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Iejimalide B   

30 July 2006 7,804 views 12 Comments

Iejimalide B.jpg

Fürstner, Nevado, Tremblay, Chevrier, Teplý, Aïssa, and Waser. ACIEE, 2006, Early View. DOI: 10.1002/anie.200601860.

An interesting read by Fürstner, into the synthesis of this cytotoic and anticancer polyene macrolide. The most active member of the family, it’s certainly a useful target, but one would think that the disconnections for the retrosynthetic analysis would be relatively straight-forward. However, that tempting macrolactonisation failed so their approach to this campaign had to be revised. They decided, then, to complete the macrocyclisation using a RCM strategy. (Two other papers by the authors are referenced as being connected to this decision, but the papers are not available yet… I’ll add them when I can. Update: Heres one… [1])
Their fragment synthesis involved a notable palladium mediated alkylation, working with a propargyl mesylate (R= H, TIPS) and an aldehyde. This transformation uses diethyl zinc, and returned a better d.r. (unsurprisingly) with the TIPS-bearing acetylene.

Iejimalide B_1.jpg

Other fragments were built using more traditional means, leading them to the assembly stage. The ester was returned using Yonemitsu methods, and RCM with Grubbs II completed the macrocycle to give the desired product in a quantitative transformation. This is no mean-feat; RCM of polyolefins is a difficult process to say the least. However, at this point, their luck ran out; cleavage of the BOC group proved impossible without decomposition of the macrocycle! Examining this process further using a suitable model system, certain subtleties became apparent, namely the choice of alcohol protecting group [2]. Although this seems rather remote from the amine, Fürstner proposed a very interesting and plausible reason for this anomaly.
Iejimalide B_2.jpg

A replanned assembly strategy then allowed them to complete the molecule; peptide coupling at an earlier stage, Suzuki, esterification and RCM completed the skeleton, with only deprotection required to finish. Again, a great read; I have great respect for those authors who discuss their problems and setbacks, as it brings the achievement of the synthesis into greater focus.

[1] My spies in Germany say that certain “issues” have been had with Angewandte…

[2] A badge and a balloon to anyone who can tell me what a tigelate group is.

Update: NoName and Movies tie on this one, both post around the same time that the tiglate group is the tiglic acid ester:


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  • NoName says:

    must be tiglate (trans-2-methyl crotonyl), which is the possibly decent and simple surrogate for target structure.

  • movies says:

    Tiglic acid is 2-methyl-crotonic acid (or 2,3-dimethyl acrylic acid), so here’s guessing that it’s that ester.

  • movies says:

    Heh, no, I was beat!

  • Allenylmetal says:

    I am interested in hearing why you were not suprised that the TIPS group on the propargyl mesylate leads to better selectivity.

  • Tot. Syn. says:

    I might be looking at this too casually, but wouldn’t the increased steric bulk on the acetylene direct the palladium addition to the top face more effectively? Then displacement with the aldehyde would lead to better overall d.r. Do correct me if I’m wrong – I’ve not examined this closely.

  • Allenylmetal says:

    Check out the reference in the paper for that reaction as well as this paper (http://dx.doi.org/10.1021/jo060542k). I have to be honest with this. My wife and I developed that TIPS reagent/methodology for Marshall and we were surprised by the increased d.r. given the proposed transition state. The reason that we used that TIPS was that the reagent was easier to make and handle. I was jusy interested in hearing you thoughts on it….

  • Tot. Syn. says:

    That’s a really nice paper – thanks for bringing it to my attention. I’m sure all here will appreciate it. The mechanism proposed for the reaction with the zinc chelate is interesting; the TIPS group is held well away from the reaction site, but perhaps forces the allene towards the carbonyl by exerting a steric force on those ethyl groups on the zinc. I’ve not got time to make a model, but TIPS is pretty damn big… I saw you tried the bare acetylene, TMS protected and TIPS protected, with a great varience in d.r.; clearly, the silicon group could have either electronic or stric effects, but as the increase from H < TMS is smaller than that of TMS < TIPS, I’d presume the steric contribution was more important. Though I’m probably very wrong – you’re the expert!

  • Tot. Syn. says:

    One of the methodology papers has been published online:

  • Allenylmetal says:

    That link won’t work for me….

  • Tot. Syn. says:

    There’s something wrong with the quoted DOI… I don’t know what, so here’s the plain URL

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  • B.R.S.M. says:

    […] comfortable with…). Not happy with just the first total synthesis of the iejimalides (Tot. Syn. here) back in 2007 and prompted by encouraging biological results obtained using the material from the […]