1 , ~ HASTINGS ~ s SARETT
247s
amount of water required stoichiometrically. An excess of water permits rapid oxidation. f i . The possible relationship betwwii this p11e
[CO\TRIBCTION FROM
THE
Vol. GS
nomenon and the observed passivity of hemoglobin is discussed. ljALlI\fORI,
K c c t ~ xE D .IPRIL 22, 1946
18, AID.
RESEARCH LABORATORIES or ~ I E R C- 4Kw Co , I v c ]
The Partial Synthesis of Dehydrocorticosterone Acetate BY LFWISH,\STINGS S IRFTT Dehydrocorticosterone, a member of the adrenal cortical hormone group, was first isolated from cortical extracts by Kendall and co-workers.l Its partial synthesis from desoxycholic acid has been accomplished by Lardon and Keichstein.' This synthesis employs the reaction of a 3-acetoxy-1I-keto-etio-cholanic acid chloride with diazomethane as a means of introducing the required ketol side chain. This has also been accomplished by lead tetraacetate oxidation." The a\.:Lilability of ant1 .li'"."-:i(cuj-acetoxy-1 1-ketopregtienes' has now m:de possible thc utilization of another method for constructing the ketol side chrtiii. The crude crystalline mixture of 90aiitl A'o,?1-:3(~ )-acetoxy-11-ketopregnenes ( I aiid la); obtained by the method previously described.' was saponified to the corresponding mixture of 3 ( a )-hydroxy- 11-ketopregnenes (II and I Ia ) , which upon oxidation with chromic acid afforded the corresponding mixture of ;3,11-diketopregnenes (111 and IIIa). Hydroxylation with os-
11,1T.4 The 5-unsaturated derivative of IV was also prepared. Bromination of Y gave 4-bromopregnandiol-17,2O-dione-3,11acetate-20 (XXI) as the crystalline alcohol complex. Rcfluxing this product with pjridine gave pregnene-4-diol-1i , 2 0 -
CrOi
I
-i-
niium tetroxide by the method of Criegee5 gave a mixture of pregnanedioldiones from which the pair of isomeric 20,21 diols could immediately be separated. This was effected by subjecting the mixture t o iiiild esterification with succinic anhydride followed by separation of the acidic from the neutral fractioii. The neutral fraction consisted essentially of a pregnanediol-1 T,20-dione-3,11,6 (IV), which was best isolated as the readily crystalline %-acetate, (I-). The structure of this dioltiioiic was sliowtl to be that g l w n by formula I\' through chroniic acid oxitlation. Tmo products were obtained, efio-cliol~netrioiie-::,1 I ,1 T (1-1I ) and pregnmoll'j-trioiic-3,lI ,L'O (1-1J . 1'11 could .tlso be obtained by ouirlation of etio-cholanol-::( a)-tlione-
__f
CHI
I11
+
CH
I
CH
HO
Ia
CH;
\ vH IIa
IIIa
i
(1) hidson, RIyers and Kendall, J . Bioi. cizcrn., 114,013 ( 1 0 ~ ~ ) . dione-3,11 acetate-20 (XXII), saponification of (2) Lardon an,l Reichstein, R d w , C k i m . A c t a . 26, 7-17 11943). ( 5 ) Criegee, A n i i . , 522, 75 (1936); Criegee, hIarchand and W a n (3) Z< i: von B u w , 1,ardiin and Reichstein, I t & . , 27, 1287 nciwius, i b i d , 550, 99 (1912). (101-1). (0) 'The stereochemical configuration of t h i i cornpound has not y e t been determined. (4) S a r e t t , J . R i d . Chcm., 162, 591 (1946).
TIIEP.\RTI.~L SYNTHESIS OF DEIIYDROCORTICOSTERONE ACET.\TE
Dec., 1'?-1C,
i
CHiOH
I
2479 CH~OAC
CH>OCO(CH*)?CO?H I
I
HOCH
HOCH 1
0- /'\
O=
AIA 1
OlA/--i
-
i
O=:b~.ij/)
+
Succinic anhydride
VI11 CHiOH
H
H~OH
I
K2CO.l
+
---+
HCOH I
+
IX.
