Spermidine alkaloid

Macroheterocyclization.1 s Pd(0) can catalyze macrocyclizations which form a C—N bond. This reaction was used in a synthesis of the spermidine alkaloid inandenine-12-one (1). 

This cyclization has been used for synthesis of four spermidine alkaloids, such as celacinnine (4). 

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... 

In the course of the structure elucidation of the natural occurring spermidine alkaloides such as inandeninone 11/108, (Scheme 11/15) the Schmidt reaction played an important role. The alkaloid is a nearly 1 1 mixture of two isomers, isolated from Oncinotis inandensis Wood et Evans. To make sure that the compounds differed only in the location of the carbonyl group at positions C(12) and C(13), the mixture was treated with sodium azide, sulfuric acid, and chloroform. The product consisted of a mixture of four ring enlarged dilactams (one of them, compound 11/109, is shown) with nearly equal ratios [84],... 

In 1968, the isolation of two new spermidine alkaloids, oncinotine (VI/1) and iso-oncinotine (VI/3), from the African plant Oncinotis nitida Benth. (Apo-cynaceae) was published Scheme VI/1 [1]. 

Scheme VI/1. The spermidine alkaloids oncinotine (VI/1), neo-oncinotine (VI/2), and iso-oncinotine VI/3). a) Base or acid or A...

Dihydroperiphylline (VI/55, Scheme VI/12), a spermidine alkaloid isolated from Peripterygia marginata (Baill.) Loes. [42] was synthesized by a /3-lactam-diazacyclooctane method [41] [43]. Thus, treatment of compound VI/52 with l-bromo-4-chlorobutane and transformation of the resulting chloro-derivative with liquid ammonia in a sealed tube gave VI/54. 

The synthesis of desoxoinandenine (VII/108) represents an application of this lactam formation process [55] [56], Scheme VII/21. Desoxoinandenine is a reduction product of the natural spermidine alkaloid inandeninone from Oncinotis inandensis Wood et Evans [57]. 

Another difficulty is the determination of the homogenity of the isolated alkaloids. To illustrate this two extreme examples are given. By different chromatographic methods and because of its spectral properties (NMR, IR, MS), the natural, approximate 1 1 mixture of the spermidine alkaloids inandenin-12-one and inandenin-13-one appeared to be a pure compound. This was supported by the sharp melting point of its hydrochloride (150- 151°C). Only after chemical degradation was the nature of the mixture determined by mass spectrometry. On the other hand, the behavior of the pure crystalline spermine alkaloid aphelandrine was that of a mixture. At least two criteria were in favor of a mixture. In the H-NMR spectrum... 

Three siderophores (microbial iron-transport agents) belong to the class of spermidine alkaloids agrobactine (32) from Agrobacterium tumefaciens... 

Other than several alkaloids of unknown structure, the spermidine alkaloid codonocarpine (104) and its /V-methyl derivative (105, alkaloid IV) were isolated from the bark of the Australian Codonocarpus australis (94). 

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. 

Walchli-Schaer and Eugster [84] applied this method to the synthesis of the spermidine alkaloid dihydropalustrine (148). Thus, as shown in Scheme 49, amino ester 147 was heated in imidazole at 120 °C for 2.5 h to achieve lactam closure. After detosylation 148 was obtained in low yield. 

Yamamoto and Maruoka [90] found that the complexation of triamino ester with tris(dimethylamino)borane is a highly efficient lactam closure method. Celacirmine (759) and other similar spermidine alkaloids were synthesized in this manner. As shown in Scheme 52, the cyclization of the linear precursor 155 was effected with tris(dimethylamino)borane in xylene xmder reflux to furnish the lactam 158 via the intermediates 156 and 157 in 90% yield. 

An acyl chloride was used in the synthesis of the spermidine alkaloid cannabisativine (162) by Natsume and coworkers [92]. As shown in Scheme 53, the precursor 160 was hydrolyzed with Ba(OH)2 and the resulting amino acid was directly converted to acyl chloride HCl salt, a cold solution of which was added dropwise to a potassium carbonate suspension in acetonitrile to achieve the lactam closure. Deprotection of the methoxymethyl groups with acid afforded macrolactam 161 in 43% yield from 160. 

