Spermidine alkaloid synthesis

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 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]. 

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. 

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. 

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 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 ... 

Spermidin and spermin alkaloids, synthesis of 81KPS263, 81YGK1151. 

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... 

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. 

Overman and Tomasi applied the copper-catalyzed amidation of compound 658 (Scheme 3.262) in the key step of the enantioselective total synthesis of the natural tetracyclic spermidine alkaloid (-)-hispidospermidin [805],... 

Synthesis in the spermidine alkaloid field is well typified by a synthesis by a long-standing alkaloid chemist, Manfred Hesse, for the construction of JV(l)-acetyl-N-(l)-deoxymayfoline (66) (Scheme 3) (1992T3775). 

Scheiper, B. Glorius, E Leitner, A. Fiirstner, A. Catalysis-based enantioselective total synthesis of the macrocyclic spermidine alkaloid isooncinotin. Proc. Natl. Acad. Sci. 2004, 101, 11960-11965. 

Intramolecular amination with allylic acetates is used for the synthesis of cyclic alkaloids (Scheme This protocol can be applied to a synthesis of 21-membered cyclic amine skeleton of the spermidine alkaloid and l-azaspirocycles.f 3-Methylenepyrolidines are provided by the nucleophilic addition of allylzinc reagents to imines and subsequent Pd-catalyzed intramolecular allyIation.[" i... 

A high-yield synthesis of the macrocyclic spermidine alkaloids (97) involves the boron-template cyclization of the aminoborane intermediate (98), and... 

Macrocyclic polyazaheterocycles include the well known spermidine alkaloids, the synthesis of which has attracted a great deal of attention over the past few years. An efficient 6-step total synthesis " of the dihydroperiphylline system (218), which has recently been isolated from plant sources, has been reported. 

Hypusine (Ne-(4-amino-2-hydroxybutyl)lysine)242 occurs in mammalian initiation factor 4D, which is utilized in protein synthesis (Chapter 29) and is formed by transfer of the 4-carbon butylamine group from spermidine to a lysine side chain followed by hydroxylation 280 2823 The lupine alkaloid lupinine283 is formed from two C5 units of cadaverine which arises by decarboxylation of lysine. Silaffins (pp. 178, 1381) also contain modified lysines. 

Maytenine (C25H3102N3 mp 158°) was shown by exhaustive spectral methods to be di-trans cinnamoylspermidine (129) (108). It is evidently not related to the tumor-active alkaloids which have been isolated from M. ovatus (109, 110). A synthesis of HN[(CH2)4NH CO CH Ph]2> which was stated to be maytenine, was achieved by treating spermidine with 1-cinnamoyloxypiperidine (111). 

Figure 9.2. Metabolism of pyrrolizidine alkaloids (PAs) in Senecio vernalis. The substrates for alkaloid biosynthesis, putrescine and spermidine, are derived from primary metabolism. Homospermidine, synthesized by homospermidine synthase (HSS), is the first pathway specific intermediate. It is exclusively incorporated into the necine base moiety of senecionine A-oxide, the backbone structure of all PAs found in this Senecio species. During allocation from the roots as site of synthesis to the shoots, it is chemically modified to provide the species specific PA-pattem.

A total synthesis of codonocarpine (104), similar to the synthesis of the Lunaria alkaloids lunarine and lunaridine (see Scheme 15), has been published (98). The activated dicarboxylic acid thiazolidine-2-thione diamide (113) was treated with spermidine itself. Because of the two possible reaction modes, 104 and the previously unknown isomer with the reversed incorporation of the spermidine moiety were isolated from the reaction products. 

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