July 5, 1952
3309
CATHYLATION (CARBETHOXYLATION) OF STEROID -4LCOHOLS
and the residual oil was extracted with petroleum ether (75 cc., b.p. 68-70') and the extract, when cooled, deposited an oil. The solution was decanted from the oil and concentrated in a current of dry air. The solid (map. 106-109') was removed and sublimed a t 90' (0.3 mm.), when it melted a t 112.5-113.5'. Anal. Calcd. for CoHlsON: C, 71.5; H , 8.66; N, 9.27. Found: C,72.0; H,8.81; N,9.40. Hydrolysis and decarboxylation thus occurred when methanolic ammonia reacted with the methyl ester. This also occurred when the ethyl ester (1 9.) was subjected to the same reaction; the product (0.31 g., 45%), after crystallization from petroleum ether (b.p. 30-60"), melted a t 108-110' alone or when mixed with that obtained from the methyl ester of the Pyrone acid. The ultraviolet absorption spectrum of VI11 (R' = H ) (c 9.9 x lo-' in ethanol was determined."
(b.p. 30-60.) produced thick, colorless needles melting a t 71.0-71.5', alone or when mixed with this pyrone obtained from the cyclopropane 11. Anal. Calcd. for ClzHlsOl: C, 64.3; H , 7.19. Found: C, 64.6; H, 7.51. The ester was subjected to hydrolysis according to the procedure of BickeP but the pyrone acid (V, R' = H ) could not be obtained as a solid. 3-Carbomethoxy-4-isopropyl-6-methyl-a-pyrone (V, R' = CHI).-Substitution of methyl malonate for ethyl malonate in the above preparation led to the methyl ester V, R = CHI (34%), but this could not be obtained as a solid. It boiled a t 140-146' (0.5 mm.); the analytical sample, still not pure, boiled a t 127' (0.07 mm.). Anal. Calcd. for C11HI&(: C, 62.8; H , 6.71. Found: C, 63.8; H , 7.39. 4 ~ ~ s o p r o p y ~ ~ 6 ~ m e ~ y(~~ 1~1~1 ~,R'p y r ~II).-The ~one methyl ester of the a-pyrone acid (1.4 g.1 was added to a saturated solution of ammonia gas in dry methanol (25 cc.) a t 0'. The flask was StODDered and set aside for 18 hours. The solvent and ammonia -were removed in a current of air
[CONTRIBUTION FROM THE CHEMICAL
(14) The complete curve may be found in the P h . D . thesir of Ralph E. Kelly, ref, 2,
MINNEAPOLIS 14, MINNESOTA
LABORATORY OF HARVARD UNIVERSITY ]
Cathylation (Carbethoxylation) of Steroid Alcohols BY LOUISF. FIESER, JOSEF E. HERZ, MURLEW. KLOHS,MIGUELA. ROMERO AND TORLIEF UTNE' RECEIVED MARCH 10, 1952 The high degree of selectivity previously observed in the reaction of methyl cholate with a large excess of ethyl chlorocarbonate to give the 3-cathyl (carbethoxyl) derivative in high yield has been interpreted by Barton in terms of the concept of polar and equatorial bonds. Study of cholestane-3fl,5a,6@-triol,cholestane-3@,5a,6a-triol, cholestane-3p,7a-diol, :holes.tane-3&7fi-diol and androstane-3P,17P-diol has now shown that equatorial hydroxyl groups a t Cs, 4 , Cl,and C17 are invariably cathylated while polar hydroxyl groups are not. Less selectivity was observed in oxidations with N-bromosuccinimide. That 3a- and 3P-hydroxy derivatives of both cholestane and coprostane all afforded cathylates, if in varying yield, probably means that ring A is less rigid than the rest of the molecule. Allylic alcoholic functions, whether equatorial or polar, invariably are subject to cathylation; hence activation by a double bond overcomes hindrance effects.
