Ircinal

Scheme 25 Sequential formation of 13- and 8-membered azacycles in Martin s total synthesis of ircinal A (129) and related manzamine alkaloids [78]...

For a total synthesis of ircinal A and related manzamine alkaloids via RCM, see Scheme 25... 

Diels-Alder reaction of the dihydropyridinones V approach to the Ircinal B core [142] OMe... 

Diels-Alder reaction of the dihydropyridinones. V Approach to the ircinal B core [78]... 

Hvdroxo-aquo-diethvlenediamino-chromic Salts, [Cr en2(H20) (OH)JR2. —These salts exist in two isomeric forms, the cis- or 1-, 2-series, and the ircins-, or 1-, 6-series, thus ... 

Microbial bioconversion studies of manzamine A and ent-8-hydroxymanzamine A have shown that they can be metabolized by several microbial species.76 Preparative-scale fermentation of manzamine A with Fusarium oxysporium f. gladioli ATCC 11137 resulted in the isolation of the known ircinal A (61) as a major metabolite. Preparative-scale fermentation of enf-8-hydroxymanzamine A with Nocardia sp. ATCC 11925 and Fusarium oxysporium ATCC 7601 resulted in the isolation of the new major metabolite 12,34-oxamanzamine F (62). The latter metabolite showed no cytotoxicity against different cell lines (>10 pg/ml). 

There are to date only two reports on total synthesis of manzamine A. The first total synthesis of manzamine A was reported in 1998 by Winkler et al., along with those of manzamine D, ircinal A, and ircinol A [63]. The second total synthesis was reported a year later by Martin et al. [64] using a different approach from Winkler s. 

Pandit et al. reported in 1996 the first synthesis of the pentacyclic core reminiscent of the ircinal and ircinol structures [86,87]. The tricyclic key intermediate 216 was prepared by intramolecular Diels-Alder reaction of 214, which was in turn prepared from L-serine 210 in 10 steps (Scheme 8.14) [77,88-93]. The second phase of the synthesis involved the construction of the 8- and 13-membered rings, which was realized by sequential RCM on compounds 220 and 224 employing Grubb s catalyst, which therefore completed the first construction of the ABCDE pentacyclic core (Scheme 8.15). The application of the RCM methodology has been... 

Manzamine A was able to block the cytosolic calcium increase induced by KCl depolarization on human neuroblastoma SH-SY5Y cells. The maximum effect was observed at 1.0 jxM, inhibiting by 31.5%. 8-Hydroxymanzamine A also showed a similar effect whereas manzamines E, F, and Y, ircinal A and weo-kauluamine did not show any significant effect [44]. In the B lymphocytes reaction assay hyrtiomanza-mine showed immunosuppressive activity with an EC50 of 2.0 xg/mL, but no activity was displayed against the KB human epidermoid carcinoma cell line [53]. 

The enantioselective total synthesis of the manzamine alkaloid ircinal A was completed in the laboratory of S.F. Martin utilizing a novel strategy. A domino Stille/Diels-Alder reaction was used to assemble the ABC ring core of the natural product. The vinyl bromide intermediate reacted with vinyl tributylstannane in the presence of Pd to afford the 1,3-diene moiety, which cyclized via an intramolecular Diels-Alder reaction to give the ABC core. 

S.F. Martin and co-workers utilized a double Swern oxidation in their synthesis of ircinal A and related manzamine alkaloids. The advanced tricyclic did intermediate was first subjected to the Swern oxidation conditions at -78 °C to afford the corresponding dialdehyde in excellent yield. In the next step, the dialdehyde was exposed to excess Wittig reagent under salt-free conditions to form the two terminal alkenes. 

Gallium can interfere with the structural integrity of transferrin, the ircin-binding protein that transports iron in the serum. Gallium is believed to bind in the protein methionine. In microorganisms like Escherichia coli, gallium suppresses the synthesis of low-molecular weight polypeptides. It also concentrates on the surface of the cell envelope. 

The enantioselective syntheses of ircinol A (38) and the related manzamine alkaloids ircinal A and manzamine A were accomplished by Martin (Scheme 5.4.9). The concise synthesis of ircinol A (38) highlights the strategy for assembling the tricyclic ABC ring core via a domino Stille coupling/Diels-Alder reaction. 

The very complex natural product ircinal A Z-196 has difficult Z-alkenes in the eight-membered ring and in the frill round the molecule s waist. Both have been inserted by metathesis with good Z-selectivity.42 The starting material 193 has three alkenes but only two metathesise to give the 13-membered cyclic frill 194. The final metathesis to close the eight-membered ring is obviously difficult and the yield is poor. 

The Baldwin and Whitehead proposal [58] went on to suggest that the initial [4 + 2] adduct 119 can undergo redox exchange to give the pentacyclic intermediate 122 shown in Figure 3.6. Hydrolysis of the iminium ion functionality in 122 leads to a tetracyclic seco-skeleton containing an aldehyde functionality. The skeleton and aldehyde functionality present in the Baldwin and Whitehead tetracyclic intermediate 123 correspond exactly with the skeleton and aldehyde functional group placement in ircinals A (102) and B (103). Finally,... 

---