MacMillan Minfiensine

Jones SB, Simmons B, MacMillan DWC (2009) Nine-step enantioselective total synthesis of (+)-minfiensine. J Am Chem Soc 131 13606-13607... 

In 2009 the MacMillan group reported an enantioselective total synthesis of (-b)-minfiensine (109). The key step in this synthesis expands upon Levy s early work ° and takes advantage of an organocatalytic cascade sequence... 

Owing to their structural complexity, Strychnos alkaloids, especially strychnine itself, are a benchmark in synthetic organic chemistry and have been prepared numerous times ]92]. Another alkaloid of the Strychnos family that enjoys increasing popularity nowadays is (+)-minfiensine. It was isolated from Strychnos minfimsis and features a l,2,3,4-tetrahydro-9a,4a-(iminoethano)-9H-carbazole motif, and hence is closely related to echitamine and vincorine [93]. A total synthesis of this beautiful structure was accomplished by MacMillan and coworkers [94]. Their key step was a highly efficient enantioselective domino Diels-Alder/isomerization/amine cycHzation reaction (Scheme 14.35). In this process, the chiral organocatalyst 226-TBA (TBA, tribromoacetic acid) was used, which reacted first with propargyl aldehyde 225 to form i minium ion 229 as intermediate, which underwent an endo-selective Diels-Alder reaction with 224... 

Scheme 14.35 Total synthesis of (+)-minfiensine (228) by MacMillan and coworkers (NR2=226 TBA, tribromoacetic acid).

Alongside the synthesis of strychnos alkaloid minfiensine (228) by MacMillan et al. (see Section 14.4), Li and Padwa [100] have prepared this natural product using an alternate domino process (Scheme 14.38). 

In the synthesis of (-l-)-Minfiensine by MaeMillan and coworkers, a novel Diels-Alder/amine cyclisation sequenee is aehieved using n with TBA (tri-bromoacetic acid) as the coeatalyst, allowing the synthesis of the complex tetracyclic pyrrolindoline core of the target molecule (87% yield, 96% ee), with low loadings possible (5 mol%). Similarly, MacMillan and coworkers have described the short nine-step synthesis of (—)-Vincorine, in which they employ the catalyst II and HBF4 as a cocatalyst for the formation of three stereocentres with the correet absolute and relative stereochemistry. The combination of an intermolecular Diels-Alder reaction with an iminium cyclisation cascade allowed formation of the tetracyclic alkaloid core in one step (70% yield, 95% ee). ... 

The MacMillan group reported recently (Scheme 53) a nine-step synthesis of the complex Strychnos alkaloid (+)-minfiensine (224) starting from commercially available compounds 194). The key step in this elegant approach was an intermolecular highly enantioselective [4 + 2] cycloaddition between 225 and propynal... 

Jones, S. B., Simmons, B., MacMillan, D. W. C. (2009). Nine-Step Enantioselective Total Synthesis of (-l-)-Minfiensine. Journal of American Chemical Society, 131,13606-13607. 

To demonstrate the power of these cascade sequences this methodology was successfully applied to total syntheses of several indole-derived alkaloids, for example, minfiensine [113]. By implementation of organocatalyzed cascade reactions the MacMillan group was able to dramatically reduce the number of reaction steps in total syntheses of strychnine, aspidospermidine, and kopsinine [114]. 

MacMillan s group demonstrated that iminium catalysis can be a general and reliable strategy for organic synthesis by employing the imidazolidinone-type catalysts successfully in a wide range of asymmetric transformations [10,12], One example is the total synthesis of the more complex natural product (-t-)-minfiensine, which was isolated from Strychnos minfiensis (Scheme 3.2) [17], Due to its unique structure and potential biological activity, (-i-)-minfiensine has also attracted considerable attention... 

Minfiensine, a secoiridoid indole alkaloid, was isolated from the African plant Strychnos minfiensis by Massiot and co-workers in 1989. The unique structure feature of the 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9//-carbazole has received much attention for the synthetic efforts and has culminated in several elegant total syntheses. For example. Overman et al. reported on the first and second total synthesis of (-l-)-minfiensine. " In addition, Qin et al. revealed a synthesis of ( )-minfiensine in 2008. Recently, MacMillan and co-workers reported on a nine-step enantiose-lective total synthesis of (-l-)-minfiensine via the key step reaction of organocatalytic Diels-Alder cyclization and amine heterocyclization cascade (Scheme 21.32). For the key step reaction in their approach, reaction of 2-vinylindole 139 and 3 equivalents of propynal in the presence of secondary amine catalyst 140 followed by the addition of NaBH4, stereoselective afforded the tricyclic alcohol 142 via a iminium activated endo-selectiye Diels-Alder cycloaddition and a 5-exo amine heterocy cliz ation. 

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