MacMillan, Carpenter, Northrup, Chung, Wiener and Kim, ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200800086.
Macrolide time again, and as this is David MacMillan, proline time too. The callipeltoside family of natural products has been reasonably popular, with syntheses from the usual suspects: Trost, Evans, Paterson, and Panek. However, all of those syntheses were of callipeltoside A, so this synthesis marks the first of callipeltoside C, including a reassignment of stereochemistry (the sugar fragment needed all is stereocenters inverted). Retro:
So far reasonably predictable/sensible disconnection – and you’ll note no organocatalysis so far. It’s also worth pointing out here that the dieneyne fragment was made using the route developed by Evans. However the fragment synthesis is where MacMillan’s favourite amino acid come in, with several proline catalysed aldol condensations.
The first of those is in the construction of the THP, in which a nice little matched-organocatalytic aldol with a derivative of the ever-popular Roche ester. However, what I liked most was their use of a Semmelhack reaction to close the THP and leave a methyl ester as a useful functional handle. (For those of you who aren’t aware of this reaction – and it’s absent for several named reaction books – MacMillan references two papers. The original paper is here; Marshall’s improved conditions for acetylinic systems are here.) In their hands this went with great diastereomeric control, and left a heavily functionalised THP after only two steps. Now that’s smart work!
The next aldol to look at is of the prodigious direct aldehyde-aldehyde variety. A spot of L-proline this time results in a great e.e. and decent yield of the semi-protected triol. Next, a bit of silyl enol-ether completes the hexose framework and leaves a differentially protected sugar (if you accept that the two TIPS protected hydroxyls will react differently). Of course, we read all about this sugar synthesis in Science a few years back.
It took them a few more steps to complete the sugar synthesis (for the second time – as I mentioned above the originally proposed stereochemical configuration of the sugar was incorrect), and a bit of Tietze chemistry allowed them to bolt this onto the aglycon.
As with many syntheses, the last step was deprotection of the silyl groups – but not with TBAF or HF.amine here. Nope, MacMillan uses tris(dimethylamino)sulfonium difluorotrimethylsilicate (or TASF to it’s friends) – useful if there’s any water sensitivity as the reagent is completely anhydrous.
An interesting synthesis, showcasing much of MacMillan’s work – and notably only using unmolested proline as the catalyst.
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