IX CHI HCOH
CHI
1
0
HCOH 11
v Br? /
+
/( /-I
1 ' 1 O = V I V I
H
lJr
XXI
I
> -
---+
Pyridine
/-\A
I I
-
I
XXIII
XXIL-
gave a mixture of the two isomers, pregnanediol-2O(a and @,?I -diene-::, 1 1 H C O A ~ (VIII IX). Separation was achieved (-OH by acetylation followed by chroma.=A;/\ tography. Since, unfortunately, the re1 1 spective dioldiones (VIII and I X ) and Alp.,,/their corresponding acetates (X and X I ) could not easily be related stereochernically to compounds of knowti conventional configuration a t (2-20, the arbitrary assignment of 2 0 ( d was made to VI11 and X, 20@) t o IX and X I . XXTI
I
-
AIA
0=-(,+
CH3
CH 9 HC'OAC -OH O=Al/\
0-
O-
1'11
which afforded the free diol ( X X I I I ) obtained as the crystalline hydrate. =\ sample of XXIII was oxidized with periodic acid and yielded, as expected, adrenosterone (XXIT.') . The acid succinate fraction, the separation of which was described above, was saponified and
I
+
2480
Vol. 68
LEWISHASTINGS SARETT
The bromination of X led to the corresponding A-brornopregnanediol-20( a ),2l-dione-X,11 diacetate (XII'i which could not be obtained crystalline. Refluxing the crude bromoketone with py-
x
XI
XI1
XVII
.1
Pyridine CH.OAc
Pyridine
.icOCH
HCOAc
ridine gave crude crystalline pregnene-A-diol-20(a),21-tlione-:l,ll diacetate ( X I I I ) , the separation of n-liich froin a s m d l amount of X was best achie\-d by saponification to the free diolrlione ( X I 7 ) m d recrystallization of the 1attc.r from water. iCeacetylation affortied t h e pure diacetate which melteil a t 1.5:1--1.5~L". U7heii a clioxiane solation of XIV was treated with one mole of acetic anhydride and pyridine-'.' anti the product then chroinatographed, pregnene~ - ( l i ~ l - ~ [ ~ ( a ~ , 2 l - ( ! i1oI I acetate-21 ie-~~, (XV)could be obtained in 2.5' yield. The partial acetylatiori of both X I Y m d XIX was found to be considerably Icss selective than t h a t of the corresponding 1i ( 3 ),2O( 3 i ,? 1 -trili~-diosycompound. iyhen XV was oxkiized n-itli cllroliiic acid, a good yield of dehvdri)corticostc.roiie acet,atey (XI-) was obtained. The isomeric pregnanedioldione diacetate ( X I ) was then submitted to the series of reactions described above. Bromination gave a non-crystalline hromoketone (XVII) which was refluxed with pyridine. The unsaturated ketone ( X V I I I ) , after several recrystallizations, had the constant melting point 20;--20>' and [ a ] % ITO" (acetone I . Formula X1711i (or the isomeric structure XI11 i has bccn shown to represent the diacetate of a I1atLir:illy occiirring adrenal cortical conipouncl, ''Substance T."" Allthough no direct w:iilmrison of XI"II1 ~ i t h"Substance T" could lw made and, in addition, physical data on the iattcr c o n i p u n d are incomplete, *" the structural eL-itierice adduced for "Substance T" and for the unsaturated ketone XL-I11 demonstrates that they ~ P identical. P Saponification of XVIII gave pregnene-4diol-"Of,3),2l-dione-3,11 ( X I X ) , which melted a t 223.5-224.5" and had [aI2'D l T ( i o (acetone). Partial acetylation afforded the 2 1 -monoacetate (XX) in XI', yield, oxidation of which gave dehydroci?rt;~ostcroIie acetate (XI'I >.
-
4
XI-I11
KlC01 CH2OH HCOH
+
4
XI 1-
4
lAC?O CHrOAc I HOCH
XIX 1 Ac10
Experimental
CH20-4~
FICOEI
CIJ204c
I
co
' I
I
CrO
f-
All melting points are corrected. Rotations wci c taken in acetone, c = 1.0. Absorption spectra \yere taken in alcohol. Pregnanediol-17,20-dione-3,11 Acetate-20 (V).--A solution of 1 l . t i g. uf crude mixture of A1T,*0- and A20.21prcgneiiol-3(a)-oiie-ll acetate in 100 cc. of 1.1 S methanolic potassium hydroxide was refluxed for thirty minutes. The solution was concentrated in z~ucuot o a small volume, water was added and the organic material taken up in ether. Thc ethereal solution was washed twice ryith watcr, tlicri co:icentrati.tl to t1ryi:ess 011 the steain-bath. T h e ..
~~
17) (7. P r i l l , :inti IZeich~teiii,!€~,l;> Chini. ..lcla, 26, 8013( ! 0 4 2 ) . ( S ) An auihen1, fur comparison was kiii*l!y f:irms!ied ' I S ?.In!-n Clinic. Rcrcheste:, h l i n ~ ~ e w t a . i !?' C k i m . i c l a 2 2 , 1122 (1939, r r f , 1'). x i r e n . 2?2-213° f,,r rile cni'!e giyci,l. nri rotations are give.i \I'A . Liasteda. Jr., and ti, hlrs. I
