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Spirangien A   

10 February 2009 14,613 views 25 Comments


Paterson,  Findlay and Noti. Chem. Asian J., 2009, ASAP. DOI: 10.1002/asia.200800445. Article PDF Supporting Information Group Website

It’s been a rather slow week in the world of total synthesis – I normally have a check on the ASAPs and EarlyViews in JACS and Angewandte every day in Google Reader (BTW, tune directly into my brainwaves under the ‘What I’m Reading’ section on the right…), and a bit less often, I’ll read Org. Lett., Chem. Comm. and OBC.  If nothing turns up, then it’s on to Chem. Eur. J, JOC, and maybe even Tetrahedron… but today I took a far eastern excursion and found this distinctly Scottish paper (66% at least…).  The thoughts going through my mind at this point were firstly, 1. I recognise that structure, 2. Ah, it’s Ian… 3. …and Alison – a former housemate from when I was living in Cambridge.  It wasn’t just a house we shared, though – we also shared group meetings, and I remember this strucuture coming up, as Alison had just finished Dolastatin (that’s some old-school TotSyn right there…).  I actually found the pentaene moiety the more interesting chunk, but of couse Ian Paterson’s all about the aldol.


I can’t actually remember if I (or the team I was working with in our synthesis-problems group) recognised the repeating stereotetrad fragment, but I’m sure it came up in the discussion.  Pulling this out of the retrosynthesis after dismembering the spiroketal leaves a far simpler problem, which I could write aldol all-over if this was a full retro.  The key, then, is building the pieces quickly and efficiently, and getting the coupling in the right order.  The key repeated unit was build very quickly, starting with an enatiomerically pure ketone, and doing a 1,4-syn-aldol using dicyclohexylboron chloride and methacrolein.  This is a methodology that Paterson has been using for decades, and it shows, with a cracking yield and control of stereochemistry.  All it needed was a diastereoselective reduction of the ketone to complete the unit, and they had two choices – Evans-Saksena (paper with Erick Carreira) or Evans-Tischenko (with Amir Hoveyda).  The former was one step quicker, as the latter required saponfication of the resulting ester, but the two-stepper was not only more efficient, but apparently easier to scale up.


A few transformations allowed development of this fragement into the two components that were to be coupled.  One required a further stereodefined hydroxyl, brought about by a Myers’ alkylation, whilst the other used a cuperate addition to append the unsaturated sidechain.  Forming the boron enolate of the ketone first, and then addition of the aldehyde allowed the coupling to complete, generating a reasonable yield and diastereomeric excess.  Various attempts at improving this yield by altering the protecting groups on the partners were performed, but nothing was gained – but that’s not to say that this wasn’t a tough reaction, and a good result.


The mixture of products was then methylated at that troublesome C-23 postion, setting up the molecule for spiro-cyclisation, brought on by removal of the acetonide protecting groups.  The result, as expected, is the doubly anomerically-stabilised spiro-ketal, with only the thorny C-23 position providing issues.  Happily, at this point the unwanted diastereomer could be removed, leaving the group ready to progress.


Treatment of this product with 9-BBN to effect a selective hydroboration of the less-substituted olfin, providing a synthetic handle for elaboration.  Oxidation and Stork-Wittig olefination gave them a vinyl-iodide, ready to build the pentaene system.  As shown in the retro, they were able to make a symmetrical bis-vinyl-stannane, and simply had to choose which way to couple the smaller and larger chunks.  Ready for instability, they used ‘strict exclusion of light and employing base-washed amberised glassware‘, and gave both alternatives a go, with the favoured route being the small then large Stille’s if you get what I mean. Nice work, folks, and congrats to Alison for getting so much done in such a short timeframe.

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  • earth23 says:

    Anyone else having trouble viewing the molecule graphic on the front page? I think the code might actually be scaling the image to fit…

  • Ni-lithium says:

    The images look fine for me.

    Good call on bringing this up, I can’t say I check up on Chem. Asian J. that often. Thanks for bringing this to the normal journal reader’s attention as well as giving some recognition to an old colleague.

