W.UT,ZORBACH,S.SAEKI,AxrJ W.HUHLEIZ
298
\-o1,
Ii
Strophanthidin Cardenolides Containing Hexoses of the Mannose Series'"
Rtceived .l.oceniber 16, 19BZ Employing a modified Koenigs-Bnorr type synthesis, strophant,hidin ( V I ) was coupled with tetra-0-acetyl-a-Dinannosyl bromide ( I ) and with tri-0-benzoyl-a-u-rhainnosyl bromide (11) to give, respectively, after saponificatjion of the reaction products, strophantliidin a-D-mannopyranoside (VII) and strophanthidin a-D-rhaninop~ranoside (VIII), the latter of which was converted to a crystalline tri-O-acet,yl derivative VIIIa. Both cardenolides 1-11 and VI11 have an "unnatural" glycosidic linkage, when compared with natural u-hexosides of strophanthidin having the 8-anoineric configuration, and show a loiv order of cardiotonic activity. The non-nat,urally occurring 6 - r ~ ~ a n n o (111) s e was converted to penta-O-acet~l-P-L-nirtnnose (IT7) which reacted with hydrogen bromideacetic acid to give tetra-O-ncetpl-or-L-iiiannos?'l bromide. The latter coupled wit,h strophanthidin (VI) t o givc, after rerrioval of the protecting groups, strophanthidin Lu-i,-niannopvranosidR ((5'-hydroxyconvallatoxin) ( I S ) which was converted into nn amorphous tetra-0-met)-1 derivative ISa. The L-mannoside 1); has a potency (hIL1) 0.069 my. kg.-1) superseding that of convallatoxin (6-deoxy-a-rJ-in:mnopyranoside of strophanthidinj and is, therefore, t,he niost potent of all known cardenolides. These results support our postulate that deoxygenation in the carbohydrate component of a cardenolide leads to t: loss in potency.
Xccording to lilyne,? cardeiiolides of iiatural origiii coritairiiiig sugars of the 1)-series are invariably B-aiiomers while those which contain L-sugars have the a-aiiomeric configuratioii. l'reviously we reported3the synthesis of the a-digitoxoside !2,G-dideoxy-a-u-I.i(,oliexoside) 3a aiid the a-1)-rhamnoside (G-deoxya-r)-maiinoside) :jb of digitoxigeiiiii (3$,1~B-dihydrosy-:iP-car~l20(22)-eiiolide) ; both po ai I "uiiiiatural" glycorisiiigly IOU- poteiicies sidic linkage aiid slio~r n.heii compared with assay values obtaiiied for se\wi liexosides of digitoxigeiiiii of iiatural o r i g i i ~ . ~T1;'s ohsrrvatioii suggest'ed to us that, in general. the pre*cticf' of an a-glycosidic liiikage i i i cardenolidw coiitaiiiiiig r)-sugars pro\-ided for a molt~ularcoiiformatioii 1111sat'isfact o ry fo r o p t8imum card iot o i i i c ac t,ivit y . I I i order to leiid support to this coiiteiitioii. TVO undertook tlre preparation of t\r-o additioiial cardenolidw, raclr to ail a-glycosidic liiilicoiitaiii a 1)-hexose and to po age. l'rior t o tlic work dr. cd iii this paper tlicl iiat iirally omirriiig coii\dlatosi I i [(j-deoxy-a-L-maiIiioside of strophaiitliidiii (1-1)] liad I,eoii considered to he tlic: most potent of all cardeiiolides a i d , bccaus;c of this, we cliosc t o prepare glycosides of strophaiitliidiii i@,.i@,l4d-t riliydroxy- 1!)-osocard-20(22) -ellolid) (\'I) coiitaiiiiiig D-maiiiiose oil tlie oiic hand a i d &deoxy-[)niatiiiose (~)-rliamiiose~) on tlie other. Iteceiit work6 iii this Laboratory has yielded iuformation which now leaves little doubt that deoxygenation in the pyranose is, in general, unfavorable for cardiotonic actix-ity. ;kcording to this, the reverse should he true and by "osygenatiiig" the sugar cornponelit of :L iintuixlly occui,i,itigcardeilolide, ot 16' sliould efTwt ail i l l v r w s t ~i t 1 potoiwy. IVitIr tllis i l k niitid, ivo iuidt~rtook
t o iiicreaw the oxygen iuiictioii of the carbohydratc compoiieiit of the potent convallatoxiii by coiivertiiig the C-5 methyl group to a hydroxymethyl group : accordiiigly such a change should result in a substaiitial iiicreahe in poteiicy. Stable ()-acylglycosyl halide-, prepared from liexostof the maiinose series (to iiiclude u-rhamnose) arc invariably a-anomers and, owing to t h e iact that the C-2 scyloxy group is ail axial subitituent, n i d i derivatives are at thc .%me time 1,2-trans halides. Uiider ipecified c.onditioii.i such halides may undergo displacemelit at C-1 nit11 net rptentzon of co~ifiguration~;i i i fact 11 itli c d i of all prex-iouqly rcaported 3yiitheses of cardeiiolidcs iiil olving 1,%-transhalide-, i i i the presence of silver caihoiiatc, ail a-glycoside \\as formed to exclude both tlic alternate d aiiomeric form niid an orthoebter. It 4iould follon- tliereforc that maniiosyl lialidcs (a- i t cll 3 - rliamiio~ylhalide\) sliould give riie to a-cardeiiolitlc., irrcspectivcl of which eiiaiitiomeric form of tlie sugar i. ill\-olvcd In the prewnt htudy, three IIPW cardciiolidcprcpared mid tlic aiiomeric (boafiguration of CYLCII I\ as ~ h o w to i bo a , it. cletermiiir'd by applicatioii of Klyiic'\ rule of molecular rotational additivities.? The kiiowii ~,,::,.l-,G-tetrs-O-acetyl-cu-D-mar~iiosyl 1x0midr \l)8 n-as coupled wit11 ~tropliantliidiii(VI) i i i tlw presence of d v e r carbonate. u h g an azeotropic di\tillation procedure essentially the same as that described by JIeystre aiid J I i e ~ c h e r . ~The 0-acylated cardeiiolide u'as iiot isolated ; instead the reaction mixtim n a4 saponified in. toto, thus rendering all extraiieoii. carbohydrate material water soluble. Extractioii with orgaiiic wli elit- g:tvc the desired 3/3-(a-i)-maiiiiopyiwio-yl)-.-ds 1 4 / 3 - d i h ~di o\y- I !)-osocartl- 20(L")e~iiolitic~ ( \71) i n 2 0 c ; yield . , i ~ t p u r t ~ l:r:.urlty ,
