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Leucascandrolide A   

31 May 2007 7,382 views 23 Comments

leucascandrolide_a.jpg

Cossy, Ferrié, Reymond and Capdevielle. Org. Lett., 2007, ASAP. DOI: 10.1021/ol070670a.

Another synthesis of this popular target, and whilst not mind-blowing, certainly a nice strategy for one of my favourite targets. However, I should point out that the synthesis is actually only a “formal”, as they didn’t bolt-on the oxazole sidechain. Rather, they focused on the macrolide core, using three allylations and a crotylation to install four of the hydroxyl units.

leucascandrolide_a_1.jpg

The rest of the molecule was constructed using a metathesis to add the ester unit to the top polyol fragment. They then closed the nearby hydroxyl onto the resultant enone to provide the -cis pyran; nice work. Also noteworthy was the Mukaiyama style coupling of the lower terpeneoid fragment to the top fragment.

leucascandrolide_a_2.jpg

So, to the allylation / crotylations. They used a TADDOL derived Ti reagent, allowing both enantiomeric and diastereo control in the initial crotylation. Credit, however, was given to Hafner of Ciba Geigy (and by inference, the legend that is Seebach), and more of this chemistry is discussed in a rather nice JACS paper.
leucascandrolide_a_3.jpg

They later used the related allylation substrate shown below to do two of the three allylations, again with good diastereoselectivity. The remaining allylation was done in a more traditional sense, using substrate control to add allyltrimethylsilane with tin tetrachloride.
leucascandrolide_a_4.jpg

Again, not particularly novel, but a damn nice implementation of existing chemistry.

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23 Comments

  • milkshake says:

    I don’t like to see a such an elaborate stoechiometric chiral reagent used on aldehyde that is a commercial and easy to make. If it was in late stages on an advanced piece that needed 15 steps then a funky reagent like this is justified.

  • willyoubemine says:

    that reagent is easy to make…its two steps from tartrate and TiCp2Cl2. As far as comparisons to the ease of borane crotylations (and inherent catalyst synth), I cant say.

  • kiwi says:

    Cossy is a big fan of those Ti allyl/crotylations – i remember seeing her talk a couple years ago and she had heaps of examples.

  • earth23 says:

    I wonder why they ended up using TBS on their secondary alcohol that was derived from the yne-one. Not only do they have to do a selective TBS deprotection (primary vs. secondary) but the final TBAF deprotection was not high yielding (38%).

  • round and round says:

    earth 23: As far as the selective deprotection is concerned, I think it was not too bad (80% of the desired) and I think the low yielding step (38%) you mentioned is more because of the transformation leading to THP ring where they might have obtained low yield and 25% of the wrong diastereomer.

  • ZZZZZ says:

    This synthesis makes me sleepy.

  • provocateur says:

    wheres prof. ley’s stuff u said????????…..zzzzzzzzzzzzzzzzz..does not meet Tot. Syn quality

  • jimbo says:

    Shouldn’t we be beyond stoichiometric enantioselective allylation reagents?

  • HR says:

    #7 : there’s also a synthesis of azaspiracid-1 by evans on angewandte early view

  • Smitty says:

    #8 Do you mean allylating reagents in general, or chiral allylating reagents? It seems that the best way to introduce an allyl group (by nucleophilic means) is the allyl boranes, silanes, titanium, etc. Once we have these reagents in hand, if they can easily be made enantioenriched, why not? What do you propose otherwise?

  • jimbo says:

    #10: there are enantioselective allylation catalysts… not as robust, but they’re getting there (starting from allyl-M or allyl-X). Chiral stoichiometric reagents are so 1990′s.

    All of the widely used methods require a stoichiometric chiral reagent ($$$) which must then be separated from product. Stoichiometric titanium reactions are especially shitty to workup, and brown allylations are famous for generating a lot of Ipc-OH which needs to be separated from the product (which is usually difficult because they are both secondary alcohols).

  • milkshake says:

    for simple substrates that lack acid-sensitive functionalities and labile protecting groups, asymmetric ene reaction can be a decent alternative to allylation/crotylation (Mikami, Evans)

  • Tot. Syn. says:

    Yep, noticed the Evans paper today… looks like top work! However, I’d expect nothing less… I’ll blog the Ley paper later today, and the Evans paper early next week. For now, I’ve got some Hunig’s base to distill.

  • European chemist says:

    As a regular participant in conferences here in Europe (hence my name), it’s now been more than 4 years that I’ve seen Cossy use the “allylation – ozonolysis – allylation – cross metathesis” strategy ad infinitum to build polyol frameworks. While from an aesthetic point of view it is not nice, it has the merits of (near) complete predictability and experimental ease. Indeed, Cossy’s group have developed special tricks to help separate the titanium salts from the product and they routinely carry out these reactions in multigram scale. Bottom line: it works and damn well it does. One of her syntheses of a natural product using this booooring strategy took only 15 days for a grad student to perform, because everything worked perfectly the first time round.

    I recall being impressed by this clever use of known reagents the first time I saw her in a talk. However, as with most repetitive chemistry, the awe-effect wears out after a while. I, for one, begin to seriously wonder whether Cossy has other strategies to build natural products. But don’t forget that while we tend to prefer innovation and “elegance” in synthetic design, there are people that will argue that “total synthesis is, above all, supposed to deliver the final products”. And Cossy, at least, does that.

  • Lurker says:

    15 day natural product synthesis? Which one was that? That’s pretty sweet…

  • jimbo says:

    #14: Yeah, she delivered a natural product… which has been made by every other natural products group. Brown first published on enantioselective allylations almost 25 years ago.

    It’s “me too” chemistry on a “me too” natural product. I think it’s important to keep in mind the job of an academician. If any of those names are PhD students and not undergrads, the question is: what did they get out of this? (this would be a stellar undergraduate project, however)

  • undergrad says:

    As an undergrad I would have to agree that this would be a stellar project, but I think it is a little to complex for someone who has only had a few adv orgo classes and some of the basic chemistry classes.

    I think that undergrads are best served working with someone(profs/grad students) to learn lab technique.. Attempting a project like this would be rather ambitious, and it is likely it wouldn’t get finished without them first wasting a huge amount of time trying to figure out technique.

  • jimbo says:

    I think you underestimate what a good undergrad can do. I’ve known several undergrads who have spend the final 2-3 years of school doing independent research, and who have completed equally complex tasks. I wouldn’t hand an undergrad Leucascandrolide without guidance… but if you give that molecule in the context of the iterative use of a particular reaction, it suddenly doesn’t sound that bad.

  • milkshake says:

    Training people in routine chemistry is not bad – if they plan to go to med chem, in industry rather than academia.

    I would prefer job candidates who did lots of routine stuff (and now they can they do it even in their sleep) rather than someone who banged his head into wall for 5 years, trying to improve the ee’s with some godawful catalyst.

  • Jimbo says:

    I disagree, milkshake… I’d like to see a BS/MS chemist like that, but would much rather have a problem solver at the PhD level. The whole game of med chem is trying to optimize 20 different parameters in the same molecule… and in process chemistry, you’re doing the same head banging (with access to much more powerful research tools).

    In academics, it doesn’t matter at all what kind of bench training you have… your job is to generate ideas and recruit hard working students who can bring them to reality.

  • ddd says:

    formal syntheses lead to formal science…they should be forbidden

  • TWYI says:

    15 day total synthesis LOL.

    It has taken me over two weeks to find the optimum conditions for a palladium catalysed cross coupling. That will be one step then. Quite early in the route too.

    :oops: