Paraherquamides

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]... 

The reactivity of compound 113 toward reactive linear and cyclic dienophiles was reported in a study directed to find a model systems for the proposed [4+2] cycloaddition in the biosynthesis of the natural products brevianamides, paraherquamides, and marcfortines. With DMAD and diethyl azodicarboxylate the formation of 114 and 115 was almost quantitative after 48 h at 80 °C (Cbz = Carbobenzyloxygroup). When relatively unreactive dienophiles such as cyclopentene and cyclohexene were used, harsh reaction conditions and/or a Lewis acid catalyst are necessary for the formation of 116a and 116b (Scheme 16). In contrast, the analogous intramolecular reaction carried out on compound 117 takes place within a few hours at room temperature, even in the absence of a Lewis acid catalyst, to give 118 in 42% yield (Scheme 16) <2000T6345>. 

Compound 331 was prepared using the free amino acid derived by coupling the product between proline and a substituted tryptophan. It was employed for studies on the biosynthesis of the anthelmintic agent paraherquamide <2001T5303>. Compound 332 was obtained by TFA-mediated reaction from the corresponding NH-/-Bu dipeptide... 

Cox RJ, Williams RM, The paraherquamides, brevianamides and asperparaline Laboratory synthesis and biosynthesis. An interim report, Acc Chem Res 36 127-139,2003. 

SYNTHESIS AND MODIFICATION OF MARCFORTINE AND PARAHERQUAMIDE CLASS OF ANTHELMINTICS... 

Williams and his coworkers have previously described as symmetric synthesis of the simplest paraherquamide derivative, PHB from (5)-proline. In approaching the synthesis of PHA which contains the unusal -hydroxy-P-methylproline residue, a new method needed to be developed to generate a suitably functionalized oc-alkyl-P-hydroxyproline moiety that could be conscripted for a multistep construction of PHA. 

CONVERSION OF MFA TO PARAHERQUAMIDES VIA A NOVEL PLATINUM-OXYGEN-MEDIATED RING CONTRACTING REACTION [33]... 

We are grateful to Professor Yamazaki at Chiba University for furnishing a sample of natural paraherquamide A. 

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

The Gassman synthesis has been utilized for preparation of a 6,7-dihydroxyoxindole unit of the natural product paraherquamide A via the key intermediate product 62 (Scheme 36) <1996JOC8696, CHEC-III(3.03.6)312>. 

Although mechanistically ambiguous, Williams and co-workers, synthesis of (-p)-paraherquamide B (79) could exemplify an alternative strategy for initiating a Heck cyclization (Scheme 6-13) [281. In this case, indole 77 was exposed to a stoichiometric amount of PdCl2, which potentially generated a 2-palladated intermediate [29]. Intramolecular insertion of the disubstituted alkene and reduction of the resulting neopentyl cr-alkylpalladium intermediate with sodium borohydride provided 78 in 63-80% yield. 

Synthesis and biosynthesis of paraherquamides, brevianamides, and asperpar-alines, bicyclo[2.2.2]diazaoctane derivatives 03ACR127. 

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