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. 2008 Apr 16;130(15):5368-77.
doi: 10.1021/ja800163v. Epub 2008 Feb 28.

Total synthesis of the strychnos alkaloid (+)-minfiensine: tandem enantioselective intramolecular Heck-iminium ion cyclization

Amy B Dounay  1 , Philip G Humphreys, Larry E Overman, Aaron D Wrobleski
Affiliations

Total synthesis of the strychnos alkaloid (+)-minfiensine: tandem enantioselective intramolecular Heck-iminium ion cyclization

Amy B Dounay et al. J Am Chem Soc. .

Abstract

A 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9H-carbazole (4) is a central structural feature of the Strychnos alkaloid minfiensine (1) and akuammiline alkaloids such as vincorine (5) and echitamine (6). A cascade catalytic asymmetric Heck-iminium cyclization was developed that rapidly provides 3,4-dihydro-9a,4a-(iminoethano)-9H-carbazoles in high enantiomeric purity. Two sequences were developed for advancing 3,4-dihydro-9a,4a-(iminoethano)-9H-carbazole 27 to (+)-minfiensine. In our first-generation approach, a reductive Heck cyclization was employed to form the fifth ring of (+)-minfiensine. In a second more concise total synthesis, an intramolecular palladium-catalyzed ketone enolate vinyl iodide coupling was employed to construct the final ring of (+)-minfiensine. This second-generation total synthesis of enantiopure (+)-minfiensine was accomplished in 6.5% overall yield and 15 steps from 1,2-cyclohexanedione and anisidine 13. A distinctive feature of this sequence is the use of palladium-catalyzed reactions to form all carbon-carbon bonds in the transformation of these simple precursors to (+)-minfiensine.

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Figures

Figure 1
Figure 1
Minfiensine (1) and two additional C19H22N2O Strychnos alkaloids.
Figure 2
Figure 2
Representative alkaloids containing a 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9H-carbazole.
Figure 3
Figure 3
Proposed rationale for stereoselection in the epoxidation of alkene 27. Model (6-31G*) of the most stable conformation of alkene 27 showing the favored approach of an oxidant to alkene carbon b.
Scheme 1
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Scheme 17
See this image and copyright information in PMC

References

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    1. For review, see: Higuchi K, Kawasaki T. Nat. Prod. Rep. 2007;24:843–868., and earlier articles in this series.

    1. Anthoni U, Christophersen C, Nielsen PH. In: Alkaloids: Chemical and Biological Perspectives. Pelletier SW, editor. Vol. 13. New York: Wiley; 1999. pp. 163–236.
    1. Ramirez A, Garcia-Rubio S. Curr. Med. Chem. 2003;10:1891–1915. - PubMed
    1. Dounay AB, Overman LE, Wrobleski AD. J. Am. Chem. Soc. 2005;127:10186–10187. - PubMed

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