3834
G. E. XRTH, G. I. Poos [CONTRIBUTION FROM
THE
AND
L. H. SARETT
Vol. 77
RESEARCH LAUORATORIES O F THE CHEMICAL DIVISIONO F MERCK& CO., INC
Approaches to the Total Synthesis of Adrenal Steroids. XIII. Reaction of Racemic 16,20-Diketosteroids BY G. E. ARTH, G. I. Poos
AND
Formation and
L. H. SARETT
RECEIVEDNOVEMBER 29, 1954 Intramolecular acylation of tricyclic acetonylacetic ester I1 derived from methallylacetic acid I provides the dZ-11,16,20triketopregnene 111. Reaction of the latter compound with isopropyl iodide affords a 6 : 4 mixture of the 16- and 20-enol ethers V and VI. Each of these is convertible into 11,20-diketo-16-pregene VIII, the former by hydrogenolytic cleavage of the 16-enol ether with subsequent oxidation of the A1B-20-alcoholand the latter by borohydride reduction of the 16carbonyl group followed by acid hydrolysis and dehydration Hydrogenolysis-hydrogenation of the 16-enol tosylate of I11 affords the 3-dioxolane of dl-11-ketoprogesterone. Two unnatural racemic 11-ketoprogesterones, isomeric with the natural steroids at Cla and Cia, are prepared via the corresponding ll,l6,20-triketones.
Previous papers in this series have described two comparison of its physical constants with those of methods for converting the key tricyclic interme- our 16,20-diket0ne.~ Recently, Inhoffen and codiate 2~,4b-dimethyl-l~-carboxymethyl-2-methalworkersg have assigned an enol form of the same lyl - 7 - ethylenedioxy - lJ2,3,4,4aa,4b, 5,6,7,8,10,10a/3( 8 ) The chemical behavior of I11 proved t o be markedly rliirerent dodecahydrophenanthrene-4a-01 (I) into dl-11- from t h a t reported by Marker for his compound (ref. 7 ) . Thus ketoprogesterone2+?and thence c ~ r t i s o n e . ~X third hydrolysis (presumably alkaline) of the 3-acetate in Marker's product appeared t o proceed without disturbing the remainder of the molecule method of closure of ring D involves an intramo- while alkaline treatment of 111 opened the D ring and gave 90% of lecular acylation of the derived acetonyl ester I1 tricyclic acid I I a along with a trace of neutral steroid for which the dito form 11,16,20-triketone 111. The practical suc- 3-ethylenedioxy-5-androstene-ll,l6-dionestructure was indicated cess of this approach to adrenal steroids depends by infrared analysis. An aluminum isopropylate reduction proreported by Marker t o give 40% of 4,16-pregnadiene-38,2Oi3upon the specificity with which the oxygen atom a t cedure diol gave, when applied t o 111, less t h a n 20% of neutral material. Clo in triketone I11 can be removed. This paper is (This result agrees with the reported failure of the Meerwein-Ponnconcerned with results obtained in the ring closure dorff method with other enolic substances. See H. Lund, Bcr., 70, and a description of reactions directed toward re- 1520 (1937); also a reference t o unpublished results of H. .4dkins and students by R. L. Frank and H . K. Hall, THISJ O U R N A 7L2, , 1645 moval of the C16-oxygen. (1950)). With sodium in isopropyl alcohol, Marker observed the conThe esterification of I was carried out more con- version of his 38-01 t o 5-pregnene-3@,20a-diolin 80% yield while veniently on a larger scale with methyl iodide and sodium alcohol reductions of I11 produced only mixtures of hydrogenolpotassium carbonate in acetone than with diazo- ysis and hydrogenation products; t h e only pure product that could isolated was a dl-3-ethylenedioxy-5-pregnene-ll~,l6E,20~-triol methane.' Oxidation of the methyl ester has been be (IV), obtained in less