Isoquinuclidine Ring Research Articles

Total Synthesis of Tabernanthine and Ibogaline: Rapid Access to Nosyl Tryptamines

AbstractWe describe the first total syntheses of tabernanthine and ibogaline. Entry to these iboga alkaloid natural products is enabled by a thermal coupling of indoles and aziridines to furnish the requisite nosyl tryptamine starting materials. This route features a Friedel‐Crafts type alkylation to form the key indole‐isoquinuclidine C−C bond. Finally, a regio‐ and diastereoselective hydroboration‐oxidation enables C−N bond formation to close the isoquinuclidine ring system and deliver tabernanthine and ibogaline in 10 and 14 % yield respectively. Both syntheses were completed in eight steps.

Gram-Scale Total Synthesis of (±)-Ibogamine.

We describe the gram-scale total synthesis of (±)-ibogamine in nine steps and 24% overall yield. The approach features a Mitsunobu fragment coupling and macrocyclic Friedel-Crafts alkylation to establish the nitrogen-containing core of ibogamine. A regio- and diastereoselective hydroboration allows for simultaneous formation of the tetrahydroazepine and isoquinuclidine ring systems via sulfonamide deprotection and concomitant intramolecular cyclization.

Asymmetric Total Synthesis of an Iboga-Type Indole Alkaloid, Voacangalactone, Newly Isolated from Voacanga africana

A new hexacyclic iboga-type indole alkaloid, voacangalactone (1), was isolated from Voacanga africana , and its structure including the absolute configuration was established by asymmetric total synthesis involving such key steps as the asymmetric Diels-Alder reaction using an aminodiene and the construction of an isoquinuclidine ring and an indole skeleton.

Total synthesis of ibogaine, epiibogaine and their analogues

Efficient total synthesis of ibogaine, epiibogaine and their analogues has been described. An intramolecular reductive-Heck type cyclization was used for the construction of seven-membered indoloazepine ring to access iboga-skeleton. Larock’s heteroannulation reaction was employed for the creation of suitably substituted indole and Diels–Alder reaction was employed for the construction of the isoquinuclidine ring present in iboga alkaloids.

Solution-Phase Parallel Synthesis of N-Arylisoquinuclidines

The naturally-occurring alkaloid ibogaine, found in the West African shrub Tabernanthe iboga, possesses the ability to diminish self-administration of substances of abuse, such as cocaine, heroin and alcohol. The presence of the isoquinuclidine ring system in the structure of ibogaine became the lead for the design of a 16-member library of N-aryl isoquinuclidines, where pyridine, pyrimidine and quinoline ring systems were attached directly to the bicyclic nitrogen. A solution-phase method for their synthesis is described.

Catharanthinol and Dihydrocatharanthinol: Two Iboga‐Class Alkaloids.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Catharanthinol and dihydrocatharanthinol: two Iboga-class alkaloids

The title compounds are indole alkaloids of the Iboga class. In both compounds, viz. catharanthinol methanol solvate, C(20)H(24)N(2)O.CH(4)O, (I), and dihydrocatharanthinol monohydrate, C(20)H(26)N(2)O.H(2)O, (II), a nitrogen-containing seven-membered ring is fused to the indole system and shares two sides with a tricyclic isoquinuclidine group. The main difference between (I) and (II) is the presence of a C=C bond in the isoquinuclidine ring in (I). The presence of amine and hydroxy groups in these molecules and of methanol [in (I)] or water [in (II)] solvent molecules results in intra- and/or intermolecular hydrogen bonding.

Simple and Convenient Synthesis of Iboga-Functionalized Isoquinuclidines

Synthesis of Iboga-functionalized isoquinuclidine ring system and alkylated derivatives from commercially available 3-ethyl-pyridine, is reported. The key-step for isoquinuclidine synthesis is a cycloaddition between methyl acrylate and N-benzyl-3ethyl-5,6-dihydropyridine obtained in situ from N-benzyl-3-ethyl-4-methoxy-1,4,5,6tetrahydropyridine. Further treatment of isoquinuclidine lithium enolate with appropriate electrophiles gave alkylated products with good stereoselectivity.

Synthesis and biological evaluation of 18-methoxycoronaridine congeners. Potential antiaddiction agents.

Variation of the methoxycarbonyl and C-18 substituents of the antiaddictive compound 18-methoxycoronaridine, and contraction of its isoquinuclidine ring segment, provided 15 congeners for SAR evaluation at opioid and alpha3beta4 nicotinic acetylcholine receptors. The opioid activities were relatively low, and the alpha3beta4 nicotinic acetylcholine receptor activities were found to correlate with in vivo antiaddictive activities.

Metabolism and pharmacokinetics of nufenoxole in animals and humans: an example of stereospecific hydroxylation of an isoquinuclidine ring

1. Nufenoxole, a novel antidiarrhoeal agent, was well absorbed in rat, monkey and human after oral administration. Systemic availability of nufenoxole was 85% in monkey and 102% in man. 2. The elimination rate was much faster in rat (t1/2 of 1.8 h) and monkey (t1/2 of 4.9 h) compared with human (t1/2 of 35.8 h). 3. After oral and i.v. 14C-nufenoxole, concentrations of 14C in human erythrocytes and saliva were approx. 3- and 4-fold lower, respectively, than plasma concentrations. 4. Nufenoxole was metabolized to metabolites hydroxylated on the methyl substituent and isoquinuclidine ring in rat and monkey. The isoquinuclidine ring hydroxylation, a major pathway in human, was stereospecific. 5. Following oral doses of 14C-nufenoxole the urinary excretion of radioactivity (about 8%) was less than the faecal excretion (66.6%) in rat, while urinary excretion was the major route of drug elimination (about 60%) in man. In monkey, urinary and faecal excretion were equally important.

Studies on the method of total synthesis of koumine: I. 4-Substituted 1,2-dihydropyridine derivatives and their function as a conjugated diene in Diels-Alder reaction

A route to the total synthesis of koumine has been suggested. Five 4-substituted 1, 2-d hydropyridine derivatives, which are supposed to be a conjugated diene of Diels-Alder reaction to produce the isoquinuclidine ring of koumine, have been synthesized. Only two of them were found to be able to undergo the Diels-Alder reaction. The stereochemistry of the reaction product has also been examined.

Novel applications of the modified polonovski reaction - VII preparation of isoquinuclidines

The first successful preparations of the biochemically important isoquinuclidine ring system by the modified Polonovski reaction are described.

Studies on 1-Alkyl-2 (1H)-pyridone Derivatives. X. The Diels-Alder Reaction of 1-Methyl-2 (1H)-pyridone with Maleic Anhydride

The Diels-Alder reaction between 1-methyl-2 (1H)-pyridone (I) and maleic anhydride was successfully carried out in 42% yield. This constitutes a new synthetic route to isoquinuclidine ring. The structure of the adduct (II) so obtained was proved by the synthesis of various derivatives. It was thereby determined that the structure of II is an endo-form IIb, that of dicarboxylic acid (III) is IIIb, that of bromolactone (IV) is IVd, the hydroxy-lactone (V) is Vd, and the dilactone (VI) is VIb.