Deacetylvinblastine amide

Hydrolysis of the methyl ester and decarboxylation at C-18 occur only under forcing conditions. Alkaline hydrolysis of the C-18 ester of vinblastine requires refluxing m 5 N sodium hydroxide for several hours to give the diacid (18), and ammonialysis of this position in anhydrous methanol is accomplished in a sealed vessel at 100°C for 60 hr to yield the 18 -decarbomethoxy-4-deacetylvinblastine amide (19) (55). Bisindole derivatives lacking the C-22 carboxyl have also been prepared by coupling the vindoline portion with an appropriately chosen ibogane precursor (Section V,G) (54). 

Unsubstituted oxazolidinediones are prepared directly from the unsubstituted C-3 amides. Treatment of 4-deacetylvinblastine amide (59) with sodium hydride in tetrahydrofuran followed by the addition of dimethyl carbonate gives 4-deacetyl-3-oxazolidinedione (101) in 40% yield. 

Peptide derivatives of the bisindole alkaloids have been prepared by appending amino acids at C-3. Reaction of acylazide 62 with an ct-amino acid ester affords amide derivatives of this type (122) (46). Conversely, the attachment of the amino acid can be inverted by reacting a C-3 amide derivative with an activated amino acid ester. Thus, treatment of 3-0-aminoethyl)-4-deacetylvinblastine amide (70) with an N-protected a-ami-noacylazide gives the alternative amide derivative (123). These techniques have been used to prepare di-, tri-, and tetrapeptide conjugates. 

Deacetylvinblastine acylazide (62) was later shown to be an exceptionally versatile intermediate for the preparation of C-3 amides. Since nucleophilic displacement of azide occurs at relatively low temperatures under mild conditions, a wide variety of C-3 derivatives have been prepared (Scheme 1, Table III). This observation is in contrast to the direct amino-lysis of vinblastine which usually fails when the amine employed is substituted (e.g., p-hydroxyethylamine) or secondary (dimethylamine). The reactions can be conveniently followed by the disappearance of the CO—N, infrared band at 2135 cm" with the concomitant appearance of the CO—NHj band in the region 1665-1675 cm". Acetylation of the... 

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