Aromatic p-carbolines

The Bischler-Napieralski (BN) method has demonstrated great utility for fully aromatic P-carboline rings. Substitution on carbocyclic ring A of the p-carboline system requires suitably substituted tryptamine which can be prepared via the Fischer indole synthesis or one of several methods for synthesis of indole rings (28, 128). 

Apart from the biogenetic scheme described above, the only other useful piece of information that could direct the development of synthetic routes to manzamine A was provided by the Kobayashi group who demonstrated that the related natural product ircinal A (17, Scheme 3) could be converted into manzamine A (1) through initial condensation with tryptamine (16) and subsequent acid-induced Pictet—Spengler cyclization (see Chapter 5 for a discussion of this reaction), followed by DDQ-mediated oxidation to complete the fully aromatic P-carboline system. Although this discovery... 

Plants have taken advantage of this successful synthetic principle for their enzymatic production of isoquinoline (as well as p-carboline ) alkaloids. In the chemical laboratory, this synthetic approach has been exploited for nearly 80 years in numerous biomimetic-type syntheses. This special form of the Mannich reaction requires electron-rich aromatics, if possible with ftee phenolic oxygen functions in ortho or para positions (Scheme 9). As for the carbonyl compound, aldehydes or 1,2-dicarbonyls (and very recently 1,2,3-tricarbonyls - ) are preferred. Due to the mild physiological reaction conditions required with such ideally reactive partners (often pH = 7, room temperature, aqueous medium), this condensation was also found to play a role in human organisms, leading to endogenous mammalian alkaloids... 

In view of the multifold important biological activities of isoquinoline and P-carboline alkaloids, increasing efforts have been made to perform Pictet-Spengler reactions stereoselectively. The most obvious chiral auxiliary to induce asymmetric control is the stereogenic center of the corresponding aromatic amino acids, such as DOPA or tryptophan. 

Topics which have formed the subjects of reviews this year include theoretical studies of the photochemistry of thiiranes, photoaddition of amines to aryl olefins and arenes, the synthesis of heterocyclic compounds, photoamination directed towards the synthesis of heterocycles, selective addition of organic dichalcogenides to carbon-carbon unsaturated bonds, photocyclisation mechanisms of c/5-stilbene analogues, synthetic utility of the photocyclisation of aryl-and heteroarylpropenoic acids, photochromic diarylethenes, spiropyrans, cy-clophanes, and polycondensed aromatics," photochromic organic media, photophysics and photochemistry of P-carbolines, and the photochemical synthesis of macrocycles.Chirality switching by light has also been described. ... 

A collection of tetrahydro-P-carbolines has been prepared [401] by first attaching various tryptamines to Novabiochem s vinylsulfonytmethyl resin (560) by Michael addition involving the tryptamine amino groups. Subsequent reaction with various aromatic aldehydes in the presence of catalytic p-TSA in toluene at 80 °C afforded the desired tetrahydro-P-carboline derivatives (563) in excellent yields (Scheme 117). 

In the preparation of (3-carbolines such as 165, aromatization of ring C has proved much more difficult from the PS tetrahydro-p-carboline intermediate than the BN dihydro-P-carboline intermediate (129, 123). Coupling 165 with macrocycle 166 yielded an amide which was reduced to the tertiary amine, manzamine C. 

The tetrahydro-P-carbolines generally exhibit higher levels of biological activity than their fully aromatic relatives. Antiviral activity is especially evident in the tetrahydro-3-carbolines that have an oxathiazepine ring, speculated to have been derived from cysteine [125]. 

X OMe), a singlet at 8 5.23 (NMe), and a complex multiplet between 5 7.2 and 8.2 corresponding to six aromatic protons. Treatment with potassium hydroxide in refluxing amyl alcohol afforded 1,2,3,4-tetrahydro-l-keto-P-carboline and 6-methylaminoveratric acid. The structure of euxylophorine A was confirmed by condensation of l,2,3,4-tetrahydro-l-keto- 3-carboline with methyl 6-methylaminoveratrate (52). 

A catalytic as5mmetric Pictet-Spengler reaction has been developed. This process furnishes enantioenriched tetrahydro-P-carbolines (88) from various tryptamines and both aromatic and aliphatic aldehydes if treated with chiral Bronsted acid catalyst (89) (Scheme 25). ... 

In 2011, Nissen and Detert [9] reported a partially intramolecular [2+2+2] aromatization for the synthesis of lavendamycin (Scheme 9.4). Lavendamydn is an antitumor antibiotic produced by Straptomyces lavendulae. Both Rh and Ru catalyses were used for this [2+2+2] cycloaddition of a 1,6-diyne and an electron-deficient nitrile. What was interesting was the observation that the symmetrical adduct was always preferred with Rh catalysis, and when Ru catalysis was employed, only the desired unsymmetrical p-carboline product was obtained. The pentacyclic core of lavendamycin was then converted to lavendamydn methyl ester via a sequence of functional group manipulations. 

Reactions of sugars with amino acids, which have more reactive functional groups (such as sulfur, hydroxy, aromatic and heterocyclic amino acids), also bypass the Amadori rearrangement and the reaction gives rise to various heterocycHc compounds. For example, glucose yields a thiazolidine derivative, 2-(d-gluco-l,2,3,4,5-pentahydroxypentyl)thiazolidine-4-carboxyHc acid (4-213), with cysteine and a P-carboline derivative, 1,2,3,4-tetra hydro-1 - o-gluco-1,2,3,4,5-pentahydroxypentyl)-P-carboline (4-214), arises from tryptophan or tryptamine. 

---