Richard J. Sundberg

Synthesis and oxidative fragmentation of catharanthine analogs. Comparison to the fragmentation — Coupling of catharanthine and vindoline

Abstract Two new analogs of catharanthine have been synthesized in racemic form. They differ from catharanthine in the fusion of the indole ring to the non-aromatic portion of the iboga skeleton, with the [2,3] fusion present in catharanthine being replaced by [2,1] and [3,2] fusions. The corresponding deethyl analogs were also prepared and methodological improvements were applied to an existing synthesis of deethylcatharanthine and a formal synthesis of racemic catharanthine. The reactivity of the catharanthine analogs toward coupling with vindoline was examined. Coupling was attempted by both the amine oxide fragmentation (Potier) and Fe3+ methods. Under Potier conditions the [2,1] fused analogs give low yields of coupling products in which vindoline is attached to the 3-position of the indole ring. The [3,2] isomers undergo fragmentation of the C16–C21 bond, as observed for catharanthine, but no coupling to vindoline occurs. The reactivity, oxidation potentials and conformation of the analogs are compared with catharanthine, deethylcatharanthine and N-methylcatharanthine.

Nitrogen-carbon linkage isomerism of histidine in ruthenium ammine complexes

Abstract The histidine complexes of pentaammineruthenium in the (II) and (III) oxidation states have been prepared and characterized. Spectral data shows that histidine is bound through the imidazole-N-3. The ruthenium (II) ion rearranges in acidic solution to give a tetrammineruthenium complex of histidine in which the histidine is bound through the imidazole-C-2 atom. The spectral properties of this linkage isomer are described. The potential biological significance of histidine N-C linkage isomerism is discussed.

Mechanistic aspects of the formation of anhydrovinblastine by Potier-Polonovski oxidative coupling of catharanthine and vindoline. Spectroscopic observation and chemical reactions of intermediates

Abstract The fragmentation-coupling of catharanthine and vindoline by trifluoroacetic anhydride has been carried out under conditions which allow observation of intermediates and comparison of reactivity by low temperature NMR. These studies have confirmed or revealed the following facets of the mechanism of the reaction: (1) fragmentation of an intermediate derived from catharanthine-N-oxide which otherwise is stable at −40°C occurs rapidly on addition of vindoline; (2) other bases including tri-n-butylamine, N,N-dimethyl- 3-methoxyaniline, N,N-dimethyl-2-(2,4-dimethoxyphenyl)ethylamine and 10-trifluoroacetyl- vindoline also accelerate fragmentation; (3) the stereoselectivity of coupling is controlled in part by the different rates of reaction of vindoline with separate precursors of anhydrovinblastine and 16′ -epi-anhydrovinblastine; (4) Na-methylcatharanthine-Nb-oxide undergoes fragmentation in a manner analogous to catharantine-N-oxide but there is an observable intermediate which can not be detected in the latter case; (5) the rate of fragmentation of Na-methylcatharanthine-Nb-oxide is also subject to some acceleration by base; (6) several products formed from the final fragmentation with the previous representation of the fragmentation-coupling mechanism but contribute new details.

Photochemistry of quinone diazides. Intramolecular oxygen transfer and carbenoid addition during photolysis of N-allylsulfonamido quinone diazides

Abstract An indole quinone diazide, 5-(N-allylsulfonamido)-4-diazo-3-methyl-4,-7-dihydroindol-7-one, which is a potential precursor of a spiro -cyclopropane-indol-7-one structure has been prepared. A study of its photolysis and that of a model compound has identified oxygen transfer from the sulfonamido substituent as a process which competes with intramolecular carbenoid addition.

Photoactive C16-C21 fragmentation of catharanthine

Photolysis of catharanthine in the presence of several potential electron acceptors and cyanide ion leads to either addition of cyanide at C3 and C5 or to C16-C21 fragmentation and addition of cyanide at C21. The product composition depends on the acceptor and the presence or absence of oxygen

The IBOGA alkaloids and their role as precursors of anti-neoplastic bisindole catharanthus alkaloids

Publisher Summary Iboga alkaloids are found in plants of the family Apocynaceae, which falls within the order Gentianales. The iboga alkaloids are examples of the broad class of monoterpenoid indole alkaloids that are considered a chemical marker for the Apocynaceae. This chapter discusses the chemistry of iboga alkaloids and their role as precursors of anti-neoplastic bisindole Catharanthus alkaloids. The iboga alkaloids are comprised of indole and isoquinuclidine rings fused by a seven-membered C-ring. There is a carboxy group at C-16 in the C 20 alkaloids, but other iboga alkaloids lack this substituent. Ibogamine and catharanthine are prototypical structures. Studies have shown the catharanthine isolated from natural sources is usually of the opposite absolute configuration from ibogamine. The chapter uses the biosynthetic numbering scheme of Le Men and Taylor. The chapter also discusses the structures in which the C-16-C-2 1 bond is cleaved. The C-16,C-21 fragmented structure occurs in the anti-neoplastic bisindole alkaloids isolated from Catharanthus roseus . The iboga structure also frequently occurs in combination with the vobasan skeleton.

Synthesis of Macromolecules

Much of the effort of organic chemists since about 1930, especially in industrial research laboratories, has been directed toward the synthesis of polymeric materials, and many such substances have come to play a prominent role in industry and commerce. In this chapter, some of the reactions that are utilized to create useful polymers will be illustrated. It will be seen from the discussion that the basic mechanisms of polymerization reactions are the same as those encountered in the reactions of small organic molecules, and that the special features of polymerizations are the result of the high molecular weights of the molecules involved.

An improved reaction sequence for electrophilic cyclization of methyl 6-(2-indolyl)-2-azabicyclooct-7-ene-6-carboxylates iboga alkaloid analogs

Abstract An improved reaction sequence for converting the Diels-Alder adducts of methyl α-( N - phenylsulfonylindol-2-yl)acrylate and 1-benzyloxycarbonyl-1,2-dihydropyridines to analogs of the iboga alkaloids is described. The sequence features selective reduction of - N - methoxy- N -methylacetamide derivatives to the corresponding aldehydes followed by facile acid-catalyzed cyclization. (±)-20-Deethylcatharanthine and 15-oxygenated derivatives were prepared.

Synthesis and intramolecular photoaddition of an indole quinonediazide

Abstract An intramolecular carbenoid photoaddition route to the unique spiro -cyclopropane indol-7-one ring system of the antibiotic CC-1065 has been explored. The diazo transfer reaction of a 7-hydroxyindole intermediate leads via a 6-diazo intermediate to an isomeric ring system.

Electrophilic Substitution Reactions of Indoles

The topic of this chapter is electrophilic substitution of indole and its derivatives. The indole ring is highly reactive at its 3-position toward protonation, halogenation, alkylation and acylation. Electrophilic substitution can be combined with inter- or intramolecular addition at C-2. Intramolecular alkylation by iminium ions (Pictet-Spengler reaction) is particularly useful. Enantioselectivity can be achieved in many conjugate addition reactions. These reactions have been applied to synthesis of both natural products and drugs.