;\larch 19iO
XOTES
321
meric basic esters in both isolated rabbit heart atrial strips and in intact dogs according to the methods reported in the preceding paper of this series1 showed no significant difference in their activities.6 Perhaps this is not too surprising since there is little difference in the activities of the (&)-cis and the (&)-trans baqic esters 2 (isomeric about the double bond); also little
HO
CH 'CH 1
2, R = CH-CH.X(CH,)-
3, R = H 4, R CjH,
lierZawere u n ~ u c c e ~ i f u l Gottsteiii . and Cheney3 have called attentioii to the merits of dehydroabietylamine as a resolving agent. T o our considerable delight, addition of thi. amine to a 1: 1 mixture of (&)-trans and ( & ) - u s acid5 3 (isomeric about the ex0 double bond) resulted in preferential precipitation of the amine salt of the (-)-tmns acid. The rotation of this salt and its high yield indicated that it was contaminated with some (-)-cis acid salt. However, liberation of the free acid and recrystallization afforded the desired (-)-h ans enantiomer. It did not prove possible to separate the (+)-trans acid 3 from the complex mother liquors. Yet this (+) acid was required in order to obtain both optically active bayic eqters for biological testing. The most likely approach a t this juncture apparently lay through resolution of pure (&)-tram acid 3 (free of the C L S form). Multiple recrystallization of a 1: 1 cis-trans mixture of ethyl esters 42a enriched the trans isomer to 93y0. Hydrolysis to acid 3 and further recrystallization then afforded a (&)-trans acid containing only l.6ycof the C I S isomer. Resolution of this (&)-trans acid 3 was then accomplished through its dehydroabietylamine salt but again with only partial success. The (-)-trans acid was isolated without difficulty but the (+)-trans acid could riot be obtained entirely pure. It \vas then discovered that the (+)-1-(1-naphthyl)ethylamine4 salt of the (+)trans acid 3 is only one-tenth as soluble in X e O H as is the diaytereoisomeric (+)-amine-( -)-acid salt. Separation of the (+)-trans acid 3 in this manner afforded it in pure form. I n order to have the physical constants of the enantiomeric salt available t o confirm melting points and rotations, the (-)-1-(1-naphthy1)ethylamine salt of (-) t i ans acid 3 was prepared arid the free (-) acid subsequently regenerated from it. The optical rotatory dispersoii data for these enantiomeric acids 3 are recorded in the Experimental Section." Pure (+)-trans and (-)-f/*ansacids 3 were converted into the corresponding basic esters 2 by reaction of the acid chlorides with dimethylaminoethano1.2a Evaluation of the cardiotonic activity of these enantio( 3 ) 11. J. Gottsteinand L. C. Chenei J Org Chem , S O , 2072 (1965). (4) Sold as Resoline-I by t h e Research and Development Department,
Rock Hill Laborator), X e n p o r t , Tenn (5) K e thank Dr. l a - h P 3 I j e r for determination of these dispersion ciirx es
5
difference when the rings are fused in a trans-trans, a cis-trans, or a trans-cis manner.2a ITet the activity drops significantly when the ridigity afforded by ring B is eliminated (structure 5).2a Concerning the decomposition of dehydroabietylamine salts, they should be treated with excess base and the desired acids then liberated from the aqueous phase. We found that dehydroabietylamine hydrochloride is so insoluble in H20 that treatment of diastereoisomeric salts of dehydroabietylamine with HCl gives difficult mixtures of free acid and amine hydrochloride. Experimental Section' Separation of (f)-trans-Acid3 Directly from a Mixture of (f )cis and (&)-trans Acids.--A solut'ion of 17.4g (0.066mol) of a 43:57 mixture of ( f)-cis and (k)-trans acids 328in 250 ml of hot UeOH was t>reatedwith 18.8 g (0.066 mol) of solid dehydroabietylamine.3 The amine dissolved and immediately a crystalline precipitate formed. The mixture was cooled t,o 45' and the solid (16.4 g) was collected. Recrystallization from 1300 ml of absolute EtOH (boiled down to 600 ml and cooled to 5 " ) afforded 12.5 g of needled, mp 227-229" dec (evac tube), [ c Y ] ~ ~-22.6' D ( 1 % in HOAc). A second recrystallization gave 9.13 g of needles of ( - )-trans acid 3 dehydroabietylamine salt,, mp 227-228.5" dec (evac tube), [CYIz5D -24.6'. Anal. (C,,HjjXO,) C, H, 3'. The (-)-trans acid salt (9.0 g) was suspended in 200 ml of Et20 and 50 ml of 1 S HC1 was added. The mixture was shaken well and filtered t,o separate a solid. The residue resulting from concentration of the Et20 layer was added to this solid. The total solid was shaken with 300 ml of H20, 20 ml of 2 .V NH4OH and 100 ml of Et,zO. Acidification of the aqueous layer gave a crystalline acid which was washed well with H2O and air dried. This acid was recrystallized from 500 ml of MeCN (concentrated to a 250-ml volume) to give 2.32 g of ( - ).trans acid 3, mp 217-219" (evac tube), [ a I z 5-48.6' ~ (lye in EtOH). A second recrystallization raised the melt,ing point t o 219-220" (evac tube); [a] -49.1' (lye inEtOH). Ethyl( f)-trans - 3,4,4a~~,4bp,5,6,7,8,8a~~,S,lO,lOap Dodecahydr0-7p-hydroxy-A*(~~),~-phenanthreneacetate (4).-The crude 1: 1 mixt,ure of cis and trans isomers of this compound (41 g ) prepared as described earlier2&was dissolved in 100 ml of cyclohexane and the solution cooled tmogive 16.5 g of a 3: 7 mixt'ure of czs and truns isomers. A second recrystallization from cyclohexane furnished
-
( 6 ) We thank Dr. G. E. Groblewski of these laboratories for this biological information. (7) .ill melting points are corrected. Nmr spectral measurements were made using a Varian 4-60 spectrophotometer with (CHs)&i as a n internal indicator. I r spectra mere recorded on a Model-21 Perkin-Elmer spectrophotometer and UT' spectra were measured on a Xodel 15 Cary spectrophotometer. Brinckmann Instruments silica gel grade PFm was used in I-mm thickness for preparative plate chromatography. Where analysea are indicated on!y by symbols of t h e elements, analytical results obtained f o r these elements were v i t h i n I O.4Y0 of t h e theoretical values.
