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Sorangicin A – pt. 1   

23 August 2009 10,046 views 5 Comments


Smith, Dong, Brenneman, Fox. JACS, 2009, ASAP. DOI: 10.1021/ja9052366. Article PDF Supporting Information Group Website

I thought I’d re-start after holiday with a tasty target, and sorangicin A certainly fits the bill.  It’s not often that I have to draw such an exotic structural motif into a target (though in reality it’s not far removed from a DHP); always a welcome feature in a synthesis.  But sorangicin A is more than just a structural challenge – it’s quite an antibiotic, with broad-spectrum activity against both Gram-positive and Gram-negative strains.  With the funding proposal in the can, the synthetic challenge was taken-up by a variety of groups, including those of Crimmins and Lee, but it’s Amos Smiths group who are first to the flag.


As is frequently the case with such large macrolides, analysis of synthesis is best done with a bit of retrosynthesis.  Splitting the molecule into four fragments, the most obvious disconnection, that of the lactone, was dealt with simply a spot of DMAP.  Two isolated alkenes were installed using Julia coupling (which were far from trivial), whilst the prickly-looking Z,E,Z-triene was eventually pressed into submission via a Stille coupling.  That leaves the simple matter of constructing the fragments, right?!

I’m starting with a look at the dioxabicyclo[3.2.1]octane unit first, mostly because my corvine-like eye is drawn to anything shiny like this.  The chiral gycolic aldehyde (derived from l-gulonic acid ?-lactone) was treated with a chromium Schiff-base and Danishefskys diene, promoting a  hetero Diels?Alder, and formation of a second stereocenter.  Functionalisation of the enone (which was a bit recalcitrant, due to the enol group) was done using the Noyori three-component coupling protocol, in which bromo-styrene was lithiated, and the metal then switched for zinc.  The enone was then added to the mixed-zincate, resulting in a Michael-addition-type product.  Using the Noyori work, this was then quenched by addition of methyl group, which required a bit of optimisation.  Initially, ten equivs of MeI in HMPA were used, giving a reasonable yield of the product as a single stereoisomer; however, dimethylation was also found.  The yield was improved by mediating the bascity of the intermediate by addition of CuI•PBu3 just prior to the methyl iodide.  Nice result, and a cracking yield over so many steps.


Creation of the dioxabicyclo[3.2.1]octane unit was yet to come, only a few steps later.  A stereoselective reduction and protection group shenanigans generated the key intermediate for this cyclisation, which when treated with base, allowed formation of a terminal epoxide as expected.  This was then attacked by the other alcohol, resulting in bicycle formation.  Nice approach.  Completion of this fragment required only formation of a vinyl iodide via Takai olefination, and an oxidative clevage of the styrene to reveal an aldehyde.  Interestingly, they used a two-step protocol – an SAD, followed by periodate.  Presumably the more direct ozonolysis was unselective, and attacked the freshly installed vinyl iodide.


The THP-containing unit was created using a more familiar approach – at least to those keen on macrolide syntheses.  Aldol time, then.  Indeed, this piece was built by stitching the siloxy side-chain on using a Suzuki?Miyaura coupling, whilst the pyran section was created by firstly aldoling the carbon skeleton together, then forming a ketal at C-23.  The extraneous methanol was reduced-out, leaving the desired pyran in an impressive brevity.


That’s all for now, kids – more on Tuesday, when I’ll tackle the other fragments and the unification…

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  • bob says:

    That domino DA/Conjugate Add/Alkylation is really nice, I saw this paper in ASAP, but didn’t read it that closely. I plan on doing so now…

  • redox says:

    why chirality of the aldehyde was not enough for the sufficient selectivity on the hetero diels-alder step?

  • js says:

    probably the dr wasn’t good enough or they just had that jacobsen catalyst in the freezer anyway :).

    off-topic: usually i wouldn’t advertise kcn’s chemistry, but his hirsutellone b synthesis has a really sweet epoxide-opening diels-alder cascade in there. maybe you want to check this one out, if you like diels-alder chemistry:


    • milkshake says:

      I know a guy working on Hirsutellone B. Maybe after this KC’s paper he can happily write up a formal synthesis paper and finally graduate.

      • anonymos says:

        The same reaction can be carried out using just Zinc chloride in Benzene instead of the Jacobsen catalyst. That gives a single Stereoisomer in 72 % yield as published by Danishefsky (Danishefsky et al. J. Org. Chem. 1982,47, 1981-1983)