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13 October 2008 7,127 views 10 Comments

Phillips and Griggs. Org. Lett., 2008, ASAP. DOI: 10.1021/ol802041c. Article PDF Supporting Information Group Website

I guess Andy Phillips has been a rather busy-boy – not many researchers get back-to-back articles in Tot. Syn.!  However, both papers are definately worth writing about; his pyranicin synthesis showcases some rather neat methodology.  From a biological perspective pyranicin is fairly interesting, as it exhibits the same nano-gram ED50 values against a variety of cancer cell-lines as the more complex acetogenins.  Phillips suggests that it was this activity, along with inhibition of electron transport, that prompted their synthetic efforts.

From a retrosynthetic point of view, Phillips sticks with the tried and tested split-it-down-the-middle-and-stitch-the-halves-together-at-the-end style of fing, but it doesn’t half work well.  The left hand fragment contains the titular pyran, built from a furan shown as the SM in the first scheme.  Treatment of this racemic material with a bit of Sharpless (in the form of a kinetic resolution described by Sato) gave the enantiomerically pure hemiacetal product, in which the ring has been expanded by one.  Technically, this is known as an Achmatowicz oxidation, but the reagents and conditions used seem to have modernised somewhat!

Reduction of this hemiacetal in situ with a bulky silane and some Lewis-acid resulted in the ether (a Kishi reduction for all you named reaction fans…), which was further reduced to the dihydropyranone, and then to the pyranol, fixing the last of the three stereocenteres on the ring.  Nice work!

Moving on to the other fragment, an interesting chiral butenolide fragment had to be built, and Phillips went for an interesting procedure developed by Stille and (later) Hoye. Carbonylative lactonization was induced by adding a bit of palladium catalyst in an atmosphere of carbonmonoxide, but the mechanism isn’t particularly simple.  Loads of work was done on it by Stille back in the late 70′s – early 80′s, with this paper giving quite a bit of insight into the process.

Last-up is the coupling together of the two fragments; following a developing theme in this paper, it wasn’t done in any traditional method.  Instead, Phillips turned to an alkyl-alkyl Suzuki coupling developed by Greg Fu, coupling a primary alkyl bromide with an alkyl borane (created by in situ hydroboration of a terminal olefin).  This impressive and ambitious coupling worked rather well, using a fair-old lump of palladium catalyst, but otherwise mild conditions.  Ace.

A deeply impressive little synthesis, I’m hoping that a full paper might follow sometime to elaborate on some of the chemistry used.  Whilst I’m waiting on that, I’ll carry-on reading the references…

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  • antiaromatic says:

    the sp3-sp3 coupling is nice. I wonder if they tried using the iodide instead of the bromide.

  • Tot. Syn. says:

    If you read the linked Fu paper, you’ll see that he finds that alkyl bromides are better partners for the coupling, as the reaction temperature can be lowered. I guess that alkyl bromides are also a little less likely to eliminate, which would always be a concern when using primary alkyl halides with beta-protons.

  • Borat says:

    Very Nice

  • milkshake says:

    Sometimes Pd(0) -catalysed coupling reactions work better with bromides: iodides do have much faster insertion rates but the produced iodide anion complexes to Pd rather strongly and saturating the coordination sites with iodide slows down the turnover – especially when bulky phosphine ligands are used or when the substrate itself is strongly coordinating. This iodide inhibition is a problem one can counteract it by adding stoechiometric Ag or Tl salt.

    In my hands, for Buchwald-Hartwig N-arylations and Suzukis, the Buchwalds bulky biphenyl ligands are best suited for aryl bromides (and chlorides), and the old fashioned tetrakis or Xanphos in THF as a solvent works better for iodides.

  • shin says:

    Picking up the furan starting material is trendy because it is readily available from sustainable sources.

  • accurate says:

    Hey guys, did you see KCN’s synthesis of aspidophytine today ? He’s on his way to making haplophytine !

  • Tot. Syn. says:

    Blogged on Thursday, hopefully :). I know the post-doc that did most of the work – Steve Dalby, who did his PhD for Paterson whilst I was at Cambridge…

  • accurate says:

    Must be a quite successful chemist !

  • Fools' gold says:

    greg always publishes communications. I dun realli see him going into full papers and doing extensive mechanistic studies for his alky couplings. Feels very much like a mix and stir “screening” approach if you ask me.

  • C. Bailey says:

    Hey, you have a typo on your structure for pyranicin–you’re missing the hydroxyl right next to the pyran!