Total Synthesis Highlights

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.