Home » Still In The RBF

Spirastrellolide A   

13 March 2008 14,185 views 30 Comments

Paterson, Anderson, Dalby, Lim, Genovino, Maltas, and Moessner.ACIEE, 2008, EarlyView. DOIs: 10.1002/anie.200705565, Article PDF Supporting Information 10.1002/anie.200705566. Article PDF Supporting Information Group WebsiteResearchBlogging.org

Now I’ve been waiting for this ‘un… those of you who have been reading for a while will remember that I used to study at Cambridge University, and shared weekly meetings with the Paterson group. It’s certainly an ambitious target, with 21 stereocenters – and when they started the work, the absolute stereochemistry was yet to be assigned! Plenty of other groups are working on a synthesis of this beast, including Phillips and Furstner, but this is the first – so let’s get on with the retro.

The big fragment couplings are outlined below, with an interesting π-allyl Stille coupling to append the short sidechain, macrolactonisation to close the ring. The seco-acid could then be split into three large fragments, with an alkyne addition allowing construction of the smaller spiro-ketal moiety, and a Julia or Suzuki coupling to unite the remaining fragment.

The Julia-route started with construction of the C-17 to C-25 fragment, for which I’ve shown a retrosynthesis, as most of the chemistry is reasonably well known. I did like the Seebach chemistry to methylate malic acid methyl ester, though.

Next was the C-40 to C-26 fragment to which the sulfone would be coupled. This began with an “Oehlschlager–Brown chloroallylation”, which I certainly hadn’t come across before. The paper referenced is a 1996 JOC article by Oehlschlager, which, whilst not particularly high yielding in this case, creates a structural motif that might be hard or time-consuming to provide otherwise.

The ketone produced in this was used to coupling the other half of this fragment in a conventional boron aldol to give epimeric products; these were then eliminated to give the corresponding unsaturated ketone product. They then reduced this with some Lipshutz chemistry – catalytic [{(Ph3P)CuH}6], with stoichiometric PhSiH3 to provide a stoichiometric reductant (a development of Stryker’s reagent).

After a few more functional group transformations, it was time for the pièce de résistance, formation of the bis-spiroketal. This isn’t actually covered in any detail in this paper – for the specifics, we need to look at a Chem. Comm. from two years ago. This paper describes the use of a double Sharpless asymmetric dihydroxylation sequence, in which the internal alkene (predictably) reacts first, forming the THF, and then the terminal alkene to form the larger ring. NMR analysis indicated a mixture of products, which were directly submitted to PPTS to cause further cyclisation, and then protected to aid purification.

What I really loved was the fact that the now separated, undesired isomers of the reaction could be resubmitted to the PPTS, removing the TES protecting groups and causing spiroacetal equilibration. After one recycle, they achieved a remarkable 65% yield, creating 5 stereocenters and three rings in the process. Incredible!

However, their success with this chemistry was shortly dampened slightly as they could not push the Julia coupling any further than 32%. Although they were able to continue with the product of this reaction, they decided to change strategy, and use an ambitious sp2-sp3 Suzuki coupling to join these fragments. This required an alternation of the functional groups to make them suitable for the coupling, but nothing too dramatic. The coupling itself, though, is sweet: in situ hydroboration of the terminal olefin gave the electropositive partner, and addition of the vinyl iodide led to product in a very satisfying 83%.

Focusing now on the C1-C-16 fragment, I have again used a retrosynthetic diagram to illustrate it’s construction (which is described, for the most part, in another Chem. Comm.). Most notable was the used of a Reetz titanium-mediated allylation with allyltrimethylsilane, and their own 1,4-syn boron-mediated aldol. Simple deprotonation of this alkyne and addition into an aldehyde analogue of the bis-spiroketal above gave them the propargyl alcohol in good yield, and allowed swift transformation into the cyclisation precursor for the next scheme.

Now, I know this next reaction, in which they remove the PMB groups to cause cyclisation onto the ketone and delivery of the desired spiroketal product isn’t new by any means. Nor is it a surprising strategy. But I can’t get enough of these cyclisations – it’s just such a neat little reaction, and nicely selective. Ain’t thermodynamics a joy when it’s working with you.

With that last ketal formation complete, they only needed to do a selective oxidation of the C-1 hydroxyl to finish the seco-acid, and complete the macrocycle. Their attention then turned to appendage of the sidechain, which then hoped to do with an interesting Ï€-allyl Stille coupling. First, though, they had to make the vinyl stannane – starting with a Corey-Fuchs product, and using the fact that trans- and cis-bromides react differently, causing selective reductive (E)-debromination, and (Z) bromine-tin exchange. Smart!

