Of paraherquamides

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

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]. 

Although mechanistically ambiguous, Williams and co-workers, synthesis of (+)-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 PdCI2, which potentially generated a 2-palladated intermediate [29]. Intramolecular insertion of the disubstituted alkene and reduction of the resulting neopentyl (7-alkylpalladium intermediate with sodium borohydride provided 78 in 63-80% yield. 

Scheme 39 Biosynthetic origin of paraherquamide A (199) with /ert-prenyl migration according to Williams and co-workers [164]...

Prenyl rearrangement. Efficient total syntheses of 3-ferf-prenylated indole alkaloids employ prenyl shifts fi om C2, which can be considered biomimetic, since it was shown by Williams that the biosynthesis of paraherquamide A (199) from Penicillium sp. proceeds via tert-prenyl shift fi om C2 to C3 starting from precursors like 198 (Scheme 39) [2, 165], in agreement with earlier proposals by Barrow [166] and by Gorst-Allman [167] for the biosynthesis of roquefortine. 

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 origin of the )8-methylproline moiety present in paraherquamide A and several congeners has recently been investigated. Examination of the absolute stereochemistry of paraherquamide A, which possesses the (S)-absolute stereochemistry at C-14, led Williams et al. to speculate that the methylated proline may be derived from L-isoleucine as opposed to proline and S-adenosylmethio-nine (SAM) and this possibility was experimentally tested in Penicillium felluta-num (ATCC 20841) as shown in Fig. 5 [39]. The position of incorporation in paraherquamide A was determined using NMR and the percentage of the labeled amino acid incorporated was also determined using NMR. 

Fig. 5. Biosynthetic derivation of the )S-methyl proline moiety of paraherquamide A [39]...

Since L-isoleucine forms the )S-methylproline ring of paraherquamide A, cydo-L-Trp-L-j8-methylproline or cydo-L-Trp-L-Ile are plausible precursors. There are numerous possible sequences of events that might occur in the formation of the final )3-methylproline ring system. Formation of the dipeptides NH2-L-Ile-L-Trp-COOH or NH2-L-Trp-L-Ile-COOH and dehydration to cyclo-L-Trp-L-Ile followed by oxidation of the terminal carbon of L-Ile and cyclization to form the )3-methylproline moiety would result in cydo-L-Trp-L-)9-methylproline. Another possibility involves oxidation of the L-Ile followed by cyclization and reduction to afford )5-methylproline followed by coupling to L-Trp to give cyclo-L-Trp-L-j8-methylproline. Many other possibilities exist that would involve formation of the jS-methylproline ring at a later stage. 

Scheme 20. A possible biosynthetic sequence that may explain why C22 and C23 are rendered equivalent in the biosynthesis of paraherquamide A. Thick bonds with the black square represent one intact C2 unit from acetate, incorporated in C3/C5 of individual DMAPP molecules, and in C21, C22, and C23 of paraherquamide A...

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

C-H alkylation strategy (Scheme 16.3a) [9]. Treatment of indole 16 with Pd(II) according to Trost s C-H alkylation procedure for the syntheses of ibogamine and catharanthine (see Scheme 16.3b) [10] afforded the corresponding heptacyclic compound. After several steps from 18, the synthesis of (+)-paraherquamide B was accomplished. Williams and coworkers also achieved a concise, asymmetric, stereocontrolled total synthesis of stephacidins A and B and notoamide B in 2007 [11]. Additionally, in 2002 and 2003, Corey s group employed an intramolecular C-H alkylation as a key step for the total synthesis of okaramine N, austamide, hydratoaustamide, and deoxyisoaustamide (Scheme 16.3b) [12]. 

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