  • Ni-lithium says:

    Whoops, I misread the prior comments, on the front page the molecule is in fact skewed too large for the “window” in which it’s designated.

    A chemistry related issue now… with these spiroketal molecules is it always just make an advanced intermediate similar to the NP and then just hope it’s a thermodynamic sink that governs the diasteroselectivity of the condensation of two alcohols on the ketone regardless of which condenses first, similar to that which happens in nature?

  • antiaromatic says:

    I think that typically is a large part of the hope. If you’re interested in a wonderful example of that kind of application in synthesis, check our Evan’s recent azaspiracid work. Fantastic stuff.

  • Tot. Syn. says:

    I almost died writing this about Evan’s work:

  • Gilgerto says:

    I always found weird these hydrogen bonds between heteroatoms and C-H hydrogens. I believe the concept was introduced (or reintroduced) by Corey in the context of oxazaborolidine mediated reactions (for ex see. JACS 124, 3808).

  • optional says:

    ACIE Asap. Bob Williams from Col. Wow. A gigantic conquer!

    • Tot. Syn. says:

      Williams?? Do you mean the Phillips synthesis of Norhalichondrin B? I’m working on a post on that just now… but it might take some time. I’ve written eight schemes so far…

  • PMP says:

    Ni-lithium – you are absolutely correct, this is how most chemists make their spiroketals – and they end up getting, in most cases, the thermodynamic product. If you want to make the other isomers, you can consult this review here on nonanomeric spiroketals:

    Nonanomeric Spiroketals

    It is easier to make the nonanomerics if you leave out the protecting groups – then you might be able to trap the kinetic isomers as well without having to wait for ages for that TBS group to fall off and isomerizing your fragile kinetic product at the same time.

  • Pilky01 says:

    Ive just created a google reader account….this thing is awesome!!!
    Thanks for showing me the light Tot.Syn.!

  • Hexacyclinol Revisited says:

    Hi Totallysynthetic, would u please remove the institute info from the above DOI link?

  • matt says:

    What is the point of the paper “……..Hexacyclinol Revisited” ?

  • Ni-lithium says:

    PMP, thank you for leading me towards that review. I think as I began growing more and more interested in the intricacies of total synthesis I gained a great appreciation (still growing!) for thermodynamic control of generating diastereomers based on the the governance of the structural control. It seems much more obvious in spiroketal formation as you have the reversibility of oxo-carbenium formation as well as the driving force of the anomeric affect. Substrate control never ceases to amaze me though.

    • PMP says:

      Hi Ni-lithium,

      To me, what is really amazing is that many natural products are apparently not under thermodynamic control at all. Many chemists assume natural products are nearly always in a local thermodynamic sink. This is not true! Some compounds are truly fragile and decompose so quickly that they leave behind a trail of congenerers – compounds that also bear the name of the original natural product but are in fact much easier to synthesize, albeit often less potent than the original natural product. Why the organisms spend a lot of €€€ (I mean ATP) to make these fragile beasts is beyond me.

      • Ni-lithium says:

        PMP, it certainly makes sense that there will also be kinetic selectivity in nature’s syntheses of natural products, that is certainly impressive as well. I sometimes wonder how often natural products are not all that “natural” after all, and are merely a product of isolation, so as to say that during the isolation process the natural product is modified somewhat. Do you have a good sense for this? I do not follow the process of isolation that closely and wonder sometimes how seemingly fragile motifs live through isolation and characterization?

        • PMP says:

          Ni-Li – sometimes the fragility of the compound is built-in as a detoxification mechanism of some sort. But you are right – things do happen during the isolation process, although in general the purification and isolation procedures tend to be much milder than, say, general deprotection conditions synthetic chemists usually resort to at the end of their syntheses.

          But of course there is a question of what gems might go undetected simply because they are not stable to isolation…

  • Ian says:

    Proves beyond doubt that LaClair is a fraud and a liar?

  • ch3mical says:

    ^pretty sure that was a joke

  • Hexacyclinol Revisited says:

    Looks like one fne day Laclair’s Hexacyclinol will be synthesized and the NMR’s will be compared to prove the things beyond doubt.