Zakarian and Lu. ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200801652.
I think his group are probably still unpacking the boxes after a move from FSU to Santa Barbara, but they’ve had enough time to finish (or at least publish) a short but sweet synthesis of trichodermamide B.Â From a biological activity perspective, it’s a reasonable human colon carcinoma beater, and ‘moderate antimicrobial’ agent, so of some interest, but one of the more interesting facets is the inactivity of the related trichodermamide A.Â The only difference between these two beasties is that trichodermamide A has a third hydroxyl group in place of the chlorine – interesting that it turns around the activity so dramatically.
Anyway, we can pretend that that’s why we’re interested in the synthesis, but that’s basically a lie – on with the synthesis.Â The first reaction is a DA between a cyclohexadienone and vinylene carbonate, resulting in a bridged, bicyclic carbonate.Â Treatment of this with lithium hydroxide resulted in the expected saponification – with a twist.Â An actual twist, in this case, of a bond, resulting in ‘virtually complete inversion of stereochemistry at C7′.Â Zakarian invokes a retro-aldol, aldol mechanism in which the product is the more stable trans isomer.Â Neat.
The acetal was binned using samarium diiodide (is there anything that stuff won’t do?), protection and we’re set for the piÃ¨ce de rÃ©sistance – a nitrosation/oxaza-Cope rearrangement.Â This seems to be a fairly straight-forward bit of chemistry, with the yield dropping into the eighties due to debenzylation.Â I wonder if they could use a bit of NMP to mediate the lewis acidity of the tickle-four – worked for Crimmins (and me).Â Not that it matters – the yield is great; no mention of d.r., so it’s presumably good.
So what’s left?Â The right-hand fragment isn’t a challange, so it’s all about functionalising the cyclohexane with some degree of synthetic elegence.Â This is often the point where this type of tot. syn. goes tit’s up, as the group flail around trying to force the functionality in.Â Not so in this case…Â A Grieco Mitsonubo inversion of stereochemistry gave them an allylic selanide in there steps from the last scheme.Â Then, treatment with peroxide resulted in in situ [2,3]-sigmatropic rearrangement leaving them with the required stereochemistry.Â Not new chemistry by any measure, but still a nice sequence.Â (I wonder if they could have formed an an allylic acetate instead; then, a bit of palladium to form the Ï€-allyl complex.Â The Pd would be on the top face, so addition of summat like p-methoxyphenol might be expected to come from the bottom face at the less-hindered side and give a simlilar product… with less smell)
Completion of the molecule was expedient; esterification went well, leaving them with deprotection of the acetal (zinc triflate in the presence of ethanethiol… interesting), and displacement of an allylic mesylate (that’ll be a reactive little beastie) with chloride in a surprising good yield.Â Nice work!
Lu, C., Zakarian, A. (2008). Total Synthesis of (Ã‚Â±)-Trichodermamide B and of a Putative Biosynthetic Precursor to Aspergillazine A Using an Oxaza-Cope Rearrangement. Angewandte Chemie International Edition DOI: 10.1002/anie.200801652