Rhazinilam synthesis coupling

An enantiospecific, gold-catalyzed pyrrole annelation reaction was utilized in a total synthesis of rhazinilam 95 <06JACS10352>. Specifically, treatment of allene 81 with gold triflate - triphenylphosphine led to the formation of annelated pyrrole 82, which was subsequently converted into 95. A gold-catalyzed direct coupling of pyrroles with 1,3-dicarbonyls led to the formation (3-(pyrrol-2-yl)enones <06ASC331>. 

Trauner applied a C-H bond activation approach to the synthesis of rhazinilam [81]. The synthetic power of direct C-H arylation on nucleophilic heteroarenes was demonstrated through formation of the strained 9-membered ring using intramolecular coupling to an unactivated pyrrole (Scheme 57). 

Conditions first described by Fagnou were used to affect the C-H to C-H bond cyclization, which proceeded in 47% yield. Mechanistically the direct coupling reaction is thought to proceed via intramolecular nucleophilic attack of the pyrrole moiety onto the Pd(II) centre. It was postulated that the electron rich DavePhos ligand facilitates both oxidative addition and forms a more reactive cationic Pd(II) species by dissociation of the halide. Following a deprotonation step, reductive elimination of Pd(0) then resulted in formation of the biaryl bond, completing the core framework. Application of this direct palladium-catalyzed biaryl coupling facilitates a very efficient and concise synthesis of rhazinilam as a racemate. 

Regjoselective C—H alkenylation of N-methyl-4-aryl-lH-pyrrole carboxylates (88) with alkenes—primarily acrylamides, acrylates and acrylonitrile—was observed by Lin, Yao, and coworkers to be dependent on the solvent used in the coupling (2014OL4884). As such, C-2 selectivity (89) was achieved when toluene was used as the solvent while inclusion of DMSO favored the C-5 product (87). The authors postulated that the carboxylate-assisted chelation of the palladium catalyst, which occurs readily in toluene, is overridden in the strongly coordinating solvent DMSO and results in an electrophibc C—H activation at the more electron-rich C-5 position. An apphcation of this work to the total synthesis of (it)-rhazinilam was also described in this account. 

Bowie AL, Hughes CC, Trauner D (2005) Concise Synthesis of (-1-/—)-Rhazinilam Through Direct Coupling. Org Lett 7 5207... 

Scheme 14.22 The DoM-Migita-Stille cross-coupling nexus in the synthesis of antimitotic rhazinilam 98 mimics [134].

One representative application of indole/pyrrole C-H arylation is the total synthesis of rhazinilam developed by Trauner (Scheme 17.15) [68a]. Treatment of 60 with conditions similar to those reported by Fagnou resulted in the formation of coupling product 61 in 47% yield. After several steps, the synthesis of rhazinilam was achieved. Trauner [68b] also synthesized rhazinal, a congener of rhazinilam, by this intramolecular C-H arylation method. 

Scheme 17.15 Total synthesis of rhazinilam via intramolecular C-H/C-X coupling.

In 2005, Trauner and coworkers reported the synthesis of rhazinilam using a palladium-catalyzed intramolecular C-H arylation of a pyrrole unit with an iodoarene (Scheme 16.12a) [24]. Treatment of compound 57 with a palladium catalyst resulted in the formation of coupling product 59 through intermediate 58. After removal of the MOM group and decarboxylation, the synthesis of... 

Synthesis by Direct Cross-Coupling Reaction Trauner and co-workers and Bowie and Trauner reported on a concise total synthesis of racemic rhazinilam 122 and rhazinal 123, axially chiral phenylpyrroles having potent antimitotic properties, through an aromatic C—H activation (Scheme 23.24). " To construct the lactam ring of the title compounds, the authors proposed the use of a palladium-catalyzed direct intramolecular cross-coupling reaction. 

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