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Organic Chemistry Highlights

Total Synthesis

Monday, December 5, 2011
Douglass F. Taber
University of Delaware

The Garg Synthesis of ()-Aspidophylline A

The pentacyclic Apocynaceae alkaloid Aspidophylline A (3) was shown to reverse drug resistance in resistant KB cells. In developing a strategy for the assembly of 3, Neil K. Garg of UCLA envisioned (J. Am. Chem. Soc. 2011, 133, 8877. DOI: 10.1021/ja203227q) the intramolecular Pd-catalyzed cyclization of 1 to 2.

The starting material for the cyclohexenone derivative 1 was the known tricyclic anhydride 7. This was readily available in gram quantities by oxidation of the commercial pyridone (4). The double decarboxylation to 8 was delicate, but could be effected by iterative small-batch microwave heating. Protection of 8 followed by fragmentation and alkylation than delivered 1.

The intramolecular Heck cyclization of 1 indeed proceeded smoothly, to give the bicyclic diene 2. Deprotection of the ketone revealed a doubly-activated enone, that could be selectively reduced under modified dissolving metal conditions to give the keto ester 12. Alkylation of the lithium enolate with allyl iodide then gave 13, predominantly as the diastereomer illustrated. Reduction followed by selective Johnson-Lemieux oxidative cleavage of the terminal alkene then completed the construction of the diol 14.

The vision for the final assembly of the alkaloid was to effect interrupted Fischer indolization of an alkylated cyclohexanone such as 15. To this end, several bicyclic ketones were explored, but none was successful. Finally, attention was turned to the more rigid tricyclic lactone 15. Happily, exposure of 15 to phenylhydrazine in the presence of trifluoroacetic acid led to an intermediate that was not isolated, but rather directly combined with methanolic K2CO3 to open the lactone, allowing closure of the tetrahydrofuran ring, to give 16.

Simple arene sulfonamides can be advantageous in synthesis, as they do not appear as rotameric mixtures in NMR, and are often crystalline. Nevertheless, they have not commonly been used, because of the perceived difficulty of deprotection. Sonication of 16 with Mg powder in methanol containing solid NH4Cl led to smooth desulfonylation. Formylation then completed the synthesis of Aspidophylline A (3).

D. F. Taber, Org. Chem. Highlights 2011, December 5.