Bioactive indole alkaloid

ACID-CATALYSED EPIMERIZATION OF BIOACTIVE INDOLE ALKALOIDS AND THEIR DERIVATIVES... 

ABSTRACT The acid-catalysed epimerization reaction of bioactive indole alkaloids and their derivatives is reviewed. The three mechanisms, which have been proposed for the (J-carboline-type indole alkaloids, are discussed. Through recent developments, evidence for all three mechanisms has been obtained, which shows the complexity of the epimerization reaction. The epimerization seems to depend on structural features and reaction conditions making it difficult to define one universal mechanism. On the other hand, the isomerization mechanism of oxindole alkaloids has been widely accepted. The acid-catalysed epimerization reaction provides a powerful tool in selectively manipulating the stereochemistry at the epimeric centre and it can also have a marked effect on the pharmacology of any epimerizable compound. Therefore, examples of this reaction in die total synthesis of indole alkaloids are given and pharmacological activities of some C-3 epimeric diastereomers are compared. Finally, literature examples of acid-catalysed epimerization reactions are presented. 

Synthesis of Bioactive Indole Alkaloids and Their Derivatives by Utilizing the Acid-Catalysed Epimerization Reaction... 

The enantioselective total synthesis of the complex bioactive indole alkaloid enf-WIN 64821 was accomplished by L.E. Overman and co-workers." This natural product is a representative member of the family of the C2-symmetric bispyrrolidinoindoline diketopiperazine alkaloids. The stereospecific incorporation of two C-N bonds was achieved using the Mitsunobu reaction to convert two secondary alcohol functionalities to the corresponding alkyl azides with inversion of configuration. The azides subsequently were reduced to the primary amines and cyclized to the desired ib/s-amidine functionality. 

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. 

In their efforts towards the total synthesis of bioactive indole alkaloids, Kerr examined the Yb(OTf)3-catalyzed addition of indoles to Michael acceptors [42]. Scheme 10.13 shows some examples of reactions involving enones and activated... 

Chen M, Shao CL, Fu XM, Xu RF, Zheng JJ, Zhao DL, et al. Bioactive indole alkaloids and phenyl ether derivatives from a marine-derived Aspergillus sp. fungus. J Nat Prod 2013 76(4) 547-53. 

Lee KK, Zhou B, Kingston DG, Vaisberg AJ, Hammond GB (1999) Bioactive indole alkaloids from the bark of Uncaria guianensis. Planta Med 65 759-760. doi 10.1055/ s-2006-960860... 

Environmental and ontogenetic control of accumulation of brachycerine, a bioactive indole alkaloid from Psychotria brachyceras. J Chem Ecol 30 2023-2036. doi 10.1023/B JOEC.0000045592.24785.33... 

Apart from these four bioactive indole alkaloids, Psilocybe mushrooms are capable of producing a number of indole derivatives (Table 18.4). Psilocybin has the molecular formula C12H17N2O4P (mol. weight = 284.27). It is a prodmg that is... 

Spirotryprostatin A 142 and B 143 are two powerfully bioactive indole alkaloids. Both compounds inhibit the cell cycle in the G2/M phase, and 143 shows cytotoxic activity on the growth of human leukemia cell lines. Meyers and Carreira reported a total synthesis of 143. The Kocienski modified Julia olefmation was used in the formation of trisubstituted olefin without scrambling at Ci8. The alkene 146 was prepared in 78% yield by reacting sulfone 145 with aldehyde 144. The final product 143 was obtained by four-step reaction from the intermediate 146. 

Asyimnetric catalytic method to generate C-C bond with adjacent quatemaiy-tertiary stereocenters ranains a challenging synthetic task. In this regard, the use of 3-substituted oxindoles as carbon-nucleophiles has attracted intensive interests due to their relevance in synthesizing bioactive indole alkaloids. Melchiorre recently reported asymmetric Michael addition of 3-substituted oxindoles to a,P-unsaturated aldehydes catalyzed by a primary amine thiourea catalyst 114 (Scheme 5.29). Good diasteieoselectivity and enantioselectivity have been achieved in most cases. However, the reactions were generally sluggish [56]. 

The formation of the indole moiety has found immense attention, since it exists in many bioactive compounds such as the indole alkaloids [302]. Whilst the Fischer indole synthesis remains the most important procedure, during the past few years several transition metal-catalyzed syntheses have been developed. Recently, a Cu11-catalyzed cyclization of anilines containing an ortho-alkynyl group was published by Hiroya and coworkers [303], which allows a double cyclization in domino fashion to provide annulated indoles. Thus, reaction of 6/4-92 in the presence of... 

Shoeb, M., Celik, S., Jaspars, M., Kumarasamy, Y., MacManus, S. M., Nahar, L., Thoo-Lin, P. K. and Sarker, S. D. 2005. Isolation, structure elucidation and bioactivity of schischkinin, a unique indole alkaloid from the seeds of Centaurea schis-chkinii. Tetrahedron, 61 9001-9006. 

Hirsutin 108, which belongs to the corynanthe subgroup of the indole alkaloids, was isolated from the plant Uncaria rhynchophylla MIQ and used for the preparation of the old Chinese folk medicine Kampo [32], It is of pharmacological interest since it shows a strong inhibitory effect on the influenza A virus (subtype H3N2) with an EC50 of 0.40-0.57 pg ml-1, which corresponds to a 11-20 higher bioactivity of hirsutin 108 compared to clinically used Ribavirin [33]. 

There are, however, a few examples in which the exclusive participation of peroxidase in the synthesis of natural bioactive alkaloids has been reported. These mainly concern the biosynthesis of some monoterpenoid indole alkaloids, especially the synthesis of a-3 ,4 -anhydrovinblastine (XLVII) [76],... 

Haplophytine (183), (Fig. 8), a polycyclic indole alkaloid, was first isolated by Snyder and coworkers in 1952, and identified as the principle bioactive component of the wild Mexican flower Haplophyton cimicidum A.D.C. (Apocynaceae) [72-77]. Haplophytine is of comparable toxicity to several widely used insecticides, and it was found to be toxic to a wide range of insects including European com borers, Mexican bean beetle larvae, Colorado potato beetle larvae and adults, grasshoppers, egg-plant lace bugs, and codling moths [75]. 

Simple indole alkaloids The a for structural development of serotonin (a simple indole alkaloid) is L-tryptophan, and the p is 5-hydroxy-L-tryptophan (Figure 2.44). Serotonin is a monoamine. It is a bioactive... 

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