Synthesis of abnormal peptides: cyclization of N^α-formyltryptophyl residue to 3,4-dihydro-β-carboline-3-carboxylic acid residue in acidic media

Abstract

Thc intramolecular reaction of Na-formyltryptophan to 3,4-dihydro-13-carboline-3-carboxylic acid is realized with high yield either in trifluoroacetic acid or in formic acid -concentrated hydrochloric acid solutions. Optically active products are obtained when fornlylated L-or D-tryptophan are used as starting compounds. The cxpcrimental conditions employed are highly specific and the cyclization of N"-formyltryptophyl rcsiduc is rcal~zcd also in pcptides without secondary lytic reactions. The general behavior of Nu-forn~yltryptophan in formic acid solutions is discussed.Canadian Journal of Chemistry, 46, 3404 (1968) Scheme 1 The compounds containing the P-carboline nucleus are of great interest in connection with their occurrence in some alkaloids. A synthetic procedure available to obtain the members of this class consists in a condensation of tryptophan, or its simple substituted derivatives, with aldehydes to yield a 1,2,3,4-tetrahydro-P-carboline (1). These products can be converted t o the fully aromatic conlpounds by dehydrogenation. Some difficulties arise when the 3,4-dihydro-Pcarboline nucleus is desired. The partial dehydrogenation is generally difficult to realize since the dihydro derivatives are completely aromatized a t a rate that does not permit their accumulation ill the reaction medium. An alte~mative procedure to synthesize the 3,4-dihydro-P-carboline nucleus has been pointed out by Spath and Lederer (2) who directly converted the amides of tryptanline to the corresponding 3,4-dihydro-Pcarboline.The attempts to effect an analogous cyclization on Nu-acyltryptophan to obtain 3,4-dihydro-Pcarboline-3-carboxylic acids showed that secondary reactions such as decarboxylation and dehydrogenation occurred and in the case of Na-formyltryptophan no product was obtained (3,4). 'Contribution No. 15 The present report is concerned with the preparation of optically active 3,4-dihydro-P-carboline-3-carboxylic acid by cyclization of Nuformyltryptophan. The reaction conditions are also used to cyclize some Nu-formyltryptophyl peptides to obtain the corresponding 3,4-diliydro-P-carboline derivatives in good yields as depicted in Scheme I.Experimental Ultraviolet (u.v.) spectra were recorded with a Cary model 15 (I cnl cells) spcctrophotonieter. Anlino acid analyses were performed with a Becknian an~ino acid analyzer model 120 B using ~i~icrocells with a 6.6 rnm light path. Paper chromatography was carried out on Whatman No. 1 paper. The two solvents eniployed were aqueous solutions of ammonia 5 % (v/v) and a~nnionium chloride 3 % (w/v). 3,4-Diliydro-!3-carboline derivatives were easily detected as yellow fluorescent spots in U.V. light (4). Na-forniyltryptoplian was obtained by treatnient of the amino acid with o n e equivalent of acetic anhydride in formic acid (5). Na-for~nyl-L-tryptophyl-L-phenylalan.ine methyl ester, No-formyl-L-tryptophyl-L-tyrosine iiiethyl ester, and No-fonnyl-L-tryptophyl-L-leucine nlethyl ester were syntliesized froni Na-forniyl-L-tryptophan, and the corresponding amino acid est...

Biomimetic Entry to the Sarpagan Family of Indole Alkaloids: Total Synthesis of (+)-Geissoschizine and (+)-N-Methylvellosimine

“…26 Finally, we discovered that the acyl selenide that was formed by the sequential reaction of 30 with isobutyl chloroformate and then sodium phenylselenide, 27 underwent facile and efficient radical decarbonylation to give deformylgeissoschizine 2 in 79% overall yield from 30. 28,29 Formylation of 2 according to the procedure of Winterfeldt 16a then delivered (+)-geissoschizine (1) in 48% yield (96% yield based upon recovered starting material) via a sequence requiring only 11 chemical operations from D-tryptophan (19). The synthetic (+)geissoschizine thus obtained was spectroscopically identical with a sample of racemic 1 previously prepared in our group, 15g and its optical rotation corresponded closely with that reported for natural…”

“…Synthesis of the Key Corynantheane Intermediate 27. On the basis of prior experience,2c we knew that vinylogous Mannich reactions involving iminium ions related to the dihydrocarboline 20 , which was prepared from d -tryptophan ( 19 ) in a single operation by modification of a known procedure, would proceed preferentially from the face opposite the carboxyl moiety at C(5). Hence, 20 was allowed to react with the vinyl ketene acetal 21 to produce 22 as the only isolable product (Scheme ).…”

“…A unified strategy for the enantioselective syntheses of the corynanthe alkaloid (+)-geissoschizine (1) and the sarpagine alkaloid (+)-N a -methylvellosimine (5) from D-tryptophan (19) has been developed. The stereocenter in 19 sets the absolute and relative stereochemistry at all stereocenters in 1 and 5.…”