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Lyconadin A & B   

2 April 2007 9,000 views 25 Comments


Smith and Beshore. JACS, 2007, ASAP. 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 – 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 (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 (more like a Krapcho? is the TMAA is mimicking LiCl to decarboxylate?). Still, a damn fine synthesis, if a little steppy (27 steps).

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  • aa says:

    some pretty nice steps in this synth for sure… one thing that impressed me was the high yields for a lot of steps… never seen a paper with so many 99% yields. and the 88% over 5 steps to get things going was sweet. mind you, not the hardest chemistry and done on huge scale (check SI, i think 88 grams of SM), but obviously a good pair of hands was doing this work. famous amos keeps rolling out nice molecules!

  • The Canadian Chromatographer says:

    Famous Amos rolling out nice molecules, and not doing something else. I think AA knows what CC is talking about!… :)

  • 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?

  • 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…

  • 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.”

  • 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 H20, but this is never the case with Boc/Fmoc/Troc etc.

  • 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)

  • TWYI says:

    sorry, post should have read aqueous or biphasic

    In short, does it always need to be aqueous…

  • Zinc says:

    I’ve protected a secondary amine with a Cbz group in DCM using Et3N, DMAP, and the nasty liquid milkshake’s talking about (benzyl chloroformate). Went in quant. yield.

  • labmonkey says:

    Off-topic question: has anyone out there done one of Fu’s alkyl-alkyl Suzuki couplings (thats sp3 to sp3 coupling)? I’m ignorant when it comes to transition metal chemistry and I don’t know how difficult these things are.

  • rb says:

    re: aqueous acylations

    Those are the classic Schotten-Bauman conditions. I have always found that they work well, b/c the polar amine will dissolve in the aqueous layer and the basic conditions keeps the amine in its basic form.

  • TheEdge says:

    Re: Me4NOAc mediated decarboxylation. One of my labmates pointed out that MeCN is nucleophilic at high temp. The Trost paper they cite uses HMPA as solvent, which is definitely nucleophilic at high temps. I guess you could say the solvent is mimicking the chloride anion in the Krapcho.

    Lots of solid chemistry all around, and on ridiculous scale. A highlight from the experimental of structure 13: Note: This reaction was run on a maximum of ~30g. On larger
    scale, yields dropped precipitously.
    Sad for them.

  • milkshake says:

    I think the anion in question was acetate. Methyl esters will do SN2 displacement on the methyl group when pushed hard enough. It would be interesting to see if the reaction would also work with CsOAc or KOAc+crown.

  • European Chemist says:

    Agree with milkshake. Probably could have been done with other acetates but don’t forget they needed ammonium to form the enamine in order to obtain the pyridone contained in the natural product.
    Also can’t access JACS, but it’s interesting (particularly after the discussion about the Baran Nature paper) how protecting groups can sometimes fulfill interesting roles. And how the otherwise unelegant Cbz deprotection/reprotection sequence (’cause in the end that’s what it is) is actually quite nice if you give it a thought.

    Also, big LOL to TheEdge – poor Amos and co-workers couldn’t scale further than 30 g! What a shame! :-D :-D

  • TheEdge says:

    I feel genuinely bad for the guy. I can’t imagine what it would be like to run a reaction on 40-60g of intermediate and have it go the wrong way.

  • W506 says:

    I am in a total syn with more than 40 steps(planned). When I joined the project, I was told that Step 14 and step 20 should be done no more than 500 mg once.

  • Doug says:

    I happen to know quite a bit about this synthesis. The use of tetramethylammonium acetate for the decarboxylation step provides a source of highly dissociated acetate, as milkshake stated. Given the right conditions, the net reaction is thermodynamically neutral, exchanging one methyl ester for another methyl ester, generating methyl acetate and the free carboxylate of the beta-keto ester. While HMPA can be used as the solvent for the decarboyxlation step in lyconadin A, we found that the yields were somewhat lower than with acetonitrile. Employing acetonitrile as the solvent was the result of a combined solvent and reagent scan during optimization of the last step, as other “Krapcho” reagents and solvent combinations delivered both lyconadin A and B, but in lower yields.

    Regarding the conjugate addition step, we did expect the desired stereochemistry upon protonation of the enol, based on purely stereoelectronic arguments, and were surprised that we exclusively got the product that we did.

    Correction of the resulting stereochemistry at C(12) was based on trapping the unfavorable equilibrium via formation of the hemiaminal to push the equilibrium in the direction of the desired stereochemistry, which provided a solution to the problem of the C(12) stereogenicity.

  • Broken IR Plate says:

    I think that this is an excellent piece of synthetic work.

  • carbazole says:

    Anyone check out the price of one of their starting substrate? Methyl-3-methylglutarate is $42.40/g. The supp info lists that first step being run on 55g, making that a $2300 reaction, unless they could find some bulk price that’s a lot better. Even then, I don’t think you’re going to find anything much more than half off that price at a bulk scale. Pretty ridiculous. (You could also do a desymetrization of the meso-diester, but that might be tough on huge scale).

  • Doug says:

    Thank you Broken IR plate. Yes, we were able to get a bulk price at a significant cost savings for the methyl-(R)-3-methylglutarate. While we had contemplated running the desymetrization to make the starting material, we calculated that the overall cost, as well the difficulty in running the desymetrization on large scale, and opted to simply purchase it. Fortunately, the transformations to construct the requisite hydrazone were very efficient, so little material was lost generating our desired coupling partner.

  • carbazole says:

    Quick question, as I was perusing the supp. info I saw that it looks like you guys recently switched from SiliCycle to Sorbent for your silica needs. Any comments or complaints? My group is contemplating the switch.
    It is a nice piece of work. Hopefully later this year I’ll open my browser and see my synthesis on Totally Synthetic too!

  • Doug says:

    Regarding Silicycle versus Sorbent, we were switching back and forth between vendors, buying similar quality silica gel, based on the bulk price that we could get. There were slight differences but the switching was principally related to cost. Thanks and good luck with your total synthesis!

  • 23 Apr ’07

    You probably won’t believe this, but I was at Harvard in Organic Chemistry as a grad student from ’60 – ’62, passes 8 out of 9 of the first cumulatives, convinced Woodward to look at carbene formation by photolysis of R CO CH N2 (I think) and then dropped out to go into medicine. I knew Sam Danishevsky back then and hope (for his sake) that he’s lost some weight. Organic chemistry was always fun and always

    came easily to me. It’s clear that the field has advanced signficantly. What would you guys recommend reading to get up to speed. If you don’t believe any of this ask fellow grad students Tom Lowry, Kathy Scheuller (Richardson) or Don Voet. I like the irreverant comments.

  • mychemist says:

    Nice job for the only one author except Amos.
    By the way, Sorbent in GA is quite bad for service. But their silica works well. So far, no problem with metal complexes.

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