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Laureatin and Isolaureatin   

11 February 2007 10,716 views 23 Comments


Deukjoon Kim, Kim, Lee, Lee and Kim. JACS, 2007, ASAP. DOI: 10.1021/ja068346i.

Continuing their fascination with natural products derived from the Laurencia family (not an uncommon fascination!), Deukjoon Kim’s group (the same team that brought you this post) has completed two more related structures, each with that eight-member ring, often found in the family. They base most of the work on an advanced intermediate, created in their synthesis of Laurencin (seven steps, 35% yield), containing that eight-membered ether ring, set for functionalisation.


The first step was halogenation, inverting the free hydroxyl; this isn’t an easy transformation, as the secondary hydroxyls on a ring tend to be quite hindered. However, using the conditions shown (notably trioctyl phosphine), they got a great yeild – conditions they used to even more success later in the synthesis. Osmylation then returned the last common intermediate in good yield.

Oxolane and oxetane formation then diverged the route; however, some complication was had when differentiating the hydroxyls. In the first case, treatment of the diol with base unexpectedly delivered the five member ring. The smaller ring of course required isolation of the required hydroxyl, preformed by formation of a stannylene intermediate, differentiating the hydroxyls. With the protection complete, treatment with base then returned the oxetane in good yield.

In the case of Isolaureatin, the conformation of the medium ring meant that inversion of the hydroxyl using the same halogenation conditions as before didn’t occur. However, they used this steric preference to their benefit by creating a vinyl bromide via formation of the vinyl triflate (the “Wulff protocol”). Then delivery of diimide from the accessable face allow overall inversion. I love diimide reductions :)

Alkylation of the amide returned the ketone, at which point they epimerised the adjacent centre using the unfavorable electrostatic repulsion between the oxygen lone pairs to deliver a 4:1 d.r. in their favour. The ketone was then reduced by L-Selectride with good distereocontrol. The sidechain was then tranformed into a terminal alkene to allow an interesting cross metathesis, using Lee’s protocol to return the desired enyne. Simple deprotection of the terminal alkyne then retuned the natural product.

They then turned to the synthesis of Laureatin, using a similar strategy. Inversion of the freed hydroxyl using the conditions show before worked well this time, and alkylation of the amide was also effective. However, epimerisation didn’t go so well…!

Reordering the steps was quite effective (alkylation with ethyl grignard, epimeriation and then halogenation), allowing completion of the target using similar chemistry. A great read!

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  • sheriff says:

    I would like to know the very mild acidic condition to cleave acetonide in presence of another epoxide to avoid the opening of it. Any idea of bis(acetonitrile) palladium(II) chloride as the mild acetonide cleavage agent( found in greene’s book) Good lewis acid?

  • sheriff says:

    very good paper. He is rocking with his IAEA methodology. I hope we will se more papers on this methodology

  • milkshake says:

    Acetonide is like mother in law – it can be helpful too but the best scenario is if there is none.

    PdCl2.2MeCN is just a mild Lewis acid – I used it to cleave O-TBS group from primary alcohol in presence of 5-membered lactam N-TBS (TBAF had opposite selectivity). You can make your own from PdCl2 – just dissolve the dark anhydrous powder PdCl2 in large volume of refluxing anhydrous MeCN, filter while hot and coold down or slightly concentrate, the yellow PdCl2(MeCN)2 is poorly soluble in acetonitrile and will crash out.

    It depends on what kind of epoxide you have in the molecule but frankly I am highly sceptical that you could cleave your acetonide while keeping the epoxide unharmed.

  • Where does the bromide come from in the Wulff protocol bit (alcohol-ketone-vinyl triflate-stannane-tosyl hydrazone reduction sequence)? No evidence of a bromo source in the third scheme with reagents given there…

    Also treatment of alcohol with POct3 and CCl4 might be expected to yield a chloride (with inversion) and not a bromide (with retention) as drawn.

  • Chinese chemist says:

    I just checked the paper. The bromide came from a separate treatment with bromine of the stannane species produced by the cross coupling, which was missed in the scheme shown here

  • Tot. Syn. says:

    Tot. Med.:
    Yep, I forgot the Br2 in that sequence, and also, as you pointed out, had a copy-and-paste error with the halogenation. However, the structure is correct – no inversion. That substitution really didn’t want to happen!

