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35-Deoxy Amphotericin B Methyl   

6 May 2008 11,388 views 36 Comments

Carreira, Szpilman and Manthorpe. ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200800590. Article PDF Supporting Information Carreira, Szpilman, Cereghetti, Wurtz, and Manthorpe. ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200800589. Article PDF Supporting Information Group Website ResearchBlogging.org

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 Frater–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!

[1] Something about ‘barrelstave ion channels’… do I look like an agar scraper?

[2] Don’t get me started…

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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  • Alex says:

    Thanks Paul

    As you note, the installation of the mycosamine sugar unit was particularly nasty. Jeff and I had days and days of fun solving that problem.

    The 2-chloro-butytic ester was the only ester that at the same time gave more of the glycoside than the orthoester, was able to control the formation of the desired beta anomer and could be removed under mild basic conditions (thank you chlorine).

    The use of the mild and sterically hindered acid 2-chloro-6-methyl-pyridinium triflate was born out of the formation of adducts between the sugar donor and the PPTS we originally applied (Nicolaou’s procedure) as described in the paper. Strong acids would rip out the unsaturated alcohol on the aglycone leading to the formation of the worlds longest allylic cation (strongly blue). Weaker ones would not induce reaction.

  • Le Dude says:


    First of all, nice work and congratulations on a tremendous accomplishment. I noticed that you guys are big fans of the TEMPO oxidation of primary alcohols. Is there a reason why you prefer that oxidation in particular when there are so many other options available?

  • Alex says:

    Yes, there are several reasons
    1. All the reagents are commercially available (you do need to titrate the bleach to make sure not to add an excess).
    2. It is easily scalable. On very large scale some strong stirring may be required to keep the temperature down.
    3. It is fast (usually done in a few minutes).
    The aldehyde is usually clean enough after water workup for use without any flash (e.g. for use in the Zinc acetylide addition or Ohira reaction.
    4. Most importantly the yields are high. The yields usually only drop if you add the bleach to slowly or if the temperature runs away with you.
    5. When necessary it is selective for primary alcohols over secondary alcohols.

  • ... says:

    The bleach titration is with starch/iodine?

  • milkshake says:

    yeah, DMSO from Swern or NMO from TPAP oxidation would probably ruin the enantioselectivity of the acetylene addition.

    By the way, the alcohol corresponding to the aldehyde depicted here (in paper the compound 5) is a side-chain building block for Lipitor and Crestor statins. It is commercially available from Takasago – we bought 1 kilo bottle of the stuff for a project that is over now and this optically pure acetonide-ester-alcohol is gathering dust in the cabinet…

  • Jeff Manthorpe says:

    … yes the bleach titration uses starch, KI, and sodium thiosulfate. The bleach oxidizes the KI to I2 and then you use the thiosulfate to titrate the I2. Here’s a procedure:

  • pm says:

    Borane dimethylsulfide complex + catalytic NaBH4 system has been used for chemoselective reduction of methyl ester (SI – compound 3). I was wondering if it can selectively reduce an ethyl ester in presence of an amide linkage.

  • Alex says:

    The selective reduction is a function of distance to the hydroxy group i.e. the alfa ester is hydrolyzed faster than the beta-ester.
    If the ethylester and amide are similarly spaced from a hydroxy (or even amino) function its should be possible.

  • pm says:

    Thanks Alex. Actually my amide is part of a 3,4-dihydroquinolin-2(1H)-one system and the ethyl ester is far away in the side chain. Sodium borohydride reduces both the ester and amide. I got ~30% yield of the alcohol.

  • Jason says:

    The TEMPO oxidation has a lot of benefits, but my work often involves conjugated dienes … my understanding is that the bleach by-products usually aren’t compatible with easily oxidized functional groups. Is that correct?

  • Alex says:

    You should be able to hydrolyze the ethyl ester and reduce the resulting carboxylic acid selectively with borane (no excess!).

    Bleach will by itself oxidize alkenes. This is the most important limitation of the scope of this method.
    However another oxidant (or method) can be used e.g. PhI(OAc)2.

  • pm says:

    Thank you very much Alex. By the way congratulations for your papers.

  • J says:

    Finally! No RCM needed; I guess you can’t given all the unsaturation.

    I like the pyran synthesis, though I would’ve like to have seen if Jenning’s oxonium cation generation would’ve worked.

  • pm says:

    Can amides be protected (by some means) from reduction?

  • gilgerto says:

    You might want to try a Luche reduction which should not touch to your amide…

  • milkshake says:

    Borohydride reduction ignores normal amides – unless you add acid or iodine in which case you generate borane in situ so dont use these additives. (Borohydride reduces imides but thats another story)

    LiBH4 2M solution in THF at 0C is a very safe bet for doing the ester in presence of amide. If the overreduction is stil a problem you can try LiAlH(OtBu)3 at low temp. Or you can hydrolyse, take the free acid, make mixed anhydride with EtOCOCl in situ and then reduce with borohydride.

  • pm says:

    Thank you gilgerto and milkshake.

