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21 October 2008 6,650 views 14 Comments

Feldman and Fodor. JACS, 2008, ASAP. DOI: 10.1021/ja807020d. Article PDF Supporting Information JOC, 2007, 72(21), 8076-8086. DOI: 10.1021/ja807020d. Article PDF Supporting Information Group Website

This one looks, at least from the JACS communication, to be short piece of work over only two pages, but it’s very reliant upon methodology and ideas presented in a JOC full-paper from back in 2007, so perhaps we be best to read that one first.  Although this synthesis is racemic, that isn’t actually an important issue, as the natural product may be racemic itself.  The lack of certainty seems a bit odd to me, as it doesn’t take much material to get a quick alpha-dee, but at least we know the relative stereochemistry for sure, from an x-ray.

The starting material for the chemistry I’m going to ramble about was made in seven steps, from simple precursors, splitting about the ever-attractive amide bond.  Treatment of the functionalised imidazole with triflic anhydride resulted in a Pummerer reaction (remember that from the first time you tried to do a Swern oxidation), which could proceed in either of the two mechanisms below.  Postulate a is a vinylogous Pummerer, where a sulfonium ion is firstly formed along with an iminium ion.  Something about this intermediate (i.e. the two charges) makes me a bit uncomfortable…  The other option is a more standard Pummerer, where the amide nitrogen attacks (hmm…) the imidazole directly, resulting in a spiro-fused intermediate that must do a 1,2 N-shift to give the 6,5-fused target.

Either way, the yield is fairly good for such a piece of chemistry!

Next up was a deprotection of the SEM group, which gave the intermediate required for the next cyclisation, which would complete the 5,5,6,5- ring system.  To do this, they simple dropped the SM into a bit of NCS, which led to a cracking yield of the target.  However, the mechanism for this reaction is again lacking clarity.

This time, though, the group were able to be a bit more proactive; repeating the reaction with other halide sources led them to conclude that a further Pummerer process was at play, probably beginning with chlorination of the sulfane.  Elination of chloride (and overall oxidation) proceeds via sulfonium ion formation (and another dication), which can be attacked by the imidazole to form the desired ring system.  The iminium ion can then be quenched by attack of the chloride ion (which has been hanging around…).

A couple of deprotections, and formation of a guanidine left them with the natural product, but I did think that the displacement of the methyl-sulfoxide by azide (in the presence of zinc iodide) was quite interesting.  Any thoughts on what is going on there?

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  • The Dutchess says:

    I think the bendy arrows are really nifty, but that’s not going to help much, is it?

  • Pete says:

    Correct me if I’m wrong, but isn’t it simply an addition/elimination sequence (expelling phenyl sulfoxide)? Zinc facilitates the process acting as a weak Lewis acid and/or forms the ‘more reactive’ zinc-azide nucleophile.

    I thought this paper was very nice. Very interesting and complex transformations with some ‘old school’ principles. Woodward chemistry at its best.

  • Tot. Syn. says:

    @Pete: Pretty much what I thought, but I was unsure what the zinc iodide was up to…

  • jack says:

    I think it expels the zinc salt of phenyl sulfenic acid (PhSOZn). It is possible that the iodide acts as a nucleophilic catalyst

  • Hokie syn says:

    Off subject, but your mention of the Swern oxidation reminds me of a paper I recently read where the Swern oxidation I rely upon is reffered to as the Katzenellenbogen modification – any name buffs want to comment?


  • gilgerto says:

    What is the difference? Besides that there using DIPEA insteat of TEA, is seems to be very typical Swern conditions

  • cheyanimal says:

    i don’t see why the NCS couldn’t directly attack the e rich double bond, and then the pendant nitrogen could close on the stabilized (by two nitrogens) cation rather than sulfur oxidation. The protecting group on the nitrogen that is proposed to assist in chloride elimination is electron withdrawing. Direct halogenation yields a more stabilized cation.

  • Howard says:

    The Katzenellenbogen modification is basically just using DIPEA rather than triethylamine in the Swern – which in itself is unremarkable, besides the fact that the extra steric bulk on the base allows its use in highly epimerizable substrates, like for example the substrate in this paper, which is the same used in the Katzenellenbogen paper – looks like it was developed specifically for that substrate. Katz also comments that they avoid silica gel and store it at 0 degrees. I don’t know if it fits my definition of “modification” of a standard Swern, but who am I to second-guess Peter Beak?

  • Pete says:

    Are the proposed biomimetic pathways that Feldman has so elegantly shown here his ideas that he has put into practice or are they ideas that stemed from the isolation paper?

    Frequently a ‘biomimetic synthesis’ is a synthetic chemists practice of what an isolation paper is ‘proposing/hypothesizing’. Thoughts?

  • Superstar says:

    The proposed biosynthesis of dibromoagelaspongin (from the isolation paper) shows an oxidative conversion of dibromophakellin into the title compound. This is clearly not the premise of the Feldman paper and the chemistry employed to perform the chemistry from the isolation paper is sketchy (at best). The Feldman/Fodor approach is distinctly different because they imply that the biosynthesis requires two distinct oxidative cyclizations! Note that in their dibromophakellin work, they employ an approach to form that compound via a single oxidative cyclization cascade.

  • Superstar says:

    Also, cheyanimal, the possible mechanism you proposed is fine, but the additional mechanism experiments described in the paper exclude this as a possibility. The ICl experiment showing chloride incorporation coupled with the inability of chloride to displace iodide “imply’s a pummerer pathway.

  • Stefanie says:

    I really like the Pummerer stuff.. But however, I think you have to remove the Hydrogens on the Sulfonium structures (behind a and b/c in the Pummerer-scheme), there are too many bonds on the sulfur!

  • gilgerto says:

    Chendraw auto-correction…

  • shin says:

    I really like to see more examples of amide nitrogen attack as a nucleophile…..sulfonium seems to be a good partner to it.