  • Does the hydrazine reduction go without Pd catalysis? [sorry don't/can't get JACS to find out for myself!] I know that process folks often use hydrazine hydrate as a hydrogen equivalent as you can control the rate of reaction much more easily (ie slow adding of the reagent) but AFAIK it also uses Pd source.

    Shows how hindered it is around these centres that the hydrazide doesn’t displace the bromide. Is this perhaps why they used tosyl hydrazine as opposed to hydrazine hydrate, which would be the more conventional choice?

  • milkshake says:

    TsNHNH2 in basic media is a source of HN=NH whih reduces C=C WITHOUT any catalyst. You can get HN=NH from hydrazine and Cu2+ also or by slow acidification of KO2CN=NCO2K

  • kiwi says:

    #1 a mild cleavage of acetonides can be carried out with CeCl3-7H2O/cat. oxalic acid in acetonitrile, a la Synlett (2001) 535-537. this will pull a primary/secondary acetonide off while leaving a secondary/secondary acetonide untouched. but as mentioned above, good luck.

  • maci says:

    I am now working on some natural products with Br. Is there any general ways to introduce the Br on molecule?

  • tom says:

    There are several ways, and I would guess that most undergrads know at least 2-3 if they have taken 2 semesters of organic chemistry. I would pick up the book Adv. Organic Chemistry by Jerry March and read up.

  • TWYI says:

    BTEA.Br3 and BTMA.Br3 are fantastic for aromatic brominations, yields constantly high in our lab

  • Tot. Syn. says:

    PR3 / CBr4 is a common system for inverstion of hydroxyls, as shown in this paper. However, it only works for primary and uncongested secondary hydroxyls (neopentyl, for example, is a big ask…)

  • Tot. Syn. says:

    TWYI: Are there variants of those reagents for other halogens? Specifically, Iodine?

    I just googled your name (but I’m respecting anonymity, so don’t ask, folks) – are you still on the project you published on in 2006 in ChemComm? That’s pretty funky work!

  • TWYI says:

    Tot-Syn- That was my PhD work, Post-doc now. Guess you can get the location from my IP address!

    Back to the original question, I think the chlorine and iodine variants do exist, SciFinder them to be sure…

  • maci says:

    I want to convert the secondary alcohol to OMs,then replace the OMs by LiBr.
    But I don’t know if this method only works for uncongested secondary alcohol?

  • sheriff says:

    You can make the iodo by treating the alcohol with imidazole/ PPH3 and molecular iodine either in DCM or ether.

  • anonym says:

    Couple of unrelated questions:

    has anyone ever reacted 2-thienyl lithium with ethylene epoxide? Reaction seems to be sluggish and very slow. Kept it at 0 for 3h still have a lot of starting material….You think MgBr2 would help?

    I am also having a hard time performing Michael addition of 2-thienylcopper with methyl acrylate. Yea 2-thienylcopper is quite robust and stable complex and does not want to react with anything… I found only one procedure where you generate copper in Et2O but then actually have to remove Et2O and replace it with CH2Cl2…not that convenient. Any suggestions?

    P.S. I will put totalysynthetic.com into my acknowledgment part for sure :))))

  • Russ says:

    Tot Syn asked about aromatic iodination reagents. Here’s my favourite: 0.4 eq. I2 + 0.2 eq. HIO3. It’s cool because every iodine atom gets used up and the only byproduct is water, so the workup consists of evaporation.

  • milkshake says:

    There is a very mild-yet-powerfull class of iodination reagents, and they were commercial. It is I+(collidine)2 BF4- (or lutidine verison) It used to be sold by Novabiochem but I could not find it in the ACD database now.

  • .... says:

    Re: comment 13.

    In one of our group meetings we discussed the possibility of R-OH -> R-Cl with PR3/CCl4 when the alcohol is neopentyl. Two examples come to mind:

    Baran’s Welwitindolinone/Fisherindole and Wood’s partial Securine synthesis (PNAS 2004)