Total synthesis of paraherquamide

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. 

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). 

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]. 

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]. 

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. 

---