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Totally Synthetic by Paul H. Docherty, 2 April 2007

Total Synthesis of Lyconadin A & B


D. C. Beshore, A. B. Smith, III, J. Am. Chem. Soc. 2007, 129, 4148-4149.

DOI: 10.1021/ja070336+

A deceptively simple looking structure, lyconadin A and the related lyconadin B were the targets of this paper by Amos Smith. The biological profile was somewhat simple, showing moderate cytotoxicity against epidermoid carcinoma KB cells, but the pentacyclic structure is reason enough to interest us, right?

The retosynthesis might not be too revealing, so I guess it’s time to look at the forward synthesis - and surprise - it’s the cyclisations that I found most interesting. The initial cyclisation precursor was produced from two fragments, coupling by deprotonation of a hydrazone and addition of an alkylhalide. Anyway, the cyclisation goes via the planned aldol reaction (acid mediated, as base led to majority polymerisation), but proceeded further still, performing a conjugate addition to provide the seven member ring.

Getting this product in only one step impressed the group as well as me, thought the were disappointed to learn that the protonation of the enol had occurred on the undesired face, and thus the C-12 centre required epimerisation. The method they used for this was really smart - they removed the Cbz protecting group, allowing it form the hemiaminal under acidic conditions. Reduction of this with borohydride then gave overall epimerisation and the desired product.

The same N-C bond was reformed shortly afterwards, after elimination of the hydroxyl resulting from reduction of the ketone and (a particularly nice) aminoiodation. With a few further functional group manipulations, they were able to perform a Michael addition of propiolamide to provide the final cyclisation material. Then, in one pot, they performed a decarboxylation, olefin isomerisation, and cyclocondensation - amazing! However, it should be noted that for lyconadin B (which required prior reduction of the olefin in the cyclisation material), those conditions were deemed less suitable, and they used LiCl instead. Still, a very fine synthesis, but a little long (27 steps).

Selected Comments

3 April, 2007 at 8:12, TotallyMedicinal says:
I’m having a hard time understanding that C12 epimerisation. It would seem to need a ring flip for the carbonyl containing ring, to bring the two centres close enough together - I am guessing (can’t access JACS) that reprotonation of this ring flipped analogue gives the desired C12 stereoisomer? So apart from reducing the distal carbonyl, what exactly is the NaBH4 doing?
3 April, 2007 at 13:55, WillisWill says:
I would say, and I can’t access JACS either, that the HCl/MeOH step can enolize the ketone. the equilibrium thus established can have either H “up” or H “down”, but only the H “down” configuration can be trapped by the amine, which drives an otherwise unfavorable equilibrium forward. Very Woodward-esque IMO. Of course, the true answer is probably written in plain sight in the article…
3 April, 2007 at 20:18, Tot. Syn. says:
To quote the article:
“the Cbz group was removed to provide the free amine, which upon heating at reflux in a mixture of water/methanol/HCl (12 N) (17:3:1) induced epimerization at C-12 bringing the nitrogen proximal to the C-13 ketone to furnish hemiaminal salt, delivering the desired C-12 stereochemistry.”
That’s some strong acid! However, the description of how they arrived at the wrong epimer is perhaps more helpful:
“Although we had envisioned formation of [the bis-ketone] via preferential axial protonation of [the] enol, formation of [the bis-ketone] can be understood on the basis of thermodynamic stability.”
3 April, 2007 at 22:50, TWYI says:
A simple one from me, but does anyone know why putting on a CBz group is virtually always done in an aqueous, biphasic system? I used to put them on in CHCl3/DCM H2O, but this is never the case with Boc/Fmoc/Troc etc.
3 April, 2007 at 23:13, milkshake says:
I have been putting Cbz group on in aqueous monophasic mix (typically with THF-water-K2CO3) using CbzOSu (gorgeous white crystals, instead of nasty smelly over-presurised corrosive liquid)