Abstract
In the past decade, metal catalyzed or promoted C-H bond activation appears as an attractive alternative to classical cross-coupling reaction. Although the studies of this methodology have grown considerably, applications in total synthesis of natural products remain rare. This short review will focus on the use of the metal catalyzed or promoted C-H bond functionalization for the total synthesis of rhazinilam and congeners and demonstrate the usefulness and the efficiency of this approach.
Highlights
In the past decade, metal catalyzed or promoted C-H bond activation appears as an attractive alternative to classical cross-coupling reaction
Its structure has been established and presents a tetracyclic system comprising a phenyl A-ring, a 9-membered lactam B-ring, a pyrrole Cring and a piperidine D-ring (Figure 1). This alkaloid is considered to be an artefact of isolation procedure, the unusual anti-mitotic properties and the original structure of 1 inspired several research groups to develop a number of approaches for its total synthesis
Transition-metal mediated functionalization of C-H bonds. To illustrate these class of reactions, this Account will focus on the synthesis of (-)rhazinilam 1,rhazinal 2 and-rhazinicine 3 (Fig. 1), three antimitotic compounds belonging to the same family whose the strategy of synthesis is based around one or two steps of C-H bond activation
Summary
(-)-Rhazinilam 1, an axially chiral phenylpyrrole compound isolated first from Melodinus australis and latter from other species, has been shown to interact with tubuline and to mimic the effects of both vinblastine and taxol. Among the various syntheses reported of (-)-rhazinilam 1, Sames and co-workers proposed an elegant demonstration of the efficiency of the concept of C-H bond functionalization and its applicability in stereoselective process.[6] This key step involved a selective dehydrogenation of the enantiotopic ethyl groups corresponding to a metal-mediated C-H insertion / β-hydride elimination process (Scheme 2). Having demonstrated the efficiency of this strategy to prepare the racemic rhazinilam 1, Sames and co-workers described a chiral auxiliary-directed diastereoselective C-H functionalization to synthesize (-)-1 (Scheme 4). For this several oxazoline Schiff base pyrrole compounds were prepared, placed in the presence of [PtMe2(μ-SMe)2]2 and submitted to the reaction conditions to induce the dehydrogenation. Direct macrolactam formation via palladium-catalyzed carbonylation reaction followed by deprotection of the methyl ester group gave the (-)-rhazinilam 1 in 8% overall yield
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