They explored the π-allyl Stille coupling for a little while with a truncated fragment containing only the bis-spiroketal, unsure of how the allylic carbonate might react. Their model studies suggested that the hindered Z stannane and bulky allylic carbonate would favour terminal substitution and a trans- configured product, which was born-out beautifully in practice, resulting in an excellent 96%yield.

Removal of the acetonide protecting groups then left the natural product (or at least the methyl-ester of it), completing a tour-de-force of total synthesis. I’ve learnt an amazing amount of chemistry reading this, and take my hat off to Professor Paterson and the Pat-Lab! I’d also like to say “Hi” to all those in that lab, and who worked on this, especially Dr. Ed. Anderson (lead post-doc on this work). He recently moved to Oxford University (you know it makes sense), setting-up lab next-door to the Burton group. :)

Research Blogging Citation: Paterson, I., Anderson, E.A., Dalby, S.M., Lim, J.H., Genovino, J., Maltas, P., Moessner, C. (2008). Total Synthesis of Spirastrellolide A Methyl Ester—Part 1: Synthesis of an Advanced C17–C40 Bis-spiroacetal Subunit. Angewandte Chemie International Edition DOI: 10.1002/anie.200705565

InChiKey Data:
MRMBEOJFXSSQEB-SFBBXQEVBH SXDCKSSXFPOLRX-UHFFFAOYAP HQYAEVOLIPXEPZ-HTQZYQBOBF ARTKCMAQFDEBMR-UPGXPEFVBN VANOJHQOTAMGIR-KMEMJZCQBA ISEXPVYMZVKPMI-PZZOWKEOBB JCBGUKBBVXKXQZ-PIHILMGUBD RJKIRAOONKIZOS-OLMSDWHIBS JRMXEECODNDAOK-JYUJPSKOBP NQDGEPLQWTZSIL-WYFKGBTPBR OCHMXVSFSDGPGO-HUHOVQGDBW GYRUEAWNTLJGKF-RXMQYKEDBF ZRSSSCZECGOGHD-CZNRRTBNBC

1 Star2 Stars3 Stars4 Stars5 Stars (No Ratings Yet)
Loading ... Loading ...

30 Comments

  • lemi says:

    since i notice that Edward A.Anderson’s name appearred in all Paterson’s papers concerning Spirastrellolide A, i dare to say this guy(Ph.D from EJSorensen) may have a brilliant future…

  • Madforit says:

    incredible…the king of the spirothereal molecule.Great piece of work.

  • Chemmer says:

    Ed Anderson was a PD with Sorensen and not a PhD student

  • GYA says:

    Anderson PhD with Holmes, PD Sorensen, and Patterson!

  • Diego says:

    Don´t know this guy Ed Anderson, but Paterson´s work is one of my favorities.

  • Madforit says:

    The Baran’s paper on ACIEE is really great…thanks Antiaromatic

  • Newbie says:

    Just wanna ask a Qn. How different is the UK grad sch different as compared to the USA? I know that the us students get their fellowships via teaching assistants. For the UK, the students get their stipends purely through their supervisor? So their stipend depends on how much your supervisor is willing to pay for you? Is Ian patterson a nice guy? He looks rather fierce on his website. haha

  • Tot. Syn. says:

    Funding for postgraduate students in the UK *generally* comes from the large governmental funding bodies, such as the EPSRC and the BBSRC, though it’s common for foreign students to bring funding from their own country. The EPSRC/BBSRC set minimum stipends to be given to the students – working out at about £13,500 per year just now ($27,000 or so), and is untaxable.

    In organic chemistry, it’s common for a “CASE collaboration” to exist with a company – in my case, that was AstraZeneca. This can bring additional cash for the student and the research group, but each studentship different. One can also make a “fat pile of cash” (I believe that’s the correct term) doing tutorials or lab-demonstrating – I easily made another £3k per year doing that. So, in other words, it’s funded rather well!

    As for Professor Paterson, he’s a really nice bloke, his group are fun, and the chemistry is, well, like Spirastrellolide A. His group isn’t enormous, so the students get lots of his time.

  • gschool says:

    Tot. Syn. Don’t forget to mention the difference in time to PhD between UK and USA, 3-4 yrs versus 5-6 yrs.

