DECEMBER
1960
SOTES
221i
The Synthesis of Esters of Angelic Acid’,? verted to 8-brornoangeloyl chloride (11) by reaction with phosphorus trichloride. The absence of isumerization to the tigloyl isomer was demonstrated by subsequent conversion to the known methyl and Received A p r i l 6, 1960 ethyl esters of angelic acid. The relative stability of I toward isomerization is presumably attributThis report roncerns the development of a able to the polar repulsion of the bromine atom general method for the synthesis of esters of angelic and the carboxyl group and the consequent greater acid. The need for a widely applicable synthetic stability of the geometric isomer in which the route arose during our studies of the structures of bromine atom and carboxyl group are farthest the naturally-occurring veratrum angelate esters from each other. The acid chloride (11)was allowed germanitrine8 and ~ e v a d i n e .It ~ was felt that to react with various simple alcohols to yield the ambiguity concerning the nature of the unsaturated respective 3-bromoangelate esters (111). Catalytic acid residue present in each of these alkaloids could hydrogenolysis of the latter rompounds (111) best he resolved by partial synthesiq of authentic yielded the desired angelate esters (IV). The hydroangelate esters for comparison with the natural genolyses were run under atmospheric pressure materials. over potassium hydroxide-washed 1 0 7 palladium Methyl angelate and ethyl angelate have been on charcoal in the presence of excess triethylamine. prepared by displacement reactions of the carbox- Triethylamine was found to be an efficient inhibitor ylate ion with the appropriate alkyl halide.5-6 which minimized the competing reduction of the &Menthyl angelate was reportedly prepared by double bond. I n all cases, the hydrogenation was acylation of I-ment hol n-ith angeloyl chloride syn- terminated after the uptake of one mole equivalent t hesized from sodium angelate and phosphorus of hydrogen was complete. The yields and properoxychloride.’ In our hands, repetition of Rupe’s ties of the 3-bromoangelate and angelate esters of preparation yielded /-menthyl tiglate. Furthermore, methyl, ethyl, and phenethyl alcohols and of Zthe acid chloride prepared from sodium angelate menthol are summarized in Table I. The properand phosphorus oxychloride yielded tiglic acid upon ties of I-menthyl tiglate are included for comparison hydrolysis. Subsequent attempts to prepare purposes. angeloyl vhloride by other standard procedures The same sequence of reactions was used to invariably yielded tigloyl chloride. It became ap- prepare the alkaloid angelate esters germanitrine, parent that the well known6 facile isomerization of cevadine, and escholerine.s In the alkaloid series, angelic acid to tiglic acid precluded synthesis of sodium acetate was added to neutralize hydrogen angeloyl chloride by the standard procedures. bromide liberated in the hydrogenolysis step; The method subsequently developed is shown in these cases, the alkaIoid apparently served as in formulas I-IT’. BBromoangelic acid (I)5was con- the inhibitor. In each of the three cases, the synthetic ester was identical with the naturallyderived material, thereby confirming presence of the angelate residue in each ester alkaloid. / \ / \ Certain spectral differences between the angelate Br CH; Br CK and tiglate esters became apparent upon eompariI I1 son of the two series. In the ultraviolet, the locatioii ROH of the absorption maximum (216 i 1 mp) was approximately the same for both series (see Table H,C COOK. HsC COOR 11). However, the extinction coefficients for the Hz \ / \ / c=c fc=c tiglate esters appeared to be consistently higher Pd/C ,/ \ / \ (ca. 11,000) than those of the angelate esters (ca. H CHI Br CH, 9000). In the infrared, the tiglate esters in chloroIV I11 form solution showed characteristic bands at 8 . i 5 p ( 1 ) This is palt XYXVI of a series entitled “Veratrum Alkaloids,” Part XXYV, S. M. Kupehan and K. Gruen- (s) and 15.30 p(w) which were absent from the fcld, J . Anz Pharrn - ~ S \ O C , 48, 727 (1959). spectra of the angelate esters. On the other hand, ( 2 ) This invwtigation \!as supported in part 11) 21, ic- the aiigelate esters in c*hloroforinsolutioii showed search grant from the Rewttrch Committec of the Graduate characteristic bands att 8.0.5-8.10 p ( s j and 11.80 School from furidb supplic~lby the Wisconsin Alumni Rep h i ) which did not appear in the spetktra of the erarch Foundation. tiglate esters. These generalizations einhracd the (3) S.M. Kupchan and A Afonso, J . A m Pharm Assoc., 48,731 (1959). spectra of the alkaloidal esters as well. I11 the (4) S.M. ICupchan and A. Aforiso, J. &4m.Pharm. ASSOC., spectra of liquid films, the tiglate esters wore char49,242 (1960). (5) R. E Huchlc~iand C: 1‘. ?*loc,k,J . Ory. Chem., 15, acterized by a single band at 13.65 p i s ) and one at 8. MORRIS KCPCHAX AND ADRIANO AFOXSO
680 ( 1950j. ( 6 ) For an i n f n r m a t ~ vr~w i w of the rhemBtr> o f tiglic atid angelic*acids, reci H E. Burkles, G. V. Moch, and L. LwatPII, JI , l ‘ h f t t [ . / < ( t55,h59(1955). ~,
( 7 ) H. RUN, .-inn., 569,337 (1909). ( 8 ) P. icI. Kupchan and C. I, Byre@,J . i t t t i . Phartta. Llss.oc.. 48,735(1959).
221s
VOL.
SOTES
25
TABLE I PHYSICAL PROPERTIES OF SOMEAXGELATE ESTERS Calcd. Esters
B.P., mm.
Yield,
Methyl 3-bromoangelate Ethyl 3-bromoangelate I-Menthyl 3-bromoangelate Phenethyl3-bromoangelate Methyl angelate Ethyl angelate I-Uenthyl angelatea Phenethyl angelate I-Menthyl tiglateb
96 (53) 110 (51) 11210.6) 144 (3) 128 (740) 142 (740) 130 ( 5 ) 109 (1.8) 138 (9)
97.3 88.5 78.2 85.5 64.3 71.0 89.0 89.7 91.7
a [a]'," -86"
ic, 9.54, benzene.
9;
d:*
ny
1.444 1.342 1.175 1,324 0.9202 0,9272 0.9656 1.053 0.9494
1,4890 1.4796 1.4906 1.5418 1.4332 1.4296 1.4651 1.5101 1.4668
Asla. max,
Methyl tiglate Ethyl tiglate I-Menthyl tiglate Phenethyl tiglate Methyl angelate Ethyl angelate I-Menthyl angelate Phenethyl angelate
37.33 4.70 40.46 5.53 56. 76 7.94 55.12 5.34 63.16 8.83 65.64 9.43 75.57 10.99 76.47 7.90 75.57 10.99
41.41 38.46 25.19 28.23 -
-
4.97 5,36 7.99 5.13 8.46 9.48 ( 0 . 4 2 10.96 i6.40 7.97 75. i 7 11.08
37.25 40.34 56.53 55.13 62.68 65,22 F-
40.90 37.24 24.99 27.75
-
-
/ a ] : -87" (c, 9.54, benzene).
TABLE I1 ULTRAVIOLET ABSORPTIONS Ester
Found ~~
C, % H, % Br, 9; C, '/