than 30% yield. Finally, catalytic hydrogenadescribed previously2; both reactions occur in ex- tion of the Marker compound with platinum in alcohol was reported t o cellent yield. Conversion of the side-chain meth- reduce the 5,d-double bond while reduction with platinum in acetic acid in ylene group to the eventual Cz0carbonyl oxygen was followed by treatment with alkali gave allopregnane-3~,20B-diol yield. Catalytic hydrogenation of I11 proceeded readily t o give a effected as before in this series5 by hydroxylation 80% non-enolic mixture from which no single product was isolated either with osmium tetroxide followed by periodic acid before or after treatment with base. These contrastscast serious doubts cleavage of the resulting mixture of glycols. The on the structure of the Marker compound. Very recently IC. Heusler and A. Wettstein, Ber., 87, 1301 (1954), have questioned the hlarker yield of I1 over the four steps was about 75%. formula (ref. 7) on the basis of their inability to convert a With sodium methoxide in benzene, the acetoiiyl nologenin 16-acyloxy-17-hydroxy-20-ketone (the intermediate proposed by ester I1 cyclized nearly quantitatively. The prod- Marker) t o a 16,20-diketone under the Marker conditions. Thus it uct of this reaction had properties which would be would appear t h a t the entire hlarker interpretation is incorrect. (9) H . H. Inhoffen, F. Blomeyer and K. Bruchner, Ber., 87, 593 anticipated for P-diketone 111. Thus the conipound was soluble in cold alkali from which it could (1954). The alkali stability, extraction froin aqueous potassium hysolution with chloroform, the lower position of the ultraviolet be recovered by acidification. I t gave an imrnedi- droxide maximum and acetylation with acetic anhydride in pyridine t o form a ate violet color with ferric chloride and showed an single product reported by Inhoffen for his compounds are difficult t o rationalize with a 16,2O-diketo structure in the light of the properties ultraviolet absorption maximum a t 285 m,u.6 behavior of 111. T h e ease of rearrangement of 17-hydroxy-20is. 16,20-diketo steroid structure (5-pregnene-XP- and steroids under alkaline conditions (see R . B. Turner, THISJOURol-16,20-dione acetate) has been assigned to a deg- keto KAL,76, 3484 (1953), and references therein) suggests the a-diketone radation product of nologenin by Marker.' This structure iv-v for the Inhoffen compound which could be expected substance is insufficiently characterized to allow from a dehydration of the intermediate keto1 iii. Calculated values (1) G. E. Arth, G . 1. Poos, R. M.Lukes, F. M. Robinson, W. F Johns, M. Feurer and L. H. Sarett, THISJOURNAL, 76, 1715 (1954). (2) W. F. Johns, R. hf. Lukes and L. H. Sarett, ibid., 7 6 , 5 O Z i 11954). (3) G. I. Poos, \V. F. Johns and I,. H . Sarett, ibid., 77, 1026 (19533. (4) G . I. Poos, R . M Lukes, G. E. Arth and L. H . Sarett, ibid.. 7 6 , 5031 (1954). (5) L. H. Sarett, W. F. Johns, R. E. Beyler, R. M. Lukes, C. I Poos and G. E. Arth, ibid., 76, 2112 (1953). Cx-epimers X I 1 and X V I I (see below) had the (6) T h e C I ~ and same maximum while emoi values varied from 5300 for I11 t o 5900 for XI1 and 9100 for XVII, which indicated a variable degree of enolization for the three a-diketones. For XVII, the absorption maximum in aqueous methanol varied from 287 mp, emOl 9100 at pH 1 t o 303 mg, emoi 19,500 a t pH 13. See E. R. Blout, V . W. Eager and D. C. Silverman, THISJOURNAL, 68,566 (1946). (7) R. E. Marker, ibid., 69, 2395 (1947).
