A delicate Diels–Alder reaction and a late-stage hydroxylation are the key steps in a total synthesis of a marine natural product.
Caribenol A possesses strong inhibitory activity against the causative agent of tuberculosis, and has an unusual structure. The tetracyclic structure including a 5-7-6 all-carbocyclic core and six stereocentres provides a synthetic challenge, and combined with the useful biological activity provides all the justification necessary for a total synthesis effort. Now, Zhen Yang and co-workers from Peking University, China have developed1 a convergent total synthesis of this Caribenol A.
Not unusually for a carbocyclic compound with several stereocentres, a key reaction in the synthesis is an intramolecular Diels–Alder reaction. Yang and co-workers were able to rapidly construct the precursor for this reaction from three smaller fragments, two of which — a dienyl iodide prepared in seven steps and an enone prepared in five — each contain a single stereocentre. Having successfully combined these three fragments to form the Diels–Alder precursor, however, this key reaction was problematic. Despite the dienophile portion being a highly activated alkyne, the expected reaction did not occur even at high temperature. Yang and co-workers also tried lower-temperature conditions in the presence of various Lewis acids but these were also unsuccessful. The problems experienced in this step are presumably a combination of both starting material and product instability.
Ultimately, Yang and co-workers found that addition of a sterically hindered phenol to the reaction promoted the desired Diels–Alder reaction in a high yield. The total synthesis was then completed by a series of six steps that proceeded fairly smoothly — with the exception of a final hydroxylation that required another screen of suitable conditions.
Liu, L.-Z., Han, J.-C., Yue, G.-Z., Li, C.-C. & Yang, Z. Asymmetric total synthesis of caribenol A. J. Am. Chem. Soc. 10.1021/ja106585n (2010).
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Davey, S. Conquering caribenol A. Nature Chem (2010). https://doi.org/10.1038/nchem.875