Toste, Radosevich, Chan and Shih, ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200800554.
Another paper from the Toste group that doesn’t use recycled Rolex watches in any of the steps. Indeed, the metal of choice today is vandadium – read-up on the methodology in this tasty JACS from 2005. Anyway, the target is octalactin A, a medium ring lactone with a bit of murine melanoma and colon tumor busting activity. Previous syntheses by Buszek, Clardy, Shiina and my boss with Andy Holmes, so it’s certainly seen a bit of action…
I’ve not bothered with a full-retrosynthesis, cause there’s a lot going on in a tight space, but much of the action revolves around the synthesis of the olefin shown below. Toste noticed that this bad-boy contains two units of similar relative stereochemistry and connectivity, and that they might be produced together as the two products formed in a kinetic resolution of a racemic mixture.
Said racemic compound was produced quickly using a rather neat Darzens condensation, rearrangement and oxidative hydroboration protocol. Then, treatment with a bit of vanadium catalyst along with some ligand (no actual figure of the ligand in the paper, so I’m going on ChemDraw’s ‘Name To Structure’ function) resulting in an excellent mass recovery of two products, both in good enantiomeric excess.
Transformation of these products into the desired partners for the Horner-Wadsworth-Emmons reaction was efficient and quick – with one particularly neat reaction. The Î±-keto ester required decarboxylation which they performed using an intreguing oxidative process, treating the analogous Î±-keto carboxylic acid with iodosobenzene. The procedure was developed by one Robert Moriarty (good name!), and follows this mechanism:
Transformation of the product into a mixed anhydride, and addition of a lithio-phosphonate gave the desired ketophosphonate, and allowed a high-yielding coupling of the two fragments.
Completion of the medium ring invoked an under-used protocol for formation of lactones; a Wolff rearrangement. Of course, there are two main methods for the expulsion of nitrogen – silver salts and light. In this case, they tried both, and found that the photo-Wolff was the more efficient process. Worth noting (and absent from the prose) was the high dilution required for the reaction. Presumably this is to prevent the competing intermolecular reaction.
Synthesis of the sidechain used the neat Kocienski procedure for the opening of DHPs via a 1,2- metalate rearrangement (discussed more fully in this previous post). Coupling of the two fragments using an NHK coupling completed the carbon skeleton, leaving them with only a few more steps to finish the molecule. Smart stuff…
Radosevich, A.T., Chan, V.S., Shih, H., Toste, F.D. (2008). Synthesis of (Ã¢Ë†â€™)-Octalactin A by a Strategic Vanadium-Catalyzed Oxidative Kinetic Resolution. Angewandte Chemie International Edition DOI: 10.1002/anie.200800554
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