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Totally Synthetic by Paul H. Docherty, 10 October 2007

Total Synthesis of Anguinomycin C


S. Bonazzi, S. GŁttinger, I. Zemp, U. Kutay, K. Gademann, Angew. Chem. Int. Ed. 2007, 46, 8707-8710.

DOI: 10.1002/anie.200703134

When I saw this structure in Angewandte, I thought “great, aldol reactions and Wittigs…” and moved on to the next article. I was partially correct, in that there are certainly aldol reactions in this paper, but there’s a whole lot more too. Anguinomycin C offers selectivity on pRB tumor suppressor inactivated, immortalized cells, which means induction of apoptosis in such tumor cell lines in picomolar concentrations, and, remarkably, only growth arrest in normal cells. Now that’s a biological activity profile worth considering.

The synthesis is also rather sweet, starting with the left-hand dihydropyranone fragment. This was constructed via a dihydropyran, developed in a Jacobsen Cr-mediated asymmetric hetero Diels-Alder reaction:

Nice result! But the stereochemistry wasn’t quite right - the acetal center needed inverting. Simple treatment of this with acidic isopropyl alcohol did the job… They then lost the TES group with a bit of TBAF, and hydrozirconated to give them the coupling partner for a Negishi reaction with a vinyl dibromide. Interestingly, adding a substoichiometric amount DiBAL-H to the reaction gave the best result… A second Negishi coupling provide the required trisubstituted double bond, and also “isomerized” to the cis configuration. This interesting result is discussed here and here by Negishi himself, but the exact mechanism at play is still unconfirmed.

Now for the other partner, a bit of Evans aldol chemistry. Rather than Evan’s own oxazolidinone, they used the Seebach DIOZ auxiliary, which they recommend due to its propensity for crystalline products and higher selectivities. One alkylation and two aldol reactions later, they had their vinyl iodide and were set for the final coupling - a sweet sp2-sp3 Suzuki coupling, completing the carbon skeleton of the natural product in great yield. A bit of deprotection, and they were there. A nice total synthesis!