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Sorangicin A – pt. 2   

25 August 2009 12,537 views 8 Comments


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

Read the first post?  Good.  Let’s get on with the one remaining fragment, a further DHP.  Work on this fragment was conducted via a coupling of an enone with the ready-elaborated sidechain – reaction that might be a little sluggish, as the enol functionality is again working against the group.  However, forming a cuperate of the vinyl bromide solved this, allowing a highly selective and reasonably high yielding reaction (60%, 20:1 d.r.).  BTW, the two fragments weren’t particularly challanging – a Myers alkylation provided the single stereogenic center in the vinyl bromide, whilst a hetero-Diels-Alder using Danishefskys diene and the same Jacobsen catalyst we saw on Sunday did for the DHP.


However, removing the silane (subsequent to an oxidation) has left a ketone rather than the required DHP.  Installation of unsaturation and removal of the extraneous carbonyl looked quite a challenge to me, but not for this group.  A regioselective enolisation using LDA allowed selective formation of the correct alkene.  Triflation using Comin’s reagent then set them up for some slightly unusual palladium chemistry – a catalytic reduction using tributyltinhydride as the terminal reductant.  Neat, and very selective.


Their success with this fragment was somewhat perturbed when tackling the main course – as the C-10 secondary alcohol was missassigned in the original paper.  Inversion was required, but Misonubu conditions (which would have been quick) were recalcitrant.  That doesn’t surprise me – ring-bound inversions are subject to the complex conformation thermodynamics, and the allylic nature doesn’t help either.  In the end, they resorted to an Ley oxidation / Luche reduction sequence, which whist more awkward, had the prized benefit of actually working.  The primary silanol was deproteced and the sulfone require for the Julia chemistry appended by Mitsonubu / oxidation  of the thiol.

It was the other Julia coupling that the group first targeted; the DHP-diol fragment was the ready to couple with the dioxabicyclo[3.2.1]octane aldehyde to complete the LHS.  However, and to no massive surprise, the olefination required quite a bit of optimisation.  The choice of base, and more specifically, counterion, was highly influential – tBuLi in HMPA/DMF was the winner, with a 39%yield.  Next up was the second Julia coupling, this time with the now epimerised DHP above.  The lessons learned in the first coupling were useless – this time, KHMDS in DME prevailed, delivering 86% product solely as the desired trans- isomer.


Now, the carbon skeleton needed only the triene unit – definitely the most fragile moiety.  This had to be treated lightly, so the group must have been jubilant to see that a Stille coupling with a diene-yl stannane was very effective – especially as a ‘less risky’ dienyne route was prone to isomerisation.  An 88% yield for that step is magnificent, so congrats to the student with the stinky fingers…  Notable is the use of excess Ph2PO2NBu4, which Smith describes as preventing the isomerisation.  The last major step is the cyclisation – something there are a million (okay, quite a few) methods for.  My former Boss used to say that any reaction that has a huge set of possible conditions is crap, and macrolactonisation is one of those buggers.  However, an effective protocol was found using a modified Mukaiyama reagent, containing a tetrafluoroborate counterion.  Smith says that this non-nucleophillic counterion was key in preventing isomerisation of the triene, and allowed ring closure in an impressive 85%.

Global deprotection was again, non-trivial (to quote a former colleague when discussing a bastard-hard reaction).  They needed to remove both a t-butyl ester and a MOM group, clearly using some sort of acid.  It’s amazing to see how much solvent choice influences the reactivity of acids, but I’ve seen conditions where acetals were rock-solid, but TBDPS groups were falling-off like lemmings.  TMSOTf was reactive enough to remove both groups, but buggered the triene.  So a stepwise protocol was used, in which the less-reactive TBSOTf was used to cleave the ester, then mineral acid used to remove the MOM group.  This must have been exceptionally frustrating to conduct, but it delivered deprotection in 70% over the two steps, and the natural product, so buckets of nervous sweat aside, good job chaps!

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  • Pilky01 says:

    Good job indeed and nice write-up Paul. Im a fan of Smiths full papers, there’s always a good discussion on interesting dead-ends with some nice references to some bread and butter papers -lots to learn and take in. Looking forward to the full disclosure on this one.
    Heres a nice example DOI: 10.1021/ja8084669…….It was blogged in 2007 but this is the full paper from earlier this year with an excellent discussion.

  • InfMP says:

    nicolaou finished haplophytine. not out online yet (angew)

    • mt says:

      Hopefully it won’t take as long to go from VIP->Early View as Fukuyama’s did. Really looking forward to this one.

      Nice two part write-up on Sorangicin. Corey also used that Pd-cat’d enol triflate redcution to transform ketone->alkene in his 1999 synthesis of aspidophytine.

  • GYA says:

    did nicolaou finish haplophytine or did david chen?

  • krest17 says:

    Congratulations DC – looking forward to see it :-), CSL rules!!! Only Peaty that not first.

  • curious says:

    was reading over this synthesis and the papers cited within…found it odd that there have been four people to work on this molecule but only three were on the total syn paper? i didn’t see much change in the orignial paper vs the total synthesis….