I n 1924 Borsche2 reported that methyl cholate reacts with ethyl chloroformate in pyridine solution to yield the 3-carbethoxyl derivative. In recent publications we have confirmed Borsche's observation,' shown that methyl 3-carbethoxycholate is the exclusive reaction product even when a large excess of ethyl chloroformate is employed and can and reported certain be obtained in 93% other observation^^)^ indicating special advantages of the process of carbethoxylation for effecting selective acylation and for producing derivatives often characterized by excellent crystallizability and stability. It is now suggested that the useful reaction be designated cathylation and that the products be described as cathyl derivatives, analogous to tosyl, mesyl and trityl derivatives. T h a t methyl cholate is selectively acylated a t Ca but is oxidized with almost comparable selectivity a t C7* presented a perplexing problem until Barton6 advanced a plausible interpretation based upon the general theory7 of polar (p) and equatorial (e)
bonds. 1n.a steroid of the coprostane series, such as methyl cholate( I, assuming the chair-chair-chair conformation6) the 3a-hydroxyl group is equatorial and hence more vulnerable than the polar oriented
(1) We gratefully acknowledge fellowship support from the Abbott Laboratories (J. E. H.), Riker Laboratories, Inc. (M. W. K.), and the Dreyfur Foundation (M. A. R . ) . (2) W. Borsche, Bsr., 67, 1620 (1924). (3) L. F . Fieser and S. Rajagopalan, THIS J O U R N A L71, , 3935 (1949). (4) L. F. Fieser end S. Rajagopalan, ibid.. 72, 5530 (1950). (5) L. F. F i e s u and S. Rajagopalan, ibid., 73, 118 (1951). (6) D . H. R . Barton, Exprricnlio, S, 316 (1950); see also D. H. R. Barton and W. J. Rosenfelder, J . Chem. SOC.,1048 (1951). (7) 0. Hassel and B. Ottar. Acta Chcm. Scand., 1, 149 (1947); C. W. Beckctt. K. S. Pitzer and R . Pitzer, Tms JOURNAL. 69, 2488 (1947).
7a- and 12a-hydroxyl groups. Since in an oxidation the rate-determining step is attack of the carbon-hydrogen bond,' the equatorial hydrogen atom a t C7 is more vulnerable to attack than the polar hydrogen atom a t Ca; that Cl2 is less vulnerable than C7 is probably attributable to the shielding effect of the two angular methyl groups. In the case of cholestane-3P,5a,6P-triol (11) the theory predicts selective oxidation a t CSand selec-
t
t
t
Cathyl.
Oxid.
&-I (P)
t
Cathyl.
Oxid.
I
I1
t
OH (e)
Cathyl.
t
Cathyl. I11
(8) F. H. Westheimer and N . Nicolaides, ;bid., 71, 25 (1949).
I,. F.FIESER, J . E. HERZ,M. W. KIAHS,M. A.
3310
tive acylation a t C3. Fieser and Rajagopalang indeed showed that the trans-triol is attacked exclusively a t Ce on oxidation by N-bromosuccinimide and affords cholestane-3@,5a-diol-6-onein yields of 93-96t>. IVP h a w now verified the second prediction 1 9 7 the observation that the ncathylate is the sole product of reaction of I1 with excess reagent a t room temperature (yield 8.7:;). The structure was established by conversion of the irioriocathylate by oxidation with N-bromosuccinimide and saponificatioii io cholestane-3p,5a -diol&one. In line with expectations, cholestane-3@,5a,Bcr-triol (111)) in which both secondary alcoholic functions are in the equatorial orientation, gave rr dicathylate. In the cholestane series a 3P-hydroxyl group is equatorial and a hydroxyl group a t C? is equatorial in the @-orientation(IV) arid polar in the cr-orientation (TrI). In keeping with expectations, we iound CH,'
p
,/A, ,/'
t
(e!
t
Cathy].
Cathyl.
