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Totally Synthetic by Paul H. Docherty, 14 December 2006

Total Synthesis of Oasomycin


D. A. Evans, P. Nagorny, K. J. McRae, L.-S. Sonntag, D. J. Reynolds, F. Vounatsos, Angew. Chem. Int. Ed. 2007, 46, 545-548.

DOI: 10.1002/anie.200603652

D. A. Evans, P. Nagorny, K. J. McRae, D. J. Reynolds, L.-S. Sonntag, F. Vounatsos, Angew. Chem. Int. Ed. 2007, 46, 537-540.

DOI: 10.1002/anie.200603653

D. A. Evans, P. Nagorny, D. J. Reynolds, K. J. McRae, Angew. Chem. Int. Ed. 2007, 46, 541-544.

DOI: 10.1002/anie.200603654

No biological data given as a raison d’etre, so we’ll focus on the fact that this is a complex structure, that is constructed using several aldol reactions. Indeed, over the three communications outlined above, Evans et al go seriously rich in aldol reactions in the synthesis of this 41-member macrolide. So, to the retrosynthesis (and probably the most complex I’ve drawn so far:

Now that’s what I call a disconnection approach! It’s all in the execution from here, and for the most part, it’s known chemistry. Their methods and retroanalysis ensure that the synthesis is very convergent, but I’m not going through much of it. However, two steps caught my eye:

Using a HWE, they built the diene starting material, and were ready to hydrogenate the less-substituted alkene (the trans-4-olefin). However, various methods, including use of Lindlar’s catalyst, resulted in over-reduction and inseparable byproducts. But they did get success using Crabtree’s catalyst (this JOC), which chelated to the free hydroxyl, allowing reduction of only the desired alkene. This required deprotection of a TES group to free the hydroxyl in question, and then reprotection, but they managed an 80% yield over those three steps. Not new chemistry, but new to me…

Lastly, I really liked this aldol reactions, using Evan’s own methodology; a C2 symmetric copper catalyst to generate the chiral product in good e.e., on the “Chan Diene”. However, I couldn’t find a yield for this!