Organic Chemistry Portal
Organic Chemistry Highlights

Total Synthesis

Monday, August 7, 2006
Douglass Taber
University of Delaware

Adventures in Complex Indole Synthesis: (-)-Fischerindole I, (+)-Fischerindole G and (+)-Weltwitindolinone A

Phil S. Baran of Scripps La Jolla has described (J. Am. Chem. Soc. 2005, 127, 15394. DOI: 10.1021/ja056171r) an elegant entry to the complex indole-derived natural products (-)-fischerindole G (1), (+)-fischerindole I (2) and (+)-weltwitindolinone A (3).

The starting point for the preparation of 1 and 2 was the epoxide 4 of R-carvone. Enolization followed by opening with vinyl magnesium bromide 5 delivered the alcohol 6. The yield of this reaction was modest, but it directly provided 6, with all of the non-indole carbon skeleton of 1, suitably oxidized, in enantiomerically-pure form.

Remarkably, chlorination of the hindered secondary cyclohexyl alcohol proceeded cleanly, to give 7. Oxidative condensation of the enolate of 7 with indole 8 gave the key intermediate 9. After some experimentation, it was found that the clay Montmorillonite K-10 would effect the cyclization to 10. There is not yet a general reductive amination procedure for converting a cyclohexanone to the equatorial amine, so 10 was reduced to the axial alcohol, which was converted to the equatorial azide. Selective reduction then delivered the amine 11, the formamide of which was dehydrated to give 1. The alkaloid 1 so prepared was the enantiomer of the natural product.

It was not possible to dehydrogenate 1 or the precursor formamide to 2. The ketone 10 was therefore reduced selectively to the axial amine 12. Exposure of the derived formamide to t-BuOCl followed by silica gel and Et3N installed the desired double bond. Dehydration with the Burgess reagent then gave 2.

With the absolute configuration of the series established by the preparation of 1, the enantiomer of the alkaloid 2 was prepared from S-carvone. Both R-carvone and S-carvone are inexpensive and available in bulk. Exposure of the 2 so prepared to t-BuOCl followed by trifluoroacetic acid induced oxidative rearrangement to (+)-weltwitindoline A (3), identical, including sign of rotation, with the natural product.

These three syntheses, which remarkably proceed without resort to functional group protection, underline the power of the oxidative indole coupling illustrated by the union of 7 and 8 to give 9. The authors suggest that the facile conversion of 12 to 2, contrasted to the difficulties encountered in attempting to prepare 2 from 11, could indicate that it is in fact the axial amine 12 or a derivative that is the biosynthetic precursor to 2.

D. F. Taber, Org. Chem. Highlights 2006, August 7.