  • Tot. Syn. says:

    True. Part of that is accounted for in the increased lab-time in a UKian PhD – most univeristies only have very short and undemanding lecture courses for 1st year PhD students, so they can devote more time to the lab right from the start.

    This all stems from the differences between the UK and US undergraduate systems – where the UK heads straight for depth, but the US encourages (enforces?) a broader range of subject material. I’ve experienced both, and can see benefits from each system.

    The UK PhD is getting longer, though. Quite a few of the CASE collaboration studentships I mentioned are now four years as standard…

  • Diego says:

    In Spain a PhD is 4 years and you get funding from the Spanish Government. In my case coming from south america i have an scolarship from Spain and don´t have to teach, only research. Wich has it´s pros and cons.

  • labguy says:

    The first year in the US PhD program one will be paid as a graduate teaching asst. (gta) while taking course work and cummulative exams. After that, when one has chosen a supervisor, whether one needs to continue to be a gta or if the supervisor is well funded he will pay you as a reasearch asst. (ra). Normally the amount is the same (27-30,000 depending on the school) and often extra scholorships are given. Health insurance is relatively cheap as the university normally offers a plan. The time for the degree depends normally on how much work the supervisor expects, or what you have accomplished that is publishable. If the boss is a real tough one it is possible to be forced to leave with a master rather than a PhD. This is why the supervisor chosen is as important as in picking who you will marry. In france, the system is similar too the UK where normally a company will fund the thesis and the start to final defence takes less than 4 years and in france it is pretty much guaranteed. One can expect to be paid just enough not to live comfortable and doing extra “travaus pratiques” is often necessary.

  • jimbo says:

    Is it possible to get an industrial job in the UK without a post-doc? I know a bunch of Americans (myself included) who got jobs right out of grad school. Does that happen elsewhere? It does help to come from a good lab: any Oxford/Cambridge blokes skip the post-doc?

    My 5-year grad school only had 1 year of coursework. The rest was hard labo(u)r.

  • TWYI says:

    Jimbo, I know tons of people (in the UK) who have industrial posts despite not doing a post-doc

  • Newbie says:

    Thanks for the kind sharing by paul, labguy, diego and gschool. Really appreciate you all for sharing your personal experience and knowledge with me. BTW, the stipend of 27-30K is a bit on the high end right? I check out a bit and the average is like (20K to highest 25K per annum). Thats excluding the state and federal tax, etc. I think your amt is inclusive of the scholarships and stuff. And yea, choosing the wrong advisor could results in dire consequences. I heard abt this scandal in Columbia university (sames grp) doing some C-H activation. One of his grad student’s (name’s bengu or sthing like that) publications got retracted from the journals! 3-4 publications, including some from JACS. That grad student;s life is completely destroyed and now she is startign afresh in germany doing some biochem stuff. I tried to dig out more details about that story but I couldnt find much recent news. Anyone else heard abt it?

  • antiaromatic says:

    Labguy,
    I’m not sure about that 27-30,000 bit. I thought the vast majority of places in the US, the stipend was ~24K, but I could be wrong. I only know of a handful of places where the stipend is actually that high, and they tend to be in places where the cost of living is pretty high.

  • Tot. Syn. says:

    Newbie, I suggest you might be slightly more circumspect when bringing up incidents like that. That particular situation was well covered by the sorely-missed TenderButton: http://archive.tenderbutton.com/?p=59
    (Username: Tender Password: Button)

  • labguy says:

    antiaromatic,

    The amount of 27-30 could perhaps be more than average (this number is from a few years ago and before taxes) but this is what non-bigten schools in the midwest have to throw at students in order to compete in their regions and attract people from overseas who will want bring their wife and kids. Also, in the bigger cities where the cost of living is up and the streets can be mean at night, it helps in paying the undecided prospective grad students a little more to sway their decision towards the department.

  • Andrei says:

    Hey! why should the young people who didn’t get the chance to live in the tenderbutton time be more circumspect about asking the inside-dirty stories? I think people should speak! this is the only way things can change! as long as the level of the discussion stays correct he can ask anything!

  • clueless says:

    “Hey! why should the young people who didn’t get the chance to live in the tenderbutton time be more circumspect about asking the inside-dirty stories?”

    Good point, where is the next generation of chembark and tenderbutton?

  • Newbie says:

    Everyone makes mistakes some thing in our lives. The key point is to admit the mistakes and move on. I am not saying that who is right and who is wrong. I am just puzzled that the story got “chopped-off” (covered-up). There is no eventuality to the event and hence how can anyone learn from the mistake? Covering up errors only make the events more dubious and suspicious and I’m sure pple will keep on harping on it for years to come.

