Michellamine

These related reactions have been utilized for total syntheses of natural products such as makaluvamine D (54), makaluvamine I (55), makaluvamine M (56), makaluvamine F (57), and michellamine A (58). Furthermore, synthetic studies on ellagitannin (59),benzo[c]phenanthridines (60), and rebeccamycin (61) have also been carried out. 

Recently, the anti-HIV alkaloids michellamines A (4) and B (5) have attracted much attention. The tetraaryl skeleton of the michellamines is constructed by first forming the inner (nonstereogenic) biaryl axis and then adding the two other (stereogenic) axes by means of a double Suzulci-type cross-coupling reaction between binaphthalene ditriflate (2) and iso-quinolineboronic acid (3) (Eq. (13)) [31]. 

Another total synthesis of michellamines A-C, korupensamines A-D, and ancistrobrevine B has been developed by Hoye et al. [32], who emphasized that Suzuki coupling of the boronic acid derived from the naphthalene moiety with a THIQ-iodide proved to be the most generally effective method for forming the hindered biaryl bond. A racemic isochromane analogue of michellamines has been synthesized by a similar procedure [33]. 

Cepheranthine and related bis-isoquinoline alkaloids (AA) michellamine B and related isoquinoline alkaloids (AA) chelerythrine and related benzophenanthridine alkaloids (AA) ellipticine and related indole alkaloids (AA)... 

The products from Step 1 were dissolved in 2 ml methyl alcohol containing a trace amount of 10% palladium on carbon and hydrogenated 3 days at ambient pressure. After removal of the solvent, the residue was dissolved in 5 ml methanolic HCl, refluxed 10 hours, and the products isolated as a Michellamine A and B mixture in 85% yield, mp = 175-177 °C. H-NMR data supplied. 

Other chemical modifications of michellamines extracted from Ancistrocladus novum are described (3). 

The dimeric stereoisomer alkaloids michellamines A, B and C (38) were obtained From the liane Ancistrocladus korupensis (Ancistrocladaceae). On the basis of their structural similarity to other PKC inhibitors, they have been studied for this activity. Michellamines inhibited rat brain PKC, with IC50 values in the 15-35 pM range. Michellamine B was a non-competitive PKC inhibitor with respect to ATP, whereas mixed-type inhibition was observed when the peptide concentration varied. The results indicate that the dimeric alkaloids bind to the PKC kinase domain and not to its regulatory domain. All three michellamines blocked both the ATP and the... 

Bringmann, G., Gulden, K. P., Busemann, S., Calculation of circular dichroism spectra of michellamines A and C, based on a complete conformational analysis. Tetrahedron 2003, 59, 1245-1253. 

Between 1987 and 1996, the NCI tested over 30 000 plant extracts in an in vitro cell-based anti-HIV screen (http //www.niaid.nih.gov), which determined the degree of HIV-1 replication in treated infected lymphoblastic cells versus that in treated uninfected control cells. Several natural products showed in vitro activity and michellamine B, the calanolides, and prostratin are discussed below. 

Michellamine B (67) is the main in vitro active anti-HIV constituent isolated from the leaves of the liana, Ancistrodadus korupensis, a new species collected in the Korup region of southwest Cameroon. It showed... 

G., and Boyd, M. R. (1997) Michellamines D-F, new HlV-inhibitory dimeric naphthylisoquinoline alkaloids, and korupensamine E, a new antimalarial monomer, from Ancistrocladus korupensis. J Nat Prod. 60, 677-683. 

The synthesis of michellamine A (6) from korupensamine A (198) commenced with the N-formylation of 198 with pivalic formic anhydride (Scheme 27). Subsequent treatment with acetyl chloride provided diacetate 210 where the chelated C-5 hydroxy group was not protected. Dimerization was then achieved under conditions described by Laatsch for simple naphthol dimerisation (ref. 88) which involved treatment of with Ag20 in chloroform in the presence of... 

NEt3- The resulting binaphylidendione 211 was then carefully reduced with sodium borohydride and deprotection was effected in a single step with methanolic HCl to provide michellamine A (6). 

SCHEME 27 Biomimetic synthesis of michellamine A (6) from kompensamine A (198). 

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