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Platensimycin Pt. VI… return of the bacterium…   

25 April 2008 5,483 views 9 Comments

Lee, Kim, Jang, Choi and Chung. ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200800568. Article PDF Supporting Information Group Website ResearchBlogging.org

Antibiotic… blah blah… Merck… Nicolaou… other synthesis covered

Yep, you all know about platensimycin, and half of you have probably worked on / are working on syntheses of this ‘popular’ target. Eun Lee hasn’t bothered with a full total synthesis, instead satisfying a neat formal of the right-hand ‘cage’ motif. Key to this was the optimisation of a substrate for a rhodium catalysed carbonyl-ylide cycloaddition.

They suggest that they knew that a terminal olefin would have the incorrect electronic configuration to lead to the desired product in the [3+2] before attempting the chemistry. However, they did the reaction anyway, and ended out with a cracking yield of the wrong isomer and only a trace of the desired. Playing with the HOMO coefficient by using a vinyl halide in place of the terminal olefin allowed the chemistry to proceed in a tasty 83% yield, with small amounts of the competing products. They then had to remove the extraneous halide – using hypophosphite.

All the optimisation of this reaction was performed on racemic material – but their synthesis of enantiopure substrate was quite nice. They took (S)-propylene oxide and opened it with the enolate of isopropyl cyanoacetate. This of course leaves a free hydroxyl anion, which closes onto the isopropyl ester to give the gamma-lactone – a reaction I did not so long ago with dimethyl malonate. It’s trickier than you might imagine… They then went one-further, and alkylated in-situ with iodoallyl iodide to give the desired product in pretty decent yield (and what appears to be 5:1 d.r.). Transformation of this into the key substrate was straight forward.

However, transformation of the cyclisation product into the formal synthesis intermediate was more challanging. An HWE olefination onto the ketone gave an enone in good yield, but reduction of said enone was apparently trying – an hydrosilylation and hydrolysis of the silyl enol ether was required. A few more steps took them to the desired intermediate – but in which synthesis? Did I miss that reference?


Kim, C.H., Jang, K.P., Choi, S.Y., Chung, Y.K., Lee, E. (2008). A Carbonyl Ylide Cycloaddition Approach to Platensimycin. Angewandte Chemie International Edition DOI: 10.1002/anie.200800568

InChiKey Dump
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9 Comments

  • pmgb says:

    Is part of the SI in Korean? I could not download it.

  • milkshake says:

    I think this is an exceptionally nice example of methodology-driven tot synthesis, because they did the electronic tailoring on the substrtae to get the “disfavored” regioisomer so they showed a straightforward way how to extend the meethodology scope. The molecule si small, complex and the most problematic part is right at the start of the scheme so if things go wrong only few months of work would be wasted. I think this kind of project teaches the students more than completing a marine polyether toxin with 12 consecutive fused rings, from segments made by other group members

  • chemist says:

    Milkshake,

    I think that different projects teach different things. Completing a marine polyether toxin very often is an extremely complicated task (working on a micromilligram scale, optimizing the final steps without significant spectral data, and even having the pressure of not waisting 10 mg of some advanced intermediate that took 3 man-years to prepare). I wouldn’t give such a project to uneducated person…

  • Madforit says:

    Milkshake:i would like to have some explanation about the mechanism of the oxidative dearomatisation of substituited phenol (with ipervalent iodine)that you proposed about one year ago for the synthesis of the spiro ald.(first enantiopure synth.of this target by KCN).Thanks in advance,sorry for the english…

  • milkshake says:

    The oxidative spirocyclisation is for example here:

    ACIEE 44(38) 6193-6 (2005)
    Tet Lett 47(3) 385-7 (2005)
    PCT Int. Appl., 2008022462, 28 Feb 2008

    Oxone puts OOH into 4-position of 4-subst phenols, to get the useful p-quinolhydroperoxide: Org Lett 9(24) 5019-22 (2007)

    There is also electrophilic version of spirocyclisation:Pummerer reaction: Org Lett 10(7) 1441-4 (2008),
    Michael addition: Org Lett 9(24) 5035-8
    and various Claisen-rearragement-like 4-allylations on 4-substituted phenols

  • Madforit says:

    thank you so much milkshake…

  • J says:

    Very interesting attempt at the heterocyclic cage; would have never expected that iodine to survive (elimination product, maybe?) I attempted this molecule in my ORP, but limited myself to using water as a solvent in all of the transformations (the cage would’ve been assembled in some sort of Diels-Alder cyclization). I got hammered by my committee about how it would probably never work; they’re probably right.

    I’m still curious to know which total synthesis of platensimycin is the most scaleable (assuming it is still being prepared/researched by Merck). I wonder if Merck is considering a semi-synthetic method?

  • SMILES says:

    Nobody find weird that in the supporting information they have done the calculation of the dipole on a HF 6-311G basis in one part , and on a HF 3-21G basis in the other part concerning the dipolarophile.
    And after they mixed all the data together….For me it’s strange.
    Furthermore, the rhodium can act as lewis acid and can orient the reaction through complexation and modify the orbital coefficients, which is not mention in the paper.

  • Jorden says:

    J,

    The cage has been assembled by a Diels-Alder cyclization last summer by a member of our group

    Org. Lett., 9 (20), 4013 -4016, 2007.