Polycyclic amine alkaloids synthesis

Polycyclic amine alkaloids (3-alkylpiperidine alkaloids) containing a complex skeleton with several macrocyclic rings have been isolated from marine sponges. They include manzamines, sarains, haliclamine A and ingenamines. Their structures, synthesis and biochemical aspects have been recently reviewed [35]. Our focus, therefore, is on the biogenetic origin of the bis-pyridinium macrocycle and on the role of precursors in their biosynthesis, as summarized in the retrosynthetic analysis for manzamines demonstrated schematically in Fig.(23). 

POLYCYCLIC AMINE ALKALOIDS (3-ALKYLPIPERIDBVE ALKALOIDS) - NOVEL MARINE BIOACTIVE COMPOUNDS STRUCTURE, SYNTHESIS AND BIOCHEMICAL ASPECTS... 

Rodriguez, J. (2000) Polycyclic amine alkaloids (3-alkylpiperidine alkaloids) novel marine bioactive compounds structures, synthesis and biochemical aspects, in Studies in Natural Products Chemistry, vol. 24 (ed. Atta-ur-Rahman), Elsevier, pp. 573—681. 

Primary and secondary amines also react with epoxides (or in situ produced episulfides )r aziridines)to /J-hydroxyamines (or /J-mercaptoamines or 1,2-diamines). The Michael type iddition of amines to activated C—C double bonds is also a useful synthetic reaction. Rnally unines react readily with. carbonyl compounds to form imines and enamines and with carbo-tylic acid chlorides or esters to give amides which can be reduced to amines with LiAlH (p. Ilf.). All these reactions are often applied in synthesis to produce polycyclic alkaloids with itrogen bridgeheads (J.W. Huffman, 1967) G. Stork, 1963 S.S. Klioze, 1975). 

The 1980s witnessed a revival of interest in synthetic photochemistry, largely based on the successful application of intramolecular arene-olefin and enone-olefin photochemical cycloaddition reactions to the synthesis of polycyclic natural and unnatural products. The potential application of intramolecular arene-amine addition to the synthesis of alkaloids was suggested in 1973 by Btyce-Smith et al.," based on their observation of intramolecular photochemical 1,4-addition reaction of the (N,A/-dimethylaminoalkyl)benzenes I and 2 to yield 3 and 4, respectively. Intramolecular addition reactions have subsequently been observed for a large number of (aminoal-... 

Alkaloids with polycyclic skdetal frameworks are, when it comes to their synthesis, excellent candidates for RCM. Illustrative are the indolizidines rhynchophylline (43) and its C(7)-epimer ixo-rhynchophylhne (44), both isolated from the plant Uncaria rhynchophytta (Rubiaceae) [26]. Deiters total synthesis of 43 and 44 started with the efficient construction of diallylamine 39 via amide formation between indole-3-acetic acid (38) and diallylamine (Scheme 2.10). One-pot RCM-carbomagnesation of 39 was smoothly achieved with only 1 mol% of [Ruj-I catalyst and 4 equiv. of EtMgCl to afford the 2-ethyl-3-butene-amine derivative in 71% yield. It appeared that the electron-withdrawing carbonyl moiety was critical to the success of the RCM-carbomagnesation steps. Amide reduction and subsequent treatment with acryloyl chloride dehvered the second metathesis precursor 40. Cyclization with [Ruj-I (5 mol%) then furnished the a,j8-unsaturated lactam 41 in a high yield of 91%. Continuation of the total synthesis of alkaloids 43 and 44 included a Bischler-Napieralski cychzation (42) and subsequent rearrangement into the oxindole framework. 

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