CH3 I
-
H
CHs OH \ /
CHa OH \ /
FORMATION AND REACTION O F RACEMIC 16,2@DIKETOSTEROIDS
July 20, 1955 CHa
'2%
C=CH,
I c=o
I
11, R CHa IIa, R = H
I
CHa
CHJ
CHOH
co
I
O~A,),,~O
I
t-
IV
,
I11
CH3
CHa
I
I
co o\,A!+-OR
c-
-
V, R = 2-propyl Va, R = tosyl
VI1
CH3
+
I
co
CHI
I
reduction were unsuccessful. Catalytic, sodium-alcohol and aluminum isopropylate reductions of I11 failed to give useful products.8 Reductions with lithium aluminum hydride (inverse addition) and sodium borohydride also were investigated. I n both cases only complex mixtures were obtained. The triketone I11 could be converted readily to its enolic derivatives but in all cases mixtures of nearly equal amounts of 16- and 20-enols were obtained. Thus upon heating in acetone solution with potassium carbonate and isopropyl iodide, I11 was converted in excellent yield to a 6 : 4 mixture of the 16- and 20-isopropyl ethers (V and VI).loJ1 These isomers were readily separable by a combination of crystallization and chromatography. Lithium aluminum hydride reduction of 16-isopropyl ether V gave the hydrogenolysis product dl-3-ethylenedioxy-5,16-pregnadiene-l1/3,20f-diol (VII) in 40% yield. The structure of VI1 was assigned on the basis of its infrared spectrum and its oxidation with chromium co trioxide-pyridine to the known3 dl-3-ethylenedioxy-5,16 - pregna0 diene-11,20-dione (VIII). The I 20-isopropyl ether VI also was AI).,converted to the ATB-20-ketone VIII. Sodium borohydride reduction of VI provided a crystalline mixture which was treated with dilute sulfuric acid in tetraIX hydrofuran to selectively hydrolyze' the enol ether. Passage of the crude hydrolysis product C H ~ over alkaline alumina afforded 60% of VIII. The reduction of VI11 to dl-3-ethylenedioxy-5pregnene-1 1,20-dione (IX) has been d e ~ c r i b e d . ~A more vigor' I ous sodium borohydride treatment of VI served to reduce the 11-carbonyl group and afforded, after acid treatment and chromatography, 50% of dl-3-ethylx enedioxy-5,16-pregnadiene-llP01-20-one (X). With p-toluenesulfonyl chloride in pyridine,12
\AlA
yo ~
+
t-
VI11
alcohol, dehydration and reduction of the resultant 16,17-double bond; or (2) preferential formation of a single enol derivative (e.g., V or VI); or (3) formation of a readily separable mixture of the two enol derivatives and utilization of both isomers. Each of these approaches was investigated, with the
I
I
3835
VI, R = 2-propyl
structure to a product resulting from the action of alkali upon 5-pregnene-3/3,16a,17a-triol-20-one. Of the C16-oxYgen atom (e.g.1 111 + Ix) in a practical yield requires either: (1) preferential reduction of the 16-keto group to an for the positions of the ultraviolet absorption maxima for iv and its acetate are 278 and 245 mp, respectively (L.Dorfman, Ckcm. Reus., 6% 47 (1953)) while the values recorded by Inhoffen are 277 mr for the free compound and 244 mp f o r its diacetate. We have discussed this interpretation with Professor Inhoffen, who is in agreement with the D-homo-a-diketone formulation and indicates t h a t he plans further characterization of his product. T h e conversion of 5-pregnene3.B.l6~,17a-triol-20-one3,ltLdiacetate t o a non-enolic D-homo steroid under mild conditions has been described very recently h y K. Heusler and A. Wettstein, Bcr., 87, 1301 (1984)
Ho'p:-
(10) In the infrared, the 16-enol ether V had Xmax 5.83 p (CII C=O), 6.10 p (Cm C=O) and 6.32 p (CIS C=C) while the 20-enol c=o), 5.90 (cis c=o) and 6.18 ether VI showed x~~~ 5.81 (cI1 ('217 C=C). The absorption of a conjugated steroid 20-ketone in t h e infrared is known t o be a t a higher wave length (ca. 6.00 p ) than of a steroidal conjugated cyclopentenone (ca. 5.90 p ) ; see R. N. Jones, V. 2. Williams, M. J. Whalen and K. Dobriner, THISJOURNAL, 70, 2024 (1948). (11) T h e ultraviolet spectra (V, A%": 274 mp e 14,700; VI, 281 mp e 16,500) also served t o distinguish the two ethers. T h e higher absorption maximum (281 m p ) of VI can be attributed t o the bathochromic effect of the exocyclic double bond. See L. Dorfman, Chcm. Revs., Lis, 47 (1953). and references cited therein. (12) L. Ruzicka. A. Plattner and M . Furrer, Hclv. Chim. A r t n , 27, 524 (1944).