I\. CHsI 1 f i /i~~"'
1
HO
+-NBS
v\\o
ITI
'r. UTNE
YoI. i4
stanol would be expected to undergo acylation more readily than coprostanol, both epimers yielded cathylates, isolated in pilot experiments by chromatography in 51 and 34% yield. The results suggest that there is little energy barrier to a reversion in ring A to a conformation other than that representing niaximum stability. In androstane-3P,17P-diol (VII) both hydroxyl groups are equatorial. *\lthough the hydroxyl H,C.\/\ OH (e) CH31
\'I I
CH,
1
CHsOH
1'111
function in ring D is subject to some hindrance, the diol was found to yield a dicathylate. Lithocholanyl alcohol (VIII), prepared by lithium aluminum hydride reduction of lithocholic acid, was studied with the idea of comparing the ease of cathylation of primary and secondary alcoholic functions. The diol formed a dicathylate readily, but attempted monocathylation was unsuccessful. The behavior of the cholestenediols IX-XI1 was investigated to see if an allylic hydroxyl group
SBS ___f
( e ) H Q . " d ~ dH\ C J H
ROMERO AND
( e ) HO,'
A
& H
(p)
t
v
Cathyl.
IrI
that under the same conditions cholestane-3 fl,7Bdioli0 (IV) yields a dicathylate whereas cholestane3 P,7cr-diolg yields only a monocathylate. However, both 3,S-diols are oxidized by N-bromosuccinimide to i-ketocholestanol (V), and a polarimetric study revealed no substantial difference in the reaction rates. Thus in this instance selectivity is not as pronounced in oxidation as in cathylation. The anomalous resistance of methyl Ag(ll)-lithocholenate to oxidation by N-bromosuccinimide in aqueous acetone or aqueous tbutanol has been reported.5 'The cathylates of cholesterol, dehydroepiandrosterone, cholestanol and A7-cholestenol were all obtained in high yield. If 2-stenols resemble cholestane derivatives in conformation, l 2 these reactions all involve attack of an equatorial hydroxyl group. Epicholestanol reacted less smoothly, and a reaction product was isolated only by chromatography and in low yield. That a cathylate was produced a t all is in contrast to the all-or-none reactions of the 6- and 7-hydroxy compounds discussed above and is contrary to theoretical expectations. Similarly, whereas epicopro(9) L.F. Fieser and S. Rajagopalan, THISJ O U R N A L , 71, 3938 (1949). (10)Absolute proof of the configurations a t C7 is presented by H. Heymann and L . F. Fieser, Hdu. Chim. A d a , 35, 631 (1952) (11) The preparation of cholesteryl cathylate is described by J. Robbercct, Bull. SOC. chim. B&.. 47, 497 (1938); see also 0.Ddumer, Dissertation, Halle, 1912. (12) Evidence in support of this proposition is available from csperimento on complex formation to be reported by one of us (1,. F. F.).
I
011
I
OH
IS
x
XI
XI1
in any of the positions and orientations represented would resist cathylation, since such a result might provide evidence of the conformation of the unsaturated steroids. However, all four isomers gave dicathylates; evidently activation in the allylic systems overcomes steric hindrance effects. Some of the experiments reported were done with the view to possible improvement in the process for the conversion of cholic acid into a cortisone intermediate via a methyl ester dicathylate. l 3 Acetylation of methyl cholate-3-cathylate gave the 3-cathylate-7-acetate in over-all yield substantially the same as in the conversion of methyl cholate into the 3,7-diacetate. Optical rotations of typical cathylates are summarized in Table I. In eight instances the specific rotation in dioxane is slightly more dextrorotatory than the value in chloroform and in one instance the solvent effect operates in the opposite direction : the average difference is +4.5'. In compounds of three structural or configurational types, the MLI (13) L. F. Fieser, S . Rajagopalan, E. Wilson and hl. Tishler, THE 73, 4133 (1951).