In the synthesis of the spermidine alkaloid (+ )-dihydroperiphylline 271), Kibayashi and coworkers [164] employed intramolecular iminium cyclization to achieve the ring closure. As shown in Scheme 91, cleavage of the Boc group of aldehyde 269 resulted in in situ cyclization to the 13-membered ring via iminium formation and subsequent reduction by NaBH4 afforded 270 in 61% yield. 

Trost and Cossy [165] developed this method to construct the macrocyclic ring of the spermidine alkaloid inandenin-12-one (274). As shown in Scheme 92, subjection of amino ketone 272 to 10 mol% of (Ph3P)4Pd and 8 mol% of... 

Weinreb and coworkers [166] achieved the synthesis of the spermidine alkaloid anhydrocannabistivene (277) using alkylation of sulfonamide as a ring closure means. As shown in Scheme 93, the linear precursor 275 was treated with an excess of K2CO3 in refluxing CHjCN to afford the desired lactam 276in 58% yield. 

A l,4-diazepan-2-one system is also incorporated in the new spermidine alkaloid dovyalicin D isolated from Dovyalis macrocalyx <03OL2793>. A solid phase synthesis of peptidomimetics based on a 3,6-disubstituted-l,4-diazepan-2,5-dione skeleton has also been described <03JOC7893>. 

The participation of a 7,6-double bond in a six-membered carbocyclic ring poses no problem even if it leads to a spiroiminolactone intermediate. Palustrine (LXXII), a representative of the interesting class of spermidine alkaloids (Eugster, 1960) yielded a 7-lactone (LXXIV) (rm x 1770 cm ) with N-bromosuccinimide, probably via the intermediate spiroiminolactone (LXXIII) and hydrolysis (Eugster, 1961). A similar NBS-cleavage has been observed by Patchornik (personal communication) with peptides of phenylalanine after reduction with Li in CH3NH2. 

The enantioselective aldol-type reaction of benzhydrylimines using 28 has been applied as the key step in the total synthesis of the spermidine alkaloid (+)-dihydro-periphylline (54) [55]. 

Macrocyclic spermin and spermidin alkaloids, total synthesis of ... 

One of his special interests was the correlation of compounds by partial syntheses, including the determination of the absolute configuration of these natural products. During structural investigation of the spermidine alkaloid oncinotine, he observed a ring enlargement known as the Zip reaction. 

It is often easier to build a new molecule from more simple materials than to modify an available compound. Methods that allow the formation of polyamines from smaller moieties are of great interest. The formation of polyamines with ethyl, propyl, or butyl bridges between nitrogen atoms has developed in recent years. These types of compounds are important for the preparation of synthetic cyclams that are similar to natural spermine and spermidine alkaloids (Marecek and Burrows, 1986 Wasserman and Wu,... 

Synthesis of the spermidine alkaloid (-)-(4R)-dihydroisomyricoidine involves the intramolecular cyclization of an amino acid 66 in the presence of DEPC which leads to a 13-membered amino lactam 67,26... 

This section will also deal with Lunaria and spermidine alkaloids, since these are undoubtedly derived in part from amino-acids. 

Details concerning the structural elucidation of homaline (57) and the related alkaloids hopromine, hoprominol, and hopromalinol, isolated from Homalium pornyense, have been published. The related spermidine alkaloid periphyllene (58) has been recently isolated from the leaves of Peripterygia marginata. Its structure and absolute stereochemistry were determined by spectral and chemical-degradation studies. 

Maytenine, a pharmacologically active spermidine alkaloid from Maytenus chuchuhuasha (see Vol. 4 of these Reports), has been synthesized by two different routes.Details of the previously reviewed synthesis of ( )-tetrahydrolunari-dine (see Vol. 3 of these Reports) have been published. 

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