Spermidine amide

Traditional alkaloids have not been found, but spermidine amides have been isolated from the pollen of Myrica gale. In the tests reported here, Myrica asplenifolia gave a positive lest the following did not Comptonia peregrina, Myrica burmannii, M. califomica, M. cerifera, M. conifera, M. cordifolia, M. inodora, M. mexicana, M. oblongata, M. pilulifera, M. rubra, M. serrata, M. tomentosa. 

Having established the spermidine amide 38, the wrong stereochemistry at C14 had to be corrected. After three cycles of partial epimerization... 

A hydroxycinnamic acid-spermidine amide has been isolated from the drug Crataegi flos, which is raw material prepared from the flowers of a Crataegus subspecies and is reported to have cardiotoxic properties. Chemical and spectroscopic methods have indicated that this amide is iV, A, A -tri-4-( )-coumaroylspermidine (87). Also, the occurrence of this amide in flowers of various members of the Rosaceae has been investigated... 

The (S)-/ -Phe or (S)-/ -Tyr substructures of several spermidine alkaloids from plants, for example (S)-periphylline 43 [100, 101] or the spermine derivatives (S)-verbascenine 51 [101], aphelandrine 52 [102], chaenorhine 56 [103] and chae-norpine [104], hint at Michael addition of the biogenic amine to cinnamic acid 48 (or some oxidized equivalent, e.g. 49) within the /7-amino amide-forming step... 

N1,N4,N7,Nl0,Nl3-Penta-p-coumaroyl-spermidine (coumaroyl amide) Semi-synthetic - cf. N, N5,N10-Tri-p-coumaroylspermidinc HIV-1 protease (33 pM) [50]... 

Spermidines substituted with cinnamic acid derivatives seem to be widely distributed in the plant kingdom. Cinnamic acid (alkaloid maytenine), caffeic acid (caffeoylspermidine, dicaffeoylspermidine), 4-coumaric acid (coumaroylspermidine, dicoumaroylspermidine, tricoumaroylspermidine), ferulic acid (feruloylspermidine, diferuloylspermidine), and sinapic acid (sinapoylspermidine, disinapoylspermidine) are known as aromatic amide substituents of spermidine. Occurrence, structure elucidation, and syntheses are summarized in Section V. 

Two cytotoxic spermidine derivatives were isolated as a mixture from the Pacific soft coral Sinularia brongersmai 5,12-dimethyl-1-dimethylamino-5,9-diazaheneicos-l l-en-10-one (35) and its 11,12-dihydroderivative 36 (ratio 9 1). By hydrogenation of the mixture, a single compound was obtained that corresponded by GC/MS analysis to the minor component of the original mixture. Hydrolysis followed by esterification of the hydrogenated product 36 afforded methyl 3-methyldodecanoate and N,N,N-tri-methylspermidine. The results of a Hofmann degradation of 36 confirmed the conclusion on mass spectral evidence that the primary amide nitrogen is bonded to the trimethylene chain of the unsymmetrical spermidine molecule (61). 

The combination of spermidine, as the basic component, and two cinnamic acid units to form an amide is realized in some alkaloids isolated from Lunaria biennis. Structure 91 was determined by X-ray crystallography for the main alkaloid lunarine (84-86). 

Scheme 15. Protection of the ketone and transformation of the methyl esters to the activated amides in 102 yielded 103. The condensation reaction between the two primary amino groups of spermidine and 103 was achieved by using high-dilution techniques. The incorporation of the unsymmetric spermidine took place in both ways so that a nearly 1 1 mixture of ( )-lun-arine (91) and ( )-lunaridine (96) was formed.

The spermidine alkaloids of the Celacinnine group contain a 13-mem-bered ring that is built up from spermidine and one cinnamic acid residue in such a way that the primary amino group of the 1,3-diaminopropane part forms the amide linkage, and the primary amine of the 1,4-diaminobutane part of spermidine is in a benzylic position. 

Two syntheses of pseudoceratidine (120), which was reported to inhibit metamorphosis of the barnacle Balanus amphitrite, have been described [146,147]. To delineate the structural requirements for this bioactivity, the corresponding N-1 and N-8 mono-(4,5-dibromo-2-pyrrolyl) amides of spermidine were also synthesized, as well as the closely related mono- and bis-(4,5-dibromo-2-pyrrolecarboxamido) residues to test the importance of the pyrrole substituents and the positively charged secondary amine group in 120 [148]. 

In a very recent total synthesis of parabactin911, N1,N8-(2,3-dimethoxybenzoyl)-spermidine was combined with N-protected L-threonine via the N-hydroxysuccinimide ester to form the N4-amide 2 (see Fig. 6). Subsequently the amine protecting carbo-... 

Another proposition envisages involvement of one molecule of cinnamic acid, a molecule each of benzoylacetic acid and an appropriately substituted spermidine rather than spermidine itself. Elimination of the spermidine substituent (possibly involving the aziridinium ion) is followed by an attack from the carbanion derived from benzoylacetic acid with the formation of a new C-C bond. The other reactions involved in the biogenesis are of well-established nature viz, Michael addition, carbonyl reduction and amide formation. The carbonyl reduction step (and possibly even the cyclization to the y -lactam) necessarily follows the C-C bond formation and the generation of the other C-N bonds may either precede or succeed the above step (Scheme 10). 

In this chapter we describe cyclopeptide alkaloids, spermine and spermidine alkaloids, long-chain acid amides, and the cyclic oligopeptides isolated from higher plants since 1985. 

Of three hydroxycinnamic amides isolated from lochroma cyaneum (Solanaceae), only one was new, namely N, N -di-dihydrocaffeoyl-spermidine (88) (78). 

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