JOURNAL,
July 5, 1952
CATHYIATION (CARBETHOXYLATION) O F
STEROID
ALCOHOLS
3311
Methyl Cholate-3-cathylate-7-acetate (L.F.F.).-A solution of 1.O g. of methyl cholate-3-cathylate in 5 cc. of dioxane, 2 cc. of pyridine, and 3 cc. of acetic anhydride was let stand at 28-30" for 40 hr. and then diluted with 6 cc. of mater; the acetate separated in prisms, m.p. 160-162', 0.51 TABLE I g. Crystallization from methanol to constant m.p. gave ~ n i ; t l l prisms. 1n.a. 16,5-166'. OPTICAL ROTATIONS O F 3-CATHYLATES .lnal. Calcd. for CanHr80e (236.68): C, 67.14; 11, 9.02. Solvent Cathy.MD Differences (Chf) effect Found: C, 67.03; H, 9.03. late aDDi Parent alcohol J l n Chf ACath AAc uDChf Methyl Cholate-3-cathylate-7,12-diforrnate(L.F.F.).-A solution of 1.0 g. of methyl cholate-3-cathylate in 5 cc. of Cholesterol '-166 - 14 - 35 f 14" 6" 85% formic acid was let stand a t 25' for 50 hr. and diluted 7-Ketocholesterol* -414 2 $14.5 with water. The precipitated material was crushed to a 1)ehydroepiaridropowder and collected: 1.13 g., m.p. 181-184". Crystallization from methanol (moderately soluble) gave 0.87 g., sterone 0 - 3 -20 + 3 m.p. 187-188", and a second crop of 0.18 g., m.p. 183-184'. Cholestanol GO - 33 - 34 f 11" 1 Recrystallization of the first crop gave large, rectangular Cholestane-3 @ , i c y prismatic plates, m.p. 187-188". diol 10 - 23 Anal. Calcd. for C8~H1609 (550.67): C, 65.43; H, 8.12. A'-Cholestenol + 6 - 9 - 5 c 8.6 Found: C, 65.50; H , 8.51. Methyl chlolate 198 101 12jd + 3 Methyl 3a - Cathyloxy - 7~-acetoxy- 12 - ketocholanate (L.F.F.).-A solution of 5 g. methyl cholate-3-cathylate-7Epicoprostanol +195 72 6.6 acetate in 25 cc. of acetic acid was cooled t o room temperaChole&ane-3@,5a,ture (28') and treated with 1.55 g. (1.5 X theory) of sodium 66-triol - 69 + 3 dichromate dihydrate. The mixture was swirled and the Methyl 3a-hydroxy-12-ketocholanate - 5 temperature controlled to 24-28" by cooling. In ' 1 2 hr. 40 cc. of water was added and the precipitated solid was col" D. H . R. Barton, J . Chem. SOC.,813 (1945). a~ -104" The Chf; S. Bergstrom and 0. U'intersteiner, J . Biol. Chem., lected, washed and dried: 4.84 g., m.p. 153-154.5'. L. F. Fieser, THISJOURNAL, 73, 5007 substance is more soluble in methanol than the precursor 141, 597 (1941). (1951). Methyl cholate-3-acetate, a I 6 ~ 48.0" Chf; P1. alcohol, very soluble in ethyl acetate, moderately soluble A . Plattner and H. Heuser, Helu. Chim. Acta, 27,755 (1944). in 60-90" ligroin. Crystallization from methanol gave 3.83 g., m.p. 155156'; the molten liquor material, precipitated The relative molecular rotations of various series with water, dried, and crystallized from ligroin, gave 0.80 g., m.p. 153-154' (total yield, 92.5%). A sample crystalof sterol esters and ethers presents an interesting lized twice from methanol (large prismatic needles) and then problem challenging theoretical interpretation. once from ligroin (fine needles) melted a t 155-156', aZ70 In the series of cholesteryl esters, C~~HGOCOR,+69.0 i 0.5" Chf, +64.0 i 0.5" Di. Anal. Calcd. for CS0H1608(534.67): C, 67.39; H, 8.67. values calculated from available datal4 for the increment MD(R = alkyl) - MD(R = H) are as Found: C, 67.33; H, S.79. Cholestane-3P,5~,6~-triol-3-cathylate. (a) In Dioxane follows: CH3 = 4-13, C H ~ C H B = +35, (CH3)zCH = +43, CH3CH2CH2 = +50, CIH, to Cl7H36 = (L.F.F.).-A solution of 1 g. of cholestane-3P,6a,6P-triol in 10 cc. of dioxane and 1.6 cc. of pyridine was cooled to 25" +% (average for nine homologs). The order and treated dropwise and with cooling with 2 cc. of ethyl approximates the order of inductive effects inferred chlorocarbonate. Toward the end of the addition an oil separated and then soon solidified. After 1 hr. 25 cc. of from the relative rates of bromination of olefins. water and 1 cc. of 36% hydrochloric acid were added and the mixture heated for hr. on the steam-bath and cooled, Experimental when the oil solidified. The product was a granular white Methyl Cholate-3-cathylate (L.F.F.).