Quaternary indole alkaloids

The synthesis continued with the formation of the 2-azabicyclo[3.3.1]nonane ring (D, E-rings), and epimerization of the cyano group at C-20 to an axial position. Closure of the C ring using a Bischler-Napieralski cyclization gave the quaternary indole alkaloid, ( )-melinonine-E (159). A closely related analog, ( )-strychnoxanthine, was also synthesized by a similar method [67]. 

Thomson reported the reversed-phase ion-pair separation of psilocybin and psilocin. Because both alkaloids exist as zwitter-ions, cationic and anionic pairing ions can be used. Alkyl sulfonates (Cg-Cg) and tetraalkyl ammonium (C3-Cg) ions were found unsatisfactory for psilocybin. Good results were obtained with a long chain quaternary ammonium ion, cetrimonium. Optimal conditions for quantitative analysis on an octadecyl stationary phase were 0.15% pairing ion in methanol - 0.4% aqueous phosphate buffer (pH 7.Z). Some other quaternary indole alkaloids have also been separated by means of ion-pair HPLC. Parkin6 analyzed the bisquater-nary alkaloid alcuronium in biological fluids. After an ion-pair extraction, the alkaloid was analyzed on an octadecyl column with the mobile phase methanol - water (4 1) containing O.Z5% acetic acid and 0.005 M dodecylsulfate. 

A study of A. angustifolia from Indonesia resulted in the isolation of two new quaternary indole alkaloids, alstogustine (95) and 19-epialstogustine (96) from the water-soluble portion of the AcOH-MeOH extract of the stem-bark [85]. These alkaloids were characterized as their... 

In 2009, Chiba s group reported a manganese-mediated synthesis of pyridines from cyclopropanols with vinyl azides [70]. In the presence of 1.7 equivalents of Mn(AcAc)3, a variety of pyridine derivatives have been prepared in good yields at room temperature. In their further studies, they realized this transformation in a catalytic manner [71]. In their mechanistic studies, they found the reactions were initiated by a radical addition of /3-carbonyl radicals, generated by the one-electron oxidation of cyclopropanols with Mn(III), to vinyl azides to give imi-nyl radicals, which cyclized with the intramolecular carbonyl groups. Additionally, the application of this newly developed methodology in the synthesis of quaternary indole alkaloid, melinonine-E, was accomplished as well (Scheme 3.33). 

Monomeric tertiary indole alkaloids (diaboline and desacetyldiaboline (Wie-land-Gumlich aldehyde)) and quaternary indole alkaloids (C-hemitoxiferine, C-fluorocurine, C-mavacurine, and macusine A, B, and C) have been also obtained. 

Quaternary ammonium compounds are important as osmoprotectants in times of water deficiency and cold stress, as well as being constituents of membrane phospholipids, p-Alanine and phosphoethanolamine are each methylated three times on their nitrogens to produce the products P-alanine betaine and phosphocholine, respectively (Fig. ll.l).24"27 An example of O-methylation and N-methylation occurring on the same molecule can be found in the indole alkaloid vindoline from Catharanthus roseus (Fig. 11.1) 28,29... 

The vast majority of indole alkaloids contain a tryptamine unit in which Nb is linked to the j9-position of the indole nucleus by an ethylene chain. On biogenetic grounds and also from the mass spectral similarity with aspidospermine (II), it is reasonable to expect this feature in the aspidofractinine-type alkaloids. Furthermore, in kopsine lactam A (CLXXV), in which C-ll is substituted by the C-3 bridge and C-10 has been oxidized (five-membered lactam), the residual hydrogen atom on C-ll shows as a singlet (2.82 S) in the NMR-spectrum and C-12 is therefore quaternary. 

Intermediate samarium enolates derived from ketones 1522 or 1525 could stereoselectively be trapped with allyl halides, leading to tricycles 1524 and 1526. The intramolecular alkylation by the chloroalkyl terminus of compound 1527 led to tetracyclic compound 1528 with satisfactory efficiency. These cascade reactions selectively generate three continuous stereogenic centers, including a quaternary carbon atom at the 3-position of the dihydroindole moiety, a structural motif of many indole alkaloids. 