  • Jas says:

    I’ve been having a lot of trouble with the chemoselective reduction of an ethyl cyclopropaneester in the presence of an alpha-beta unsaturated amide.

    I’ve tried LiBH4, LiAlH(OtBu)3, LAB and many other reagents and so far the only thing that somehow worked was DIBAL in CH2Cl2 which gives me about 20% yield of the alcohol. Hydrolysis of the ester doesn’t seem possible either. Any thoughts?

  • milkshake says:

    there is also “TRIBAL”, iBu3Al which works quite fine as a reducing agent despite not having any Al-H bonds. I know people who have been using it in Etinascidine analog synthesis. Dont ask me about mechanism.

    It seems to work better in Et2O, at -78C, with several equivs of “TRIBAL’ . Another good reagent is LiAlH2(OEt)2 in Et2O, made by adding 1 equiv of EtOAc to LiAlH4 soln.

  • Alex says:

    Isn’t TRIBAL just DIBAL-H plus one equiv. of BuLi. I.e. it has a Al-H ?
    I tried it on one occasion (it didn’t work in my case)

  • milkshake says:

    no it isn’t. Robin Polt, who discovered its use (JOC 57(1992), 5469) was using it in combo with DIBAL but TRIBAL alone will work if used in large excess (10 equivs)

    Also, the LiAl(OEt)2H2 reference is here: Brown, JACS 86 (1964), 1089

  • anon says:

    presumably, the reduction by TRIBAL (nice abbreviation!) would proceed via a Meerwein-Ponndorf-Verley type mechanism, with the carbonyl coordinating to the Al center, followed by hydride transfer from the beta position of one of the i-Bu groups to the C of the carbonyl via a cyclic 6-membered TS, kicking out isobutene and forming (i-Bu)2Al(OR) + reduced carbonyl…

  • pm says:

    Can carbamates (RNH-BOC) be reduced by NaBH4?

  • antiaromatic says:

    Another reducing reagent that can be used is diisobutyl aluminum chloride. I’ve seen it used in MPV-type reductions to give similar results.

  • ... says:

    What’s the purpose of the pH 8.6 buffer in the TEMPO oxidation?

  • TheEdge says:

    Like all oxidations, TEMPO generates an acid (in this case, HOCl), which the pH 8.6 buffer helps neutralize. A google search of this reaction turned up the fact that you oxidize to the acid if you leave out the base (probably through the hydrate), which would be a bad thing in this case.

  • milkshake says:

    well Edge you are pulling this one out of your butt. (For example TPAP oxidation does not generate acid – it generates N-Me morpholine from NMO…)

    Unbuffered TEMPO/bleach oxidation pH would go down because HOCl is a weak acid so NaOCl is quite basic by itself, whereas NaCl is not.

    The other thing is that Chlorox bleach comes stabilised with extra NaOH because hypochlorite solution keeps best on shelf when strongly alkaline. So you actually make the bleach solution LESS basic by adding the buffer….

  • TheEdge says:

    I suppose my fault lies in saying “all” about something as broad as organic chemistry. That being said, the great majority of oxidation half reactions have H+ on one side of them, especially the ones involving oxides or alcohols. You generally either generate an acid that you have to sop up with a base, or you spit them both out via a dehydration, as in the the TPAP oxidation (where you make [RuO3H2]- that breaks down to water and [RuO3]-). The two protons you pull off the alcohol have to go somewhere if you don’t make H2.

    I am man enough to admit that I pulled the TEMPO answer out of my butt, though, and didn’t bother to check a pKa table for the acidity of HOCl. Google books doesn’t have the section of Modern Oxidation reactions about TEMPO up on the web. I apologize for shooting off without checking my facts.

  • TheEdge says:

    and that should be [RuO4H2]-, not [RuO3H2]-
    Stupid egg stains will never come out of this shirt.

  • p says:

    Why the ether 6 was pepared at 0 oC?

  • p says:

    Where did you buy the plastic apparatus for HF reactions?

  • Alex says:

    The alcohol was deprotonated with NaH at 0 degrees to prevent the reaction being to violent on large scale. Afterwards the temperature was raised to room temperature and left 24 hours.

    The plastic apparatus for the HF pyridine reaction was an old plastic ethyl acetate flask fitted with a septum instead of a cap. This solution is cheap and convenient even if stirring is not the best. Quench was done by cannulating the solution into Na2CO3. This avoids most of the CO2 bubbling that occurs with a NaHCO3 quench and is preferable if you compound is not sensitive to base.

  • InfMP says:

    Wow. these kind of discussions with the authors are really great (anyone read the tender button discussion with JJ LaClair? haha)
    I highly recommend the TEMPO/Bleach procedure to anyone I meet. It literally saved my Honours project (highly acid/base sensitive molecule needed a primary oxidation to carbox). The first big challenge I ever faced in the lab.

  • InfMP says:

    WOW SI is top notch. If only everyone cared this much….

  • […] First-up was a discussion about amphotericin B, which was blogged here back in may.  The deal was that by cutting-out the C-35 hydroxyl, one might prevent the molecule from allowing […]