Synthesis of Cephanolide A

From a retrosynthesis standpoint, the authors aimed to maximize the rapid generation of the structurally complex carbon framework of the molecule. To this end, identifying the strategic bonds that needed to be forged would simplify not only the preparation of this molecule but also any of the other members of the family, just by changing the sequence of the late state oxidations. An intramolecular inverse-demand Diels–Alder cycloaddition was identified as a strategic disconnection for the efficient construction of the carbon framework. And from this latter intermediate, the authors identified two fragments, a pyrone and an indanone, that could be linked with a two-carbon fragment by an iterative cross-coupling sequence.

The synthesis commenced with the triflation of this commercially available indanone. 

Then, an sp2-sp3 Suzuki cross-coupling took place with this organoborane, which was generated in situ from hydroboration of the vinyl reagent. The Suzuki coupling was accomplished with palladium diacetate as the catalyst in the presence of DavePhos as the ligand and potassium fluoride as the base.

The product was then subjected to another Suzuki coupling with pyrone triflate. In this case, they employed RuPhos as the ligand and potassium carbonate as the base.

The key intramolecular Diels–Alder reaction was accomplished upon formation of the silyl enol ether with two equivalents of Trimethylsilyl triflate: the first equivalent for the formation of the enol ether, and the second equivalent presumably as a Lewis acid to facilitate the cycloaddition that led to the endo-cycloadduct.

The next step was the functionalization of the bridging olefin group. To this end, several hydroborations and epoxidation reactions of the olefin group were attempted without success. Fortunately, a modified Mukaiyama hydration protocol proved effective. The Mukaiyama hydration allows the transformation of an olefin to the corresponding alcohol with Markovnikov selectivity. A plausible reaction mechanism suggests that the reaction proceeds through a cobalt peroxide adduct that leads to a silyl peroxide that is converted to the alcohol upon reduction. In this modified protocol a nonaflate peroxide is generated instead. Then, DBU induces elimination and formation of the corresponding ketone. According to the authors, the regioselectivity of the hydrocobalation likely results from a directing effect of the proximal oxygen lone pair of the lactone. Besides, the reaction had to be carried out at –78 ºC because the excess DBU at higher temperatures caused enolization of the resulting ketone and decarboxylation of the strained lactone.

The subsequent olefination reaction was attempted with several olefination reagents. For instance, the Wittig olefination failed because phosphorus ylides proved to be too basic even at cryogenic temperatures and resulted in the opening of the lactone. Finally, they found an olefination protocol, which employs less basic olefination reagents, and that gave the desired exo-methylene product.

The Riley oxidation resulted in the formation of the allylic alcohol, which was subsequently oxidized to the corresponding enone.

Hydrogenation followed by epimerization of the methyl-bearing stereocenter gave the desired ketone in two steps.

The ketone was then reduced with NaBH4 to the corresponding alcohol.

The alcohol was subjected to Suarez oxidation conditions employing iodine and hypervalent iodine to forge the desired THF ring. After TMS cleavage, the tertiary alcohol was obtained.

The alcohol was eliminated following the classical Barton–McCombie deoxygenation reaction.

Final oxygenation of the arene moiety using cyclopropane malonyl peroxide completed the synthesis of (±)-Cephanolide A.

Reference work:

J. Am. Chem. Soc. 2021, 143, 2710.