Totally Synthetic by Paul H. Docherty, 6 May 2008
Total Synthesis of 35-Deoxy Amphotericin B Methyl Ester
A. M. Szpilman, D. M. Cereghetti, N. R. Wurtz, J. M. Manthorpe, E. M. Carreira, Angew. Chem. Int. Ed. 2008, 47, 4335-4338.
A. M. Szpilman, J. M. Manthorpe, E. M. Carreira, Angew. Chem. Int. Ed. 2008, 47, 4339-4342.
35-Deoxy Amphotericin B Methyl Ester is not really a natural product, but close enough. It is actually the well-known amphotericin B with a missing hydroxyl group designed by Carreira to probe some biological activity. In addition, he has developed a completely new route to the natural product class. A previous total synthesis of the parent compound was published by KC Nicolaou in the late eighties, so it’s interesting to see what’s changed in two decades…
Time for a retroanalysis:
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 not to be very useful. 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.
The reaction with the lithium acetylide gave undesired stereochemistry in the
addition step, but an asymmetric zinc catalyst connected the terminal alkyne to
Conveniently, Carreira has
been working on
that chemistry for a few years. And a nice result it is too - high
yield and d.r.
The next reaction is one of my favourite macrolide-fragment-coupling reactions. 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. A very interesting reaction!
The synthesis of the other large fragment isn’t discussed in detail in the paper, but the stereochemistry of the methyl group is set using Fráter-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, glycosidation 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 resulted 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!