CASSAINE AXALOGS.I V
July 1967
593
dI-1,2,3,4,4a~,4bp,5,6,7,8,8aa,9,lO,lOa~-Tetradecahydro-7~fied by partitioil chromatography oii 300 g of Supercel as dehydroxy-2$-phenanthreneacetic Acid (23b) (Isomer B).-The scribed iii the general procedure. The major baiid was eluted mother liquor residues from the immediately preceding experiand the recovered oil was converted to 3.2 g (647,) of the hydroment Tvere hydrolyzed accordiiig to the general procedure to Recrystallizachloride salt of the title compouiid, mp 24i-251'. give the tit81e compouiid. Two recrystallizat,ioiis from ethyl tion from methanol with ether added afforded the arialytical acet#ateand oiie from acetone afforded 3.13 g (295,, 2 st,eps) of The free base, liberated from t,his salt, sample, mp 255-257'. 23b, mp 164-166". Furt.her recryst,allizat,ion from acet,oiie afcould iiot, be distiiiguiuhed from isomer B base by glpc. forded the aiialytical sample, mp 170-176". Tlc arialybis, done Ana(. Calcd for C?oH,jN03.1-IC1: C, 64.24; H, 9.71; C1, as with isomer A , iiidicated one conipuuiid was piebelit,, h ) 0.50, ~ 0.4s. F ~ i i d C,64.1; : H, 9.9; Cl,9.5. d n d . Calcd for C 1 6 I T 2 6 0 3 : C, 7 2 . 2 2 ; I%, 9.83. Fouiid: Dimethylaminoethyl dl-l,2,3,4,4aa,4bp,5,6,7,8,8aa,9,10,10~pC, 7 2 . 3 ; H, 10.1. tetradecahydr0-7p-hydroxy-Z~-phenanthreneacetate(23c) (isodl-1,2,3,4,4a~,4b~,5,6,7,8,8a~,9,lQ,lOap-Tetradecahydro-7p-mer B) wits prepared from 2.2 g of 23b,isomer 13, iii the staiidard hydroxy-2E-phenanthreneacetic Acid (23b) (Isomer A).-The maiiiier to give 2.53 g (81c'li)of the title compouiid as its hydroester 23a (4.5 g ) was hydrolyzed accordiiig to the general prochloride salt, nip 196-%06°. Oiie recrystallizatioii from acetoiie cedure ittid the product was re tallized oiice from ethyl acetate raked thib iiieltiiig poiiit to 202-213' aiid it was uiichaiiged upoii to give 3.95 g ((J7(;>i) of the ti cumpomid, nip 214-216". Tlc further recrys t allizitt ioii. aiialysis oii a silica gel plate uaiiig acetic acid-CIICls (3:97) for A n d . Cdcd for C~OH~jN08.HCl:C, 64.24; H, 9.71; C1, developmeiit, indicated t.hat. oiie compound was present, K f 0.48. Foiuid: C, 64.4; 11, (3.8; C1, 9.4. 0.56. Further recryst,allizatioii gave nip 214.5-21 Acknowledgments.-Appreciation is expressed t o Anal. Calcd f(ir c16112603: C, 72.2%; TI, C, 7 2 . 5 ; IT, 9.8. i\Irs. G. A. Snyder and Mrs. J . T. Dunn for technical Dimethylaminoethyl dI-l,2,3,4,4aa,4bp,5,6,7,8,8aa,9,10,lOa/3- assistance and to the Physical and Analyt~icalSect'ions Tetradecahydro-7p-hydroxy-2$-phenanthreneacetate(23c, Isoof t8heSterling-Winthrop Research Institute for spect'ral mer A).-This hasic ester was prepared from 3.5 g of 23b, isomer. arid analytical determinations. A, iii the stitiidard maiiiier to give 4.3 g of basic oil which was puri-
Cassaine Analogs. IV. Distant Analogs of Cassaine ROBERT L.
J. DAUM, PHILIP E. SHAW', THEODORE G . BROWX, JR., G. E. GROBLETVSKI, 4 S D W. T'. O'CONNOR
CLBRKE, SOL
Sterlzng-TVznthrop Research Znstztute, Rensselaei, S e w York 12144
Recezvecl December 1, 1966 ReGasecl Jlanuscrzpt Recezved Jfarch 1, 1M? Basic esters have been made which bear a distaiit resemblance t o t,he Erythrophleuin alkaloid ca3saiiie. These monocyclic aiid bicyclic analogs were needed iii order to define the role of the skeleton and various substituents of cassaiiie in its cardiac actioii.