-Methyl cholate solid; 1.19 g., m.p. 180-182". Crystallization from methwas prepared by warming 100.0 g. of cholic acid (m.p. 197anol (76 cc.) gave a first crop of 0.62 g. of prisms, m.p. 184.5198") with 300 cc. of methanol and 20 cc. of freshly distilled 185", and a second crop, 0.38 g., imp. 183-181' (total yield boron fluoride etherate on the steam-bath a t the boiling 830j,). Two recrystallizations of 1st-crop material gave point for 40 minutes (the solid dissolved in 3-5 minutes). prisms, m . p . 184--18j0,a ? * . 5-16 ~ f 1" Chf, -13 k 1ODi. After cooling t o 27", crystallization was initiated by either ( b ) In Pyridine (J.E.H.).-One gram of triol in 20 cc. of seeding or scratching and was allowed to continue a t 3' pyridine was treated with 3 cc. of ethyl chlorocarbonate and overnight. The first crop of ester was dried a t room tem- after 2 hr. the solution was diluted and the product crysperature (102 g., sintered a t 110") and then a t 80': 95.84 tallized twice from aqueous acetone to give 0.85 g., m.p. g., m . p . 154.5-156", a Z 3+22.9 ~ f 0.5' Chf; asecond crop, 184-185', a 2 * D -14 f 2' Chf. dried a t 80": 4.70 g., m.p. 147" (total yield, 96%). A ilnal. Calcd. for C30H520j (492.72): C, 73.28; H,10.80. satisfactory procedure of cathylation alternative to that describedPis as follows. A solution of 2.0 g. of methyl cholate, Found: C, 73.12; H , 10.64. m.p. 154-156', in 10 cc. of dioxane and 1.6 cc. of pyridine 3a-Cathyloxy-5~-hydroxycholestane-6-one (J.E.H.).-A was treated with 2 cc. of ethyl chlorocarbonate, added drop- solution of 1.8 g. of the triol 3-cathylate and 0.725 g. of Swise with cooling under the tap. Initially each drop pre- bromosuccinimide in 30 cc. of dioxane and 3 cc. of water was cipitated an oil that subsequently dissolved, but after the let stand a t 25" for 2 hr. and diluted with water. The half-way point the oil persisted; mild gassing occurred at crude precipitate (1.7 g., m.p. 211-213'), crystallized twice the very end of the addition. After standing for l / 2 hour from aqueous acetone, yielded 1.0 g. of ketone, m.p. 217the mixture was treated with 25 cc. of water and 1 cc. of 218', a Z 2 D -45 & 2" Di. hr. on the steam-bath, 36% hydrochloric acid, warmed for Anal. Calcd. for CaoHjoOs (190.70): C, 73.43; H , 10.27. and cooled. The initially oily product crystallized on brief Found: C , 73.66; H, 10.25. scratching and gave a white microcrystalline powder of sa:The residual material from the mother liquor was saponiisfactory 3-cathylate; yield 2.28 g. (97.5%), m.p. 143 , remelting at 174-175". The ester is so soluble in methanol fied; the product, crystallized from aqueous acetone, afthat crystallization is attended with losses (recovery, in forded crystals, m.p. 232-234', that showed no depression two crops, 64%, m.p. 177.5-178.5' with no previous soft- with cholestane-~3P,5a-diol-6-one. Cholestane-3 p , S a , 6~triol-3~6-dicathylate ( J .E .H. ).-Reening). Crystallization from benzene-petroleum ether (30-60") seemed more satisfactory and gave round tufts o,f action of 0.5 g. of cholestane-3p,5a,6a-triol,m.p. 236-238", OD +21 k 2' Di, with 2 cc. of ethyl chlorocarbonate in 20 needles, m.p. 177-178", ~ * * J D+40 f 0.2' Chf, $43 f 0.1 cc. of pyridine (18 hr., 25") and crystallization of the prodDi. uct from aqueous acetone, aqueous ethanol and aqueous The (14) Elsevier's "Encyclopaedia of Organic Chemistry," Vol. 14, methanol yielded 0.35 g. of product, m.p. 158-160". main fraction eluted from alumina by benzene on crystalliElsevier Publishing Co.. New York-Amsterdam, 1940, pp. 51-55.
increments for cathylation are of the same sign as the increments for acetylation and the effects are of the same order of magnitude.