  • Newbie says:

    I am also quite disturbed by the fact that the academia field functions like a feudal system. High impact journals feed on the “Big names” or the “offsprings” of the big names. Papers get accepted purely because of the fact that it comes from a BIG NAME and not because of the science itself. Do you know that the editor of the journals has the choice of sending it to a nasty/ friendly referee depending on WHO you are. And yea, some reactions are proprietary reactions. The BIG names OWN it. YOu who try to step in and have a share of the pie will get nuts. Referees can also stall ur publications for MONTHS, only to share ur data with UR COMPETITOR (his buddy) doing the same work and publish it ASAP whereas your paper gets rejected eventually. The academia world is sinister and unless there is a move (and there is actually, slowly but surely) towards open-access journals, the BIG names will keep on FEEDING on the system because they reap most of the benefits from it. This is just my own opinion and its open to discussions. Any views?

  • Bandit says:

    Newbie, get used to it or get out of it. Its sink or swim, not a welfare state.

  • Newbie says:

    yea bandit. gotta agree with you on that. Its a unfair world to begin with.

  • Tot. Syn. says:

    It’ll come as no surprise that I’m quite a fan of the idea of open access journals. But I don’t think we’re quite ready for it. Consider the service that the editors/reviewers of big journals like JACS provide: you can open that journal at any page and have a fair idea of the quality of the work without too much hard work. Other journals (less well known, or plainly less reputable) are bound to have excellent work fairly often, but at the same time there must be a lot of “also ran” papers too.

    Now pull the closed-access journal system away. Where’s the guarantee of quality? Sure, loads of people could read as much as possible to rate the papers, and thus the cream might rise to the top… but I find it hard to believe that this system wouldn’t be open to abuse. The most popular and perhaps important open-access website is Wikipedia – and just look at the amount of controversy about abuse by core “superusers” et c.

    Open-access is important – but it needs to grow-up a bit…

  • Devil's Advocate says:

    Hey Newbie,

    Do you have examples of this nefarious backstabbing of which you speak? Some of those are pretty serious allegations. I see a lot of excellent work in JACS and Angewante that is not published by “Big Names” and I also know of some work from “Big Names” that has been rejected. Could you also point to a few articles in the big name journals that are from “Big Names” but not actually worth being in said journals?

  • Newbie says:

    Devil’s advocate,its extremely sensitive me for to point out particular individuals. I do agree with you that big names’work can get rejected too and less well-known pple can publish in JACs too. No doubts about that. However, when you noticed that the professor is an associate editor of a certain journal and the majority of the papers he publishes is from the identical journal, isn’t that an obvious case of a conflict in interest? I refer to a recent C&EN article for your ref: http://cenpeerreview.wordpress.com/2008/02/08/is-peer-review-honest/#more-8

  • Devil's Advocate says:

    Newbie,

    As it says at the end of the referenced article, “Also, the perception, particularly among less well established scientists, of more widespread reviewer impropriety hurts morale at a time when young researchers already may be discouraged.” You make it sound like these improprieties are the norm in our field when they’re actually very rare. It’s easy to make non-specific and unsubstantiated allegations in an anonymous setting such as this and it may make you feel better about some percieved unfairness in your career, but it does have a negative impact on all of us.

  • Dione says:

    Devil’s Advocate,
    I am not sure as to how “rare” these events are. I know a collegue of mine who had a very nice tot syn and it got rejected from JACS…later to be published in ACIE. The reason was as simple as “work is predictable and lacks novelty”, both the comments were baseless. I had a similar thing happen to me recently. We sent out our data to another high profile journal and the refree report was excellent. Infact, one of the two refrees wanted the work to be published as a letter (!) and the second one pointed out a few grammatical corrections but had all praise for the synthetic logic.So, if two out of two referees say yes you would expect the editor to say yes..however the editor rejected the paper without giving any reasons. Later after we demanded one he actually pointed out things which were no way related to our work…ultimately we had to send it somewhere else where it was accepted in a week !!! So, you know I am definately polarised to beleive that all is not fair up there..and I will have to live with it.

  • InigoMontoya says:

    There are too many carbons between the pmb protected alcohol and the ketone in the reactant for the DDQ mediated deprotection/spiroketalization reaction. As shown it would form a 7,6 spriketal and not a 6,6 as shown in the product.