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Organic Chemistry Highlights

Total Synthesis

Monday, February 1, 2010
Douglass F. Taber
University of Delaware

The Nakada Synthesis of (-)-FR182877

The Streptomyces metabolite (-)-FR182877 (3) binds to and stabilizes microtubules, showing the same potency of anticancer activity as Taxol. Masahisa Nakada of Waseda University assembled (Angew. Chem. Int. Ed. 2009, 48, 2580. DOI: 10.1002/anie.200900097) the hexacyclic ring system of 3 by the tandem intramolecular Diels-Alder – intramolecular hetero Diels-Alder cyclization of 1, generating seven new stereogenic centers in a single step.

The construction of the pentaene substrate 1 started with the known aldehyde 4, prepared by homologation of commercial ethyl 3-methyl-4-oxocrotonate. Addition of the propionyl oxazolidine anion 5 proceeded with high diastereocontrol, to give 6. The acyl oxazolidinone was not an efficient acylating agent, so it was converted to the Weinreb amide. Protection and deprotection then delivered the allylic acetate 7.

The key step in the pentaene assembly was the carefully optimized Negishi-Wipf methylation of 8, followed by Pd-mediated coupling of the alkenyl organometallic so generated with the allylic acetate, to give 9. Condensation of the derived keto phosphonate 11 with the known aldehyde 12 then delivered the enone 13.

The Nakada group has worked extensively on the intramolecular Diels-Alder reaction of substrates such as 1. They have shown that protected anti diols such as 1 cyclize with substantial diastereocontrol and in the desired sense. In contrast, cyclizations of protected syn diols proceed with poor diastereocontrol. The enone 13 was therefore reduced to the anti diol and protected, leading to 14. Oxidation of 14 at room temperature led to a complex mixture, but slow oxidation at elevated temperature delivered 2. Although the yield of 2 was not much better than if the reactions were carried out sequentially, first the intramolecular Diels-Alder cyclization, then the intramolecular hetero Diels-Alder cyclization, with the cascade protocol pure 2 was more readily separated from the reaction matrix.

With 2 in hand, there was still the challenge of assembling the seven-membered ring. Cyclization was effected with an intramolecular Heck protocol. The two diastereomers of the allylic alcohol 15 cyclized with comparable efficiency. Ir-catalyzed alkene migration then converted the allylic alcohols to a mixture of ketones, that was equilibrated to give the more stable diasteromer. Reduction of the ketone then set the last stereogenic center of 3. Deprotection and subsequent lactone formation completed the synthesis of (-)-FR182877 (3).

D. F. Taber, Org. Chem. Highlights 2010, February 1.