+
+
+ + +
+
+ +
+ +
+
+
1,. F. FIESER, J. E. HERZ,hf. W. KLOHS,l f . '4. ROMEROA N D T. UTNE rntioii from aqueous ethanol melted a t 165-167'. N% t l 2 3 f 2" Di, yield 0.25 R. (52%). (56i:;Nj: C, 70.32; I i , 9.99. ilrral. Calcd.-for C33H5e07 Found: C, 70.08; H, 9.97. Preparation of 7c~-and 7p-Hydroxycholestanol (T.U. ).-Reduction of 18.6 g. of 7-ketocholestanyl acetate with lithium aluminum hydride (20% excess) i n ether was contlucted as described,'E but it was found that separation of the epimers does not require chromatography but can be accomplished by crystallization, as follows. A solutioii of the total reaction mixture from 200 cc. of benzene on cooliug tleposited 5 g. of crude 7p-epimer, m.p. 155159'; coiiceiitration of the mother liquor afforded three further crops totaling 2.7 g. Recrystallization of the total crude 70el~itnerfrom ethanol water (lowmclting form, m.11. 136I & " ) and then from benzene (high-melting form) gave it total of 5.9 g. (35%) of cholestaneJp,7S-diol, m . p . I f i O 170", CY% f53.3" Chf. 0 1 1 saturation of the resicju:il 1x11zeiie mother liquor with 30-60' ligroin, 3 g. of crude 7 ~ 2 epimer was obtained, m.p. 138-145", a e 4 u$7" Chf. Further crops totalling 2.5 g. were obtained 011 concentratiiig the mother liquor, and finally by addition of inethnnol, :icetone and a little water. Recrystallizatioii of the crude product from benzene-ligroin and finally from aqueous ethanol gave 3.9 g. (23yc)of cholest;iiic-:~R,7n-tiiol,i n . p . 1 3 L34', C X * ~ D+8.5" Chf. Cholestane-3p,7,~-diol 3-Cathylate (T.U.).--A solution of 0 . 5 g. of 7a-hydroxycholestanol in 20 cc. of pyritliiie W:IS treated with 2 cc. of ethyl chlorocarboriate, Irt stand for 14 hr.. arid diluted with water. The oily precipitate was crystallized from ethanol-water several times aiid gave 0.29 g . of crystals, m.p. 135O, CY??L) +".I & (J.:3' Chf. d ~ d .Calcd. for cpoI-Tjy04 (476.72): C', 75.58; 11, 1 1 .NJ. J~ouiid: C, 75.43; 11, 11.00. Cholestane-3 p,7p-diol 3,7-Dicathylate ( T .U. ).--Cat hylatioii of the 78-epimer in the same way gave an oily product that on scaveral crvstallizations from ethanol-water afforded
.Anal. Calcd. for C33HjtiO6 (518.78): C , 72.22: 1-1, l(1.29. J;ountl: C, 7'7.25; 1-1, 10.29. Oxidation of 7c~- and 78-Hydroxycholestanol with NBromosuccinimide (T.U.).---A solutiou of 0.40 g . of 7u-hytlroxycholesterol in 30 cc. of dioxane and 2 cc. of \rater was treated at 28' with 0.41 g. of S-broinosucciiiiinide and the mixture was shaken until the solid had dissolved. The solution became brownish; after 1 hr. dilution with about 10 cc. of water caused separation of a crystalline product. Recrystallization from ethanol-water gave 0.26 g. (05%) of 7-ketocholestanol, m.p. 16Uo, CPD -33.8' Chf (aiialysis a, litlow), identical iii irifrarcil spectrum with a11 authentic
