Natural paraherquamide

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

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>. 

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>. 

This is an indole alkaloid isolated from Penicilliutn paraherquei [31]. A number of naturally occuring and semi-synthetic analogues (17b-d and 18a, b) of paraherquamide possess marked anthelminitic activity [32,33]. 

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>. 

Lion and colleagues prepared 5,6,7-trimethoxyindole for a molecular mimic of combretastatin [30], and indole 21 became the indole unit in rapalexin B in a synthesis of this cruciferous phytoalexin by Pedras and colleagues [31], Indole 22 was needed for a biosynthetic study of the paraherquamide natural products [32], and Corey s team employed 6,7-dimethoxyindole (16) (71%) in their synthesis of aspidophytine [33]. 

Finally, Zeeck et al. isolated the interesting substances aspergamide A and B from Aspergillus ochraceus [36]. These metabolites, including VM55599, are the only natural members of the paraherquamide family that do not have a spiro-ring system but instead a 2,3-disubstituted indole-derived system. 

Although a stoichiometric palladium complex was often required, palladium-catalyzed C-H alkylation of indole at the C2 position was used in syntheses of complex natural products decades ago. For example, in 1993, the total synthesis of (-l-)-paraherquamide B was reported by Williams and coworkers using a reductive... 

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