi-solid residue was obtained from which 8.87 g. ergostadien-Jp-74,l la-triol 3-acetate (111); m.p. 253of mono-epoxide (11) was obtained by crystallization from 255', ID +83" (0.5%, CHC13).19 -4nal.- Calcd. for C30H4~04:C, 76.22; H , 10.24. Found: acetone; m.p. 205-206", [&ID -26.6', sufficiently pure for utilization in subsequent reactions. Pure A7tzZ-ergo- C, 76.28; H, 10.19. stadien-38-01-9a,l la-epoxide acetate (11) was obtained by One gram of 111 was refluxed with 50 cc. of methanol, 20 rapid chromatography of this material over acid-washed cc. of benzene and
