Paraherquamides synthesis

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. 

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. 

In 2002, Williams reviewed studies on total synthesis and biosynthesis of the paraherquamide family, with a focus on the biological Diels-Alder construction of the bicyclo[2,2,2]diazaoctane ring system [119]. 

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>. 

The ew-dimethyl 2,3-dihydro-5/f-l,4-benzodioxepin moiety occurs in several natmal products, for example, in the paraherquamides, which exhibit potent anthelmintic and antinematodal activity, and in the marcfortines (72 marcfortine B). In the course of the total synthesis of (+)-para-herquamide B (71), the synthesis of the benzodioxepin unit by phenylselenoetherification and by epoxidation followed by a Lewis add-mediated ring closure was explored, but the phenylselenoetherification only gave poor yields of (74). The dehydration of the secondary alcohol (77) was effected with methyltriphenoxyphosphonitun iodide (MTPI) in HMPA (Scheme 7) <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. 

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]. 

Applications of the Gassman oxindole synthesis in total synthesis are uncommon. Savall and McWhorter prepared a 6,7-dihydroxyindole derivative, part of the potent antihelmintic compound paraherquamide A, by using a chlorosulfonium ion (15) obtained from ethyl methylthioacetate and sulfuryl chloride.The intermediate oxindole 23 was obtained in 80% crude yield. The starting aniline was obtained in good yield from 2,3-dimethoxybenzoic acid via a modified Curtius rearrangement. Removal of the thiomethyl functionality with Raney nickel gave the final product in 62% yield. 

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... 

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]. 

Figure 10.48 Generation of an olefinic compound from an alcohol for the cleavage of a C-C bond for use in the reconstitution approach synthesis of 2-desoxo[V-methyl- H3] paraherquamide...

C H3MgI and reduction of the indol system afforded the anthelmintic drug substance 188 ([ H]PNU-141962, 2-desoxo[l -methyl- H3]paraherquamide), thereby reconstituting the skeleton of 184 in a slightly modified form. The synthesis depicted was designed as a pilot smdy for the preparation of the respective tritium and carbon-14-labeled isotopomers. It illustrates a more general C-dealkylation-realkylation approach that is otherwise difficult to accomplish (Section 10.1.2). ... 

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