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Organic Chemistry Highlights

Total Synthesis

Monday, January 5, 2009
Douglass F. Taber
University of Delaware

The Wood Synthesis of Welwitindolinone A Isonitrile

Welwitindolinone A Isonitrile (3) is the first of a family of oxindole natural products isolated from the cyanobacteria Hapalosiphon welwischii and Westiella intricate on the basis of their activity for reversing multiple drug resistance (MDR). A key transformation in the total synthesis of 3 reported (J. Am. Chem. Soc. 2008, 130, 2087 DOI: 10.1021/ja057640s) by John L. Wood, now at Colorado State University, was the chlorination of 1, that in one step established both the axial secondary chloro substituent and the flanking chiral quaternary center.

The starting material for the synthesis of 3 was the diene acetonide 5, readily prepared from the Birch reduction product 4. Intermolecular ketene cycloaddition proceeded with high regio- and diastereoselectivity, to give the bicyclooctenone 6.

The triazene-bearing Grignard reagent 7 added to the ketone 6 with the anticipated high diastereocontrol, to give, after reduction and protection, the cyclic urethane 8. Selective oxidation of the diol derived from 8 followed by silylation delivered the enone 9. Conjugate addition of hydride followed by enolate trapping gave the triflate 10. Pd-catalyzed methoxycarbonylation established the methyl ester 11. Addition of CH3MgBr to 11 gave 1, setting the stage for the establishment of the two key stereogenic centers of 2 and so of 3.

The transformation of 1 to 2 was envisioned as being initiated by formation of a bridging chloronium ion. Pinacol-like 1,2-methyl migration then proceeded to form the trans diaxial product, moving the ketone-bearing branch equatorial. In addition to being an elegant solution of the problem of how to establish the axial chloro substituent of 3, this strategy might have some generality for the stereocontrolled construction of other alkylated cyclic quaternary centers.

Reduction of the ketone 2 and dehydration of the resulting alcohol led, after deprotection and oxidation, to the ketone 12. Protection followed by β-elimination gave the enone 13. Direct reductive amination of 13 failed, but reduction of the methoxime was successful, giving, after acylation, the formamide 14. Reductive N-O bond cleavage followed by deprotection and isonitrile formation then set the stage for the planned intramolecular acylation to complete the synthesis of Welwitindolinone A Isonitrile (3).

The starting diene 5 used in this synthesis was prochiral, leading to racemic 3. Now that the route to 3 is established, it would be interesting to devise a method for preparing enantiomerically-enriched 6. Enantiomerically-pure variants of 5 have been prepared, inter alia by fermentation of halogenated aromatics. Alternatively, an enantioselective version of the [2+2] cycloaddition to the prochiral 5 could be developed.

D. F. Taber, Org. Chem. Highlights 2009, January 5.