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Organic Chemistry Highlights

Total Synthesis

Monday, November 7, 2011
Douglass F. Taber
University of Delaware

The Rawal Synthesis of N-Methylwelwitindolinone D Isonitrile

The complex polycyclic structure of N-Methylwelwitindolinone D Isonitrile (3) was assigned in 1999. The welwitinines show an intriguing range of biological activity, including reversal of P-glycoprotein-mediated multidrug resistance in human carcinoma cells. Viresh H. Rawal of the University of Chicago described (J. Am. Chem. Soc. 2011, 133, 5798. DOI: 10.1021/ja201834u) the first synthesis of 3, using as a key step the Pd-catalyzed cyclization of 1 to 2.

The ketone 1 was assembled by the convergent coupling of 7 with 11. The indole 7 was readily available by Batcho-Leimgruber cyclization of commercial 4 to 5. The expected 3-acylation followed by N-methylation delivered the stable ketone 6. The unstable 7 was prepared as needed.

The anisole 8 was the starting material for the preparation of the alicyclic diene 11. Although this synthesis was carried out in the racemic series, enantiomerically-enriched 9 could be prepared by Shi epoxidation of the β,γ-unsaturated ketone from Birch reduction followed by hydrolysis.

The alcohol 7 was not stable to silica gel chromatography. The mixture of 11 with the crude alcohol 7 was therefore activated by the addition of TMSOTf, then added via cannula to aqueous HClO4 in THF to deliver the coupled product 1 as a single diastereomer.

The remarkable cyclization of 1 to 2 required extensive screening. Eventually it was found that a combination of (t-Bu)3P with Pd(OAc)2 as the Pd source worked well. This concise convergent synthetic strategy makes the welwitinine core 2 available in gram quantities.

There were two problems to be solved in the conversion of 2 to 3. The first was the installation of the oxy bridge. Indoles are notoriously sensitive to over-oxidation. Nevertheless, addition of an acetone solution of dimethyl dioxirane to the bromo ketone 12 over 24 hours gave clean conversion to 13.

The remaining challenge was the conversion of the aldehyde of 13 to the isonitrile. Kim had described the inversion of an oxime to the isothiocyanate. Optimization of this protocol led to the thiourea 14 as the best for this transformation. Mild desulfurization then delivered N-Methylwelwitindolinone D Isonitrile (3).

D. F. Taber, Org. Chem. Highlights 2011, November 7.