Carbolines and Related Alkaloids

Most j8-carboline-type alkaloids known today were isolated from plants, e.g., Apocynaceae, Loganiaceae and Rubiaceae. More than 1200 representatives of this group are known today. A few tetrahydro- -carbolines have been found in mammalian tissues. 

The jS-carboline ring system is formed by means of a Mannicb condensation (D 9.5) with the participation of tryptamine. According to the carbonyl component involved two types of alkaloids may be distinguished  

Harman Alkaloids. Harman is formed in plants by the reaction of tryptamine with pyruvic acid on the pathway shown in Fig. 258. 1,2,3,4-Tetrahydro-jff-carboline was found in the urine of humans (E 1). It is probably formed from tryptamine and formaldehyde. 

Iridoid Indole Alkaloids. Most jS-carbolines are derived from tryptamine and the iridoid secologanin (D 6.1.2). In dependence on the structure of the iridoid part alkaloids of the Corynanthe-Strychnos type as well as of the Aspidosperma and Iboga types may be distinguished. The latter are formed by rearrangement of the iridoid part which is shown schematically in Fig. 259 and in detail in Fig. 261. 

A key intermediate in the biosynthesis of all iridoid indole alkaloids is the glu-coside strictosidine (isovincoside. Fig. 260). Strictosidine is transformed to aj-malicine, which is a precursor of stemmadenine, tabersonine, vindoline and catharanthine (Fig. 261). The dimeric alkaloids, like vinblastine (vincaleuco-blastine) and vincristine (Fig. 259) are derived from monomeric precursors, e.g. catharanthine and vindoline. 

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This review is an attempt to collect under one heading and to present in a systematic manner the large body of work which deals with the chemistry of the carboline ring systems. Some three hundred papers in this field have been published during the last decade, more than twice as many as appeared during the preceding fifty years. The renewed interest in the chemistry of the carbolines is due in no small measure to the discovery of serotonin and to the recent developments in the chemistry and pharmacology of the Rauwolfia and related alkaloids. 

Yang described the Pd-induced cyclization of an aryl bromide onto a pendant cyano group leading to y-carbolines and related compounds [488], Genet studied the use of chiral palladium complexes in the construction of the C-ring of ergot alkaloids, a study that culminated in a synthesis of (-)-chanoclavine I [489-491]. For example, nitroindole 388 is cyclized to 389 in 57% yield and with enantioselectivities of up to 95% using Pd(OAc)2 and (S)-(-)-BINAP. 

The carboline anhydro-bases are appreciably more basic than the parent oarbolines. Thus a pA value of 10.6 was reported for pyr-N-methyl-j8-carboline anhydro-base, for pyr-A-propyl-jS-carboline anhydro-base, and for pyr-A -methyl-l-methyl-jS-carboline anhydro-base a pKa value of 10.6 for sempervirine and values between 10.5 and 10.7 for serpentine, alstonine, and related alkaloids. A study of the relative basicities of simple a-, j8-, and y-oarboline anhydro-bases led to values of 7.75,11.11,11.20, and 10.54 for the... 

Coutts IGC, Hamblin MR, Tinley EJ (1979) The enzymatic oxidation of phenolic tetrahydroiso-quinoline-1-carboxylic acids. J Chem Soc Perkin Trans 1 2744-2750 Davis VE, Cashaw JL, McMurtrey KD, Ruchirawat S, Nimit Y (1982) Metabolism of tetrahydro-isoquinolines and related alkaloids. In Bloom F, Barchas J, Sandler M, Usdin E (eds) Beta-carbolines and tetrahydroisoquinolines. Liss, New York, p 99 Furuya T, Nakano M, Yoshikawa T (1978) Biotransformation of (RS)-reticuline and morphinan alkaloids by cell cultures of Papaver somniferum. Phytochemistry 17 891-893 Gates M (1953) Conversion of codeinone to codeine. J Am Chem Soc 75 4340-4341 Graves JMH, Smith WK (1967) Transformation of pregnenolone and progesterone by cultured plant cells. Nature (London) 214 124 8-1249... 

Carbolines. Harmine (8.40) and related carboline alkaloids are reversible MAO-A inhibitors, but are not used therapeutically. Deprenyl (8.41) is a selective MAO-B inhibitor and produces an increase in DA levels, but does not influence NE or 5-HT concentrations. It has been proposed as an antidepressant in aging males. 

Brevicolline.—The /3-carboline part of the plant alkaloid brevicolline (114) has been shown to derive from tryptophan (94) and pyruvic acid.37 Putrescine (4) and related compounds provide the pyrrolidine ring.38 A key intermediate in brevicolline biosynthesis is likely to be (113), derived by oxidative decarboxylation of (111), which in turn is formed through the condensation of (94) with pyruvic acid condensation of (113) and (112) (formed from putrescine) would lead to (114). This has been supported by successfully mimicking the biogenetic sequence, starting with the chemical oxidative decarboxylation of (111).39... 

Part 14. Indole and oxindole alkaloids related to -carboline and their derivatives... 

The motuporamines are considered as manzamine-related alkaloids owing to their structural relationship with manzamine C (57), the simplest alkaloid of this family of compounds. Baldwin and Whitehead have proposed a plausible biogenesis for these 3-alkylpiperidine alkaloids, suggesting that they could be formed from three basic building blocks ammonia, a C3 unit, and a Cio unit [54]. The motuporamines, which contain a spermidine-like side chain instead of the alkylated p-carboline substructure of manzamine C, appear to be biogenetically derived from the same precursors, ammonia, acrolein, and a long-chain dialdehyde involved in the Baldwin-Whitehead pathway (Scheme 9.2). 

Amongst the more complex brominated p-carboline alkaloids are the fascaply-sins and related metabolites from the tunicate Didemnum sp. and the sponge Pascaplysinopsis reticulata [50,51]. Several examples of each type are illustrated as 53-63. 

A variety of j5-carboline and tetrahydro-j3-carboline compounds have come to light recently which contain either a fourth ring, or four rings and a second nitrogen, or in some cases five rings and a second nitrogen these are clearly not related to the main body of monoterpene-tryptamine alkaloids. 

A successful simple appHcation of the quinazolinone aimelation is the short step synthesis of rutecarpine 16, an indolopyridoquinazoline alkaloid of Evodia rutaecarpa, from 2,3,4,9-tetrahydro-lH-j8-carbolin-l-one 80 via 2-azidobenzoyl derivative 81 (Scheme 18) [222]. Even after Kametani s practical iminoketene/amides condensation synthesis [227,228], many other synthetic routes to 16 and related systems utilizing Fischer indole synthesis [223-225] or cyclocondensation [65,226,229,230], etc. have been developed among these syntheses, above quinazolinone annelation route is one of the most facile and concise one. Recently very concise Pd-assisted biaryl coupling route to 16 as well as to luotonin A (26) and B (27) has been developed by Harayama et al. [231,232] (see Sect. 3.5). 

Carboline and Carbazole-Derived Alkaloids 7.8.1 Annomontine and Related Pyrimidine-fi-Carbolines... 

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