Paraherquamide structures

In the course of isotopic labeling studies aimed at examining the origin of the isoprene units in the paraherquamide structure, Williams et al. discovered an unexpected stereochemical distribution of the geminal methyl groups derived from DMAPP [42]. These workers carried out feeding experiments in Penicillium... 

DFT calculations have been used to study the mechanistic pathway of the intramolecular Diels-Alder cycloaddition involved in the biosynthesis of natural products paraherquamide A and VM55599. The cycloaddition involves a dihydropyrolo[l,2- ]pyrazine as the azadiene and a standard alkene as the dienophile (Scheme 1). Analysis of the results reveals that these cycloadditions take place through concerted transition structures associated with [4+2]... 

Paraherquamide, a toxic metabolite of Penicillium paraherquei, has the structure... 

The structures of asperparalines A (123), B (124), and C (125) were determined to be spiro compounds made up of an A -methyl succinimide and a cyclopent[f]indolizine having an A methyl amide bridge. Another structural characteristic of asperparalines is a bicyclo[2,2,2]diazaoctane core, and various compounds, such as those of the paraherquamide family mentioned in the following section, contain the same core in their structures. However, all these compounds have an indole moiety in their structures so, it is of great interest that asperparalines have no indole part in their structures. 

Natural products with a ew-dimethyl benzodioxepin ring have been detected, for example, the antifungal natural product strobilurin (31) <90JAN661>, and several benzodioxepin derivatives, i.e., compounds (32) and (33), with a similar structural feature have been synthesized in the total synthesis of (-I-)-paraherquamide B <90TL6325, 96JA557>. 

Williams and coworkers [42] utilized a similar palladium(II)-mediated oxidative cyclization/w situ reduction protocol in the total synthesis of (+)-paraherquamide B (101, Scheme 9.14). Indole 99 was treated with 1.2 equiv of PdC and 2 equiv of AgBp4 to presumably form an alkylpalladium species, which was reduced with NaBH4 to ultimately provide 100 in good yield. This compound was further transformed to paraherquamide B in six steps. Williams et al. [43] later described the total synthesis of paraherquamide A utilizing the palladium(II)-mediated cyclization on a structurally similar compound. 

The structurally related alkaloid marcfortine, first described by Polonsky et al. in 1980 [35] is rendered from two isoprene units, tryptophan and pipecolic acid. The structures of the members of this family of mold metabolites are presented in Fig. 4. The paraherquamides differ with respect to substitution and oxygenation in the proline ring and the prenyiated oxindole ring paraherquamide B is the simplest member of the paraherquamide family, being comprised of the amino adds proline, tryptophan, and two isoprene units. 

These experiments clearly indicate that the C5 units in paraherquamide A are introduced in stereofacially distinct manners. Since it has been established that prenylation of the indole moiety in the biosynthesis of the structurally related brevianamides occurs in an analogous fashion to that postulated for paraherquamide A [19], the prenyl transferase that installs this C5 unit must display DMAPP to the 2-position of the indole in a n-facially indiscriminate manner. 

M. Yamazaki, E. Okuyama, M. Kobayashi, H. Inoue, The structure of paraherquamide, a toxic metabolite from PenicUlium paraherquei, Tetrahedron Lett. 22 (1981) 135-136. 

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