35-Deoxy Amphotericin B Methyl
Once again, I’ve strayed off my brief and into the terratory of ‘not-really-a-natural-product’. However, this bad-boy is close enough, and is actually just yer plain-boring-old-amphotericin B with a hydroxyl group lopped-off. Designed by Carreira to probe some-biological thingy,1 he’s developed a completely new route to the target-class. Previous syntheses of the parent compound are limited to one KCN number from the late eighties, so it’s interesting to see what’s changed in two decades…
Retro-time, and it’s a busy piece this time:
The synthesis of the septaene (new word!) fragment is actually less interesting that one might imagine (though I reckon it’s probably rather frisky in the RBF…). More involved is that every-pesky glycosidation step, where model studies seem to be about as useful as Boris Johnson.2 A nitrile-oxide addition provided one of the key C-C bond formations, whilst Carreira’s own acetylene chemistry dealt with another. Let’s start with that:
So the starting material for these substrates is enantiomerically enrichate dialkyl malate; (S)- for the top fragments, (R) for the bottom. A Prasad reduction provided the desired syn-1,3-diol relationship in both cases, whilst a nice Ohira-Bestmann reaction installed the required acetylene. Studies in the lab apparently pointed to undesired stereochemistry in the addition step when using Li, so a bit of asymmetric zinc was order-of-the-day. Conveniently, Carreira’s been working on that chemistry for a few years . And a nice result it is too – awesome yield, cracking d.r.
The next reaction is one of my favourite macrolide-fragment-coupling reactions (it’s a fairly short list, actually…). Taking the product of the latter reaction and converting it swiftly to the oxime allowed them to do a nitrile-oxide cycloaddition (a [3+2] or 1,3-dipolar reaction) onto the terminal olefin to give the 4,5-dihydroisoxazole product.
The really smart bit here is the cleavage of the N-O bond; some molybdenum hexacarbonyl liberated a hydroxy ketone, which cyclised during purification to give the desired product. Ãœber Banane!
Synthesis of the other large fragment isn’t discussed in anywhere near this detail in the paper, but the stereochemistry of the methyl group is set using a tasty Fraterâ€“Seebach alkylation, followed by a Myers alkylation. After construction of the polyunsaturated chain, the linear molecule was completed by Yamaguchi esterification, leaving a HWE to complete the macrocycle.
As in many cases, appendage of the sugar unit was a process of trial and error. That’s not to say that they didn’t think hard about what might work, and what was causing them trouble – this chemistry is just hard. After a lot of work, they found that the substrate below was the best partner for the algycon, and that activation with 2-chloro-6-methyl-pyridinium triflate and 2-chloro-6-methyl-pyridine was the way forward, resulting in a 45% yield of the desired product.
Deprotection and reduction of the azide provided the target, which turned out to be an order of magnitude less active than the parent compound. This, however, backed up their biological hypothesis, which I suggest you read about yourself in these two impressive papers.
Also, congratulations to Alex for his work on both these articles – good job, mate!
 Something about ‘barrelstave ion channels’… do I look like an agar scraper?
Szpilman, A.M., Manthorpe, J.M., Carreira, E.M. (2008). Synthesis and Biological Studies of 35-Deoxy Amphotericin B Methyl Ester. Angewandte Chemie International Edition DOI: 10.1002/anie.200800590
Szpilman, A.M., Cereghetti, D.M., Wurtz, N.R., Manthorpe, J.M., Carreira, E.M. (2008). Synthesis of 35-Deoxy Amphotericin B Methyl Ester: A Strategy for Molecular Editing. Angewandte Chemie International Edition DOI: 10.1002/anie.200800589
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