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Totally Synthetic by Paul H. Docherty, 8 March 2007

Total Synthesis of Ovalicin


K. Tiefenbacher, V. B. Arion, J. Mulzer, Angew. Chem. Int. Ed. 2007, 46, 2690-2693.

DOI: 10.1002/anie.200604781

The paper by Johann Mulzer at the IOC, Vienna, Austria concerns the compact yet complex Ovalicin. The initial discussion in the publication revolves around the preference for endo selectivity in the Diels Alder reaction, and tailoring the partners to produce a highly functionalised cyclohexane. This isn’t really the most novel of approaches (and has been used in two previous syntheses of this family), but is certainly flexible. This retroanalysis then shows the rest of the synthetic plan:

They then went on to decide which partners would be most suitable for their system, and which asymmetric method might give the best enantioselectivity. Having tried Keck, Mikami, Corey and MacMillian approaches to their dissatisfaction, they moved to a chiral auxiluary-based system, which was successful, providing the product in 8:1 d.r.

Following the retrosynthesis above, relatively simple transformations allowed conversion of the α-bromo aldehyde into the exocyclic epoxide, and substrate controlled dihydroxylation completed the functional group converstions, with some protecting group manipulations required to deliver the intermediate below. This was then alkylated with the alkyllithium species following lithium-halogen exchange; I’m impressed that skipped diene remains skipped!

Completion of the target then only required a few more steps including the final epoxidation, previously completed by Nakata.