The Erythrophleum alkaloid cassaine (1) is reported to be quite similar to digitalis in its action as a cardiac stimulant.' Both of these drugs suffer from the disH
,COOCHzCHzN(CH3)z
2, R = O
3,
1
advantage of producing toxic symptoms in doses only slightly higher than those producing therapeutic effects. It was of particular interest to determine the role of the skeletal structure and the various substituents of cassaine in the cardiotonic activity and toxicity demonstrated by this alkaloid. I n papers 112and 1113of this series we have described a large number of basic esters which bear a rather close resemblance to cassaine. Presently we report some more distant analogs of this compound. The bicyclic analog 5 was prepared from the trans ketone 2. A Wittig reaction using trimethyl phos-
s.
(1) See F Eriaiec and .'Ldamilen-ski, a n d IJ-. V. O'Connor, J . M e d . Chem., 10, 582 (196i).
s.
(3) J. n a u m . AI. AI. ~ Chem. 32. 1485 ( 1 Y 6 i ) .
i p. E,~ Shaw,~ and ~R , L, , Clarke,
J,
Org,
R = CHCOOCH3
phonoacetate transformed 2 into the a,p-unsaturated ester 3 which was a roughly 1 : l mixture of cis and tmns isomers (about the double bond). Yo effort was made in the presently reported work to separate these isomers since it was found in the series of closer analogs2 that there were only slight differences in the cardiotonic activity of such cis arid trans isomers. Hydrolysis of ester 3 was accomplished with KaOH in aqueous ethanol to give carboxylic acid 4. Basic ester 5 was then formed by the reaction of 2-dimethylaminoethanol o n the acid chloride of 4. This acid chloride was best prepared by treating the sodium salt of 4 with excess oxalyl chloride in the presence of pyridine. Any intermediate function formed at C-6 from attack there by oxalyl chloride was decomposed by the treatment with 2-diniethylaminoethanol; the 6-hydroxy basic ester was isolated.2 Incidentally, the &acetate ester of 5 \vas also prepared. This same sequence of reactions vas used in the preparation of all of the basic esters reported here.
H
r
reat,edwith 68 ml of dry benzene was treated with 60 ml of SOCl2 and heated ml (0.14 mole) of 2 *I' aqueous KaOH and heated under reflux under reflux for 2 hr. The solvents were removed by warming for 1.5 hr. The alcohol was removed by warming under reunder reduced pressure and the residue was dissolved in 300 ml duced pressure arid t8heaqueous soliltmion(wit.h more H 2 0 added of dry benzene. 2-Dimethylaminoet,hanol (60 ml) was added if the hodium salt' of t,he product, had part,ially precipit#at,ed)was dropwise with st,irring and cooling, and t,he result,ing mixt,ure was washed with ether. The aqueous soliition was acidified with 2 N then heated under reflux for 2 hr. The mixture was cooled, HC1 aiid t.he precipit,ated acid was collected on a filter if it, crpst,aldiluted with 2 1. of et,her, and extracted twice with 2 *V HC1, lized. In the present case the precipitat.e was oily and was the second extract's being st.rongly acidic. The combined exseparated by ether extraction. The extract was washed with brine, dried (Na2S04),and concentrat'ed to a residue which crystalt,racts were made alkaline wit,h 35% S a O H with cooling, and t'he liberated base was extract.ed wit,h ether. These ether ext.racts lized illion t'ritiiration wit'h ethyl acet,ate. Two recrystallizations fi,oni ethyl acel.at'e gave 3.0 g (58%) of acid 4, mp 170-189', were washed with water and brine, dried (MgSOc), and concenEfOH A,, 221 mp ( e 15,900). trated to give 37.3 g of brown, oily basic ester 6. A solution of this oil in 500 ml of ether was treated with 20.4 ml A n a l . Calcd for C12H1803: C, 68.56; H, 8.63. Found: C,68.7; IT, 8.6. of 8.7 Ar ethanolic HC1 and the precipitak was collected and General Procedure for Making Basic Esters. 2-Direcryst,allized from acetone to give 35.0 g (64%) of the hydromethylaminoethyl dl-3,4,4aa,5,6,7,8,8ap-Octahydro-6p-hydroxy- chloride salt of 6, mp 172-174'. One further recrystallization A2(1Hi,a-naphthaleneacetate (5).-A solut,ion of 7.95 g (0.0378 from acetone gave the analyt,ical sample, mp 173-174", mole) of dl-3,4,4aa,5,6,7,8,8ap-oct~ahydro-6p-hydro~y-A~(~~)~~224 mp ( e 16,900). naphthaleneacetic acid (4)in 150 ml of T H F was treated with Anal. Calcd for C12H21SO2.HCl: C, 58.17: H. 8.95: C1. 2.04 g 10.03% mole) of sodium methoxide, and the mixt,ure was 14.31. Found: C, 58.4.;H, 8.8; C1, 14.5.' ,
