Totally Synthetic by Paul H. Docherty, 4 September 2011
Total Synthesis of Maoecrystal Z
J. Y. Chan, J. T. S. Yeonan, S. E. Reisman, J. Am. Chem. Soc. 2011, 133, 14964-14967.
The synthesis starts with γ-cyclogeraniol, initially TBS protecting the primary alcohol, and then epoxidising the exo-cyclic alkene using mCPBA. This takes them to the substrate for a notable reaction, coupling the epoxide with methyl acrylate. The conditions were inherited from Gansauer, first published in his 1998 paper on reductive epoxide couplings, requiring the zinc as the terminal reductant. Unfortunately, the initial results were relatively poor - only a 28% yield was possible. However, by moving to 2,2,2-trifluoroethylacrylate rather than methyl acrylate, and adjusting the rate of addition of catalyst, the group were able to increase this to a very respectable 74%. Especially nice when you consider how direct this reaction is!
Working directly from the product of that reaction, the group coupled on a sidechain by alkylation, and added a pair of stereocenters. The sidechain is constructed using a pseudo-ephidrine controlled alkylation. The other wasn’t controlled, and was later removed by oxidation of the lactone to an α,β-unsaturated lactone using a phenyl-selenation and oxidising elimination.
After this, it was time to move to the pièce de résistance, a samarium (II) iodide mediated radical coupling. Treating the advanced intermediate with SmI2 initially resulted in disappointment, as only trace quantities of the product were identified. However, utilising lithium chloride and tert-butanol as additives saved the day, allowing the group a very reasonable 45% yield, with high stereoselectivity.
Bouyed with this success, the group then went made a similar substrate, but this time with an aldehyde instead of the protected primary alcohol. When this substrate was treated in the same manner, not only did a further ring formation occur, but the yield was improved to an even more impressive 54%.
More importantly, though - this pair of C-C bond formations and ring formations took the group remarkably close to the target in a single step. From here, two acetate groups (instead of one) were installed, followed by ozonolysis and treatment of the aldehyde with Eschenmoser’s salt and triethylamine to get to an enal. They then selectively removed the superfluous actetate, completing the target in twelve steps.
This publication is a strong candidate for the total synthesis of the year!