The total synthesis of the complex bioactive indole alkaloid ditryptophenaline, having two contiguous quaternary stereocenters related by C2 symmetry, was accomplished in the laboratory of L.E Overman.In the late stages of the synthetic effort the complex diol substrate was oxidized to the dicarboxylic acid using a two-step procedure first, a Dess-Martin oxidation to the dialdehyde followed by the Pinnick oxidation. The mild reaction condition ensured that the integrity of the stereocenters at the a-positions was preserved. 

C.Martins, S. cmtdnaeana Wedd. and closely related species of the family Lo mia-cme is used. Among the many alkaloids that occur in these barks, toxiferine-I shonld be mentioned, a dimeric indole alkaloid (with strychnine-skeleton) which has two quaternary nitrogens. 

Alkaloids which inhibit acetylcholine esterase, monoamine oxidase and catechol-O-methyltransferase are tabulated in Table 11. Potent ACE blocker are indole alkaloids of the physostigmine type (e.g., eseramine, geneserine, physovenine, eserine), protoberberine alkaloids (e.g., berberine, columbamine, coptisine, jatrorrhizine, palmatine), steroidal alkaloids (leptine I, solanine, solamargine, and tomatidine), galanthamine and others. A plausible structure-function relationship is not apparent, except that all these alkaloids have a quaternary N under physiological conditions, and that an oxygen can be traced 2 to 4 carbons adjacent to the N, similar to the situation in acetylcholine. 

This chapter is a survey of recent works in the general area of oxindole and spirooxindole synthesis with specific attention on strategies for the installation of the C3 quaternary centers that characterize members of this unique family of indole alkaloids. As investigations that have resulted in modest observed selectivities represent important opportunities for further synthetic advancement, those studies will be described alongside illustrations of chemical technologies that represent the state of the art of the discipline. 

Polonoeski reaction (2, 7 5, 3). The first synthesis of the dimeric indole alkaloid vinblastine (4), used in the treatment of lymphomas, involved coupling of two indole units using a Polonovski reaction. Thus reaction of the N-oxide (1) and vindoline (2) with trichloroacetic anhydride afforded the quaternary im-monium compound (3), which was converted into (4) by standard methods (reduction with NaBH, rcacclylalion). ... 

In current scientific usage, curare refers only to those C. a. with muscle-relaxing (paralysing) effects, namely the dimeric indole alkaloids with a strychnine skeleton and two quaternary nitrogens. These compounds are extremely poisonous calabash alkaloids E and G cause death by respiratory paralysis and are among the most toxic compounds known. 

Few years after its disclosure, the potential of the Claisen-Johnson rearrangement in alkaloid synthesis was recognized. This reaction showed its utility especially in the field of indole alkaloids. Thus in 1973, Ziegler [81] applied this rearrangement as a comer stone step in the synthesis of tabersonine 350 for the constmction of the C-20 quaternary center (Scheme 6.59). In this particular case, the Claisen-Johnson gave a better yield than the Eschenmoser rearrangement... 

Strychnos toxifera is a tree that grows wild in the Amazon basins. The stem bark and root bark contain many tertiary or quaternary bis-indole alkaloids such as C-alkaloid A, C-toxiferine I, C-calebassine, caracurine II, caracurine II matho-salt, caracurine V, and nor-dihydrotoxiferine. 

Polycarpathiamines A and B were isolated from the ascidian P. aurata [48]. In general, marine invertebrates such as ascidians are prominent sources of a wide variety of nitrogenous compounds, many with novel stmctures. The authors were led to the 1,2,4-thiadiazole family based on the shift of one of the quaternary carbons at 170 ppm and the second in the 180-190 ppm range. The C NMR data for the previously reported indole alkaloid dendrodoine [49], which also contains an N,Af-dimethyl-l, 2,4-thiazole moiety provided further support for the incorporation of a 1,2,4-thiadiazole moiety in the structures of the polycarpathiamines. The constitution of the thiadiazole was based on H—HMBC data. As shown in Scheme 3, the authors assigned the substitution based on the observation of correlations from the amino protons to both nitrogens of the... 

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