Erythrinan synthesis

Reactions of 3- and 4-piperidone-derived enamines with a dienester gave intermediates which could be dehydrogenated to tetrahydroquinolines and tetrahydroisoquinolines (678). The methyl vinyl ketone annelation of pyrrolines was extended to an erythrinan synthesis (679). Perhydrophenan-threnones were obtained from 1-acetylcyclohexene and pyrrolidinocyclo-hexene (680) or alternatively from Birch reduction and cyclization of a 2-pyridyl ethyl ketone intermediate, which was formed by alkylation of an enamine with a 2-vinylpyridine (681). 

The necessary amine (XXXIX) was prepared from the acid dimerization product (XXXVIII) of acrolein. Condensation with XXVIIa using Mondon s erythrinane synthesis led to the lactam XL and thence to the amine XLI, which was resolved with dibenzoyltartaric acid. A compound of the same structure was prepared from jS-erythroidine via... 

In contrast, the erythrinane synthesis based on the above mentioned cycloadditions of 1,3-butadienes to pyrrole derivatives is fully applicable to that of the ring C-homologue alkaloids. Thus, the phenylhydroindol 100b prepared by [2 - - 2] cycloaddition according to Scheme 13 cyclizes to yield the 2,8-dioxohomoerythrinane 205, which then has been transformed via the 1,7-cyclointermediate 206 to 2,7-dihydrohomoerysotrine (207) (110) (Scheme 37). 

In the Erythrina series, the total synthesis of ( )-erysotramidine (10), an oxo-erythrinan alkaloid, isolated from Erythrina arborescens Roxb.,13 has been... 

Toda, J., Niimura, Y., Takeda, K., Sano, T., and Tsuda, Y. (1998) General method for synthesis of erythrinan and homo-erythrinan alkaloids (1) synthesis of a cycloerythrinan, as a key intermediate to erythrina alkaloids, by Pummerer-type reaction. Chemical e[ Pharmaceutical Bulletin, 46, 906-912, and literature cited therein. 

A detailed study of the Pummerer reaction of a series of A(-alkenyl-a-sulfinylacetamides has shown that, depending upon the number and position of methyl groups on the double bond, five- or six-mem-bered ring lactams are obtained. This reaction has been applied to a concise synthesis of the erythrinane... 

A completely different route devised by Prelog and co-workers (14) not only afforded a new synthesis of the erythrinane skeleton but also achieved a method of introducing an oxygen function at C-3, the site of the aliphatic methoxyl in the alkaloids. The synthesis is outlined in Fig. 5. The dihydroisoquinolinium salt XXXIV was prepared by Bischler-Napieralski ring closure of the lactam XXXIII. Hydrolysis of the vinyl chloride of XXXIV gave the methyl ketone XXXV. When this salt was made alkaline, addition of the carbanion from the acidic methyl to the C=N double bond created the spiro link. Sodium borohydride reduction of XXXVI gave a mixture of epimeric alcohols. One of them had an IR-spectrum identical with that of a transformation product (XXXVII) of erysonine (If) and on resolution w ith tartaric acid its (— )-enantiomer proved to be identical with XXXVII. 

Two minor by-products formed in the phosphoric acid catalyzed cyclization of LXI have different carbon skeletons than the main products. One is the hydroxylactam LXV, shown to arise by acid-catalyzed rearrangement of LXIII. In acid solution it exists as the colored imonium ion LXVI 33). The second by-product is LXVII. Its formation is explained by the generation of two different cations from LXII in acid, one leading to the erythrinane skeleton (LXIV), the other to the isomeric apo skeleton of LXVII. Bromination of LXI with X-bromosuccinimide afforded the bromo derivative VIII, whose cyclization led almost exclusively to the apo skeleton and a synthesis of apoerysopine (see Fig. 2). 

When these approaches proved unsuccessful, a total synthesis of erysotrine was finally achieved beginning with the oxalyl derivative (LIT) of 4-methoxycyclohexanone. The synthetic scheme has so far been reported only in preliminary communications 27, 36). The condensation with -(3,4-dimethoxyphenyl)-ethylamine leading to the tetracyclic erythrinane skeleton and the further conversion to LV have been discussed in Section III, C (Fig. 8) the remainder of the synthesis is outlined in Fig. 10. 

The heart of these biosynthetic proposals is the oxidation of LXXXVIII to XCI, and the plausibility of this conversion has received dramatic support in two laboratories. In vitro oxidation of LXXXVIII (Ri = R2 = CH3) with alkaline ferricyanide was found by both Scott and coworkers 40) and by Mondon and Ehrhardt 40a) to afford XCI (Ri = R2 = CH3) in 35% yield. Mondon and Ehrhardt were then able to convert XCI to ( + )-dihydroerysodine, using the reactions shown in Fig. 12. This synthesis incidentally confirms the substitution pattern in ring D of erysodine. The facile formation of the erythrinane skeleton in this manner supports the basic biogenetic scheme, and the results of incorporation experiments with isotopically labelled LXXXVIII and XCI will be awaited with great interest. 

The enol-lactam (30), which has occupied a central role in the synthesis of Erythrina alkaloids, has been converted in an unprecedented reaction into the dimeric isomers [31 C(6)-a-0] and [31 C(6)-/ -OJ.15 This reaction may be effected in benzene, pyridine, or acetic acid solution in the presence of lead tetra-acetate. The structures of the products were elucidated by spectral and chemical means. As enol ethers, these compounds were found to exhibit surprising stability to mineral acids. However, catalytic reduction of [31 C(6)-a-OJ under neutral conditions gave the starting enol-lactam (30) and the 7/Miydroxylactam (32 RJ = OH, R2 = R3 = H). The dimer [3 l C(6)-/i-0] yielded only compound (32 R1 = OH, R2 = R3 = H). Similarly, sodium borohydride reduction of the dimer mixture in hot isopropanol led to cleavage products (32 R1 = OH, R2 = R3 = H)and(32 RJ = R3 = H, R2 = OH). Besides the dimeric products, compound (32 R1 + R2 = O, R3 = OAc) was also isolated from the lead tetraacetate oxidation in low yields. Attempts to discover conditions for the formation of preparative amounts of (32 R1 + R2 = O, R3 = OAc), a compound of more potential usefulness for alkaloid synthesis, were fruitless. The other question of interest, whether or not the trans-dimer [31 C(6)-/i-0] could be converted into a monomeric trans-erythrinane system, remains to be answered. 

The greater electrophilicity of the A -acyliminium ion as compared with an ordinary iminium ion was nicely illustrated as early as 1957. In experiments directed at the total synthesis of erythrina alkaloids, cyclization of iminium ion (60) to the erythrinane skeleton (61) fails (equation 34). However, A(-acylim-inium ions (62) and (63) can both be converted into the desired skeleton in good yields. A recent il-... 

The present contribution will give a brief classification of the Erythrina alkaloids, a compilation of new alkaloids isolated from 1997 to 2004 covering source, structure, analytical/spectral data, a new pathway of their biosynthesis, an overview of all the synthesis strategies hitherto known for the erythrinane alkaloids including several approaches to the homoerythrinane group, and finally a short review of their biological activities. 

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