Xg:zH
VOl. 77
G. E. ARTH,G.I. Poos AND L.H.SARETT
XI
XI11
SI1
CHn
CHa
I
I
C=CH2
co
co
1
z
O \ / Y A
,AA/ XI'
XIV CH:! I
CO
x1-11
XYIII
XIX
I11 was converted in good yield to a difficultly sep- (XV) , readily distinguishable by infrared analysis arable mixture of enol tosylates. Chromatography from the corresponding C/D trans product.?J4 and repeated crystallization afforded a small Application of the same sequence of reactions to amount of 16-enol tosylate Va (conjugated 20- 2a,4b -dimethyl - 1/3- carboxymethyl - 2 - methallylcarbonyl a t 6.00 p in the infrared).1° A one-step 7 - ethylenedioxy - 1,2,3,4,4aaj4b,5,6,7,8, 10,lOaP- dohydrogenolysis-hydrogenation1? with palladium- decahydrophenanthrene-4a-01 (XVI)l was attended barium carbonate catalyst was used to convert both by equally satisfactory yields through 11,16,20pure tosylate Va and the mixture of tosylates to dl- triketone XVII and 16-enol tosylate XVIII." 3-ethylenedioxy-l l-ketoprogesterone (IX) ; in the (14) The infrared differences were principally in the "fingerprint" latter case I X was accompanied by a compound region of the spectra. C. Djerassi, W. Frick, G. Rosenkranz and F Sondheimer, THIS J O U R N A L , 76, 3496 (1953), ha\-e noted a prothat appeared by infrared analysis to be dl-3-ethylnounced band a t 9.50 in #vans C / D A*-11-keto steroidal sapogenins enedioxy-5-pregnene-11,16-dione. which is absent in the corresponding cis C / D compounds. R . J. The tricyclic intermediates isomeric a t C1 and CZ Highet (Ph.D. Thesis, University of Wisconsin, 1953) examined the with the natural series were converted to the cor- infrared spectra of a number of cis and t r a n s pairs of polycyclic anguresponding 14-iso and 13-iso-l1,16,20-triketopreg-larly methylated compounds related t o the steroids and found a rather pattern in the 9.5-10.1 p region of compounds with a carnenes by the same reactions which provided 111 consistent bonyl group adjacent to the angular site but no regular system of peaks from I. From Z,B,4b-dimethyl-la-carbomethoxy- in cis-trans pairs without an adjacent carbonyl function. The infra 2-methallyl-$-ethylenedioxy-l,2,3,4,4aa,4b,5,6,7,%,spectra of our l r a n s C / D 11-ketoprogesterone (see ref. 2) and the t w u 10,lOaP - dodecahydrophenanthrene - 4 - one (XI) cis C / D isomers X V and XX as well as their correspondin$! 3-dioxolanes (IX, XIV and X I X ) were featureless in the 9-10 p region except there was obtained dl-3-ethylenedioxy-lQ3-pregn-5- for the marked C-0 stretching vibration a t 9.0-9.1 w shown by I X , ene-11,16,20-trione (XII) in excellent yield over XIV and X I X . (15) Results of enol tosylations of the three isomeric 11,16.20three steps. The latter gave principally the 16-enol provide an intereating comparison. Both c i s C / D triketones tosylate XI11 which was smoothly converted to dl- triketones (XI1 and XVII) gave 16-enol tosylates (XI11 and X V I I I ) as the only 3-ethylenedioxy-1l-keto-14P-progesterone (XIV)l 3 products while the natural t r a n s C / D triketone 111 gave a mixture of by hydrogenolysis-hydrogenation. Acid hydroly- 16- and 20-enolates (see above). T h e yields of 16-enol tosylates are roughly proportional to the extinction coefficients of the parent sis of XIV afforded dl-1 l-keto-14/3-progesterone triketones (see footnote 6). That the trans-fused cyclopentane rini: is @
j
13) There was insuificient evidence :ivailahle t o assign configurn - in the alinorcnnl C' 1) L I T prrgnrncs S I V .ind S I X .
i t < ~ . i~t iC~
less willing t o acrommirdate a doublr bond t h a n the
