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Sorangicin A – pt. 1   

23 August 2009 10,446 views 5 Comments

sorangicin_a

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.

sorangicin_a_1

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.

sorangicin_a_4

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.

sorangicin_a_5

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.

sorangicin_a_6

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

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5 Comments

  • 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:

    doi.wiley.com/10.1002/ange.200903382

    • 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)