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Cortistatin Pt. III   

24 November 2008 11,046 views 41 Comments

Shair, Lee, and Nieto-Oberhuber, JACS, 2008, ASAP. DOI: 10.1021/ja8071918. Article PDF Supporting Information Group Website

A third showing for everybodies favourite androstane, this offering from Matt Shair adds to the quantity of inovative chemistry used in it’s contruction. As a quick reminder, first up was Phil Baran, back in May; then came Nicolaou and Chen in August – along with several ‘studies towards papers’. However, rather than my going through it all again, have a look at this excellent review by Stefan Bräse which was in ACIEE last month.

If you read it through, you’ll notice Nicolaou’s use of the Hajos-Parrish ketone (the synthesis of which I discussed in my post on that work); Shair does likewise, reinforcing it’s application towards steroid synthesis. From the single stereocenter present in that SM, Shair first does a substrate-controlled reduction of the ketone to add one stereocenter, and then a few steps later adds a pair by selective hydrogenation, and then Rubottom oxidation. Nothing new here, but it is all very neatly controlled by the substrate.

Removal of the acetal protecting group and a bit of aldol chemistry introduced a cyclohexanone, which was triflated to provide a handle for a slightly unusual palladium-mediated coupling (or at least I found it a bit special…). In this case, the nucleophilic partners for the Kumada coupling was a silyl methylene Grignard – an interesting substrate, as I’m sure there could be a competing Hiyama process, but I guess the Kumada process is far faster. Either way, it’s a neat way to make the required allyl-silanes.

A cyclopropanation of the allyl silanes using dibromocarbene gave them the final functional group required for a rather sweet ring expansion to install the seven-membered ring. However, the nature of the silyl group was quite important, as in case a) (where TMS was used), a process of proton abstraction rather than silyl group elimination competed. Moving to the disiloxane derivative favoured attack of fluoride rather than deprotonation, and removed the competing pathway entirely, resulting in a good yield for the ring expansion.

The remaining bromide was then used as a handle for a Suzuki coupling, appending the remaining carbons for the A ring. Substrate controlled dihydroxylaion of the resulting trans olefin left them almost ready for the pièce de résistance, an aza-Prins transannular cyclisation, starting with in-situ deprotection of the MEM group (which I’ve omitted for clarity), and building several rings in one step. I must admit that I had trouble visualising the freed hydroxyl ‘reaching’ over to the olefin, but building a model relieved my fears.

Completion of the molecule (and appendage of the isoquinoline) was done much in the same way as Baran and Nicolaou did, finishing a pretty tasty synthesis. However, one criticism has to be the number of yields which were quoted over multiple steps. Most were admittedly very good, but it’s always nice to know if, say, a 65% over two steps was [65% + 100%] or [80% + 81%].

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41 Comments

  • FC Barcelona says:

    They couldn’t repeat Phil Baran’s hydrogenation condition, which works like 100% yield. While in their hands, the yield is probably less than 10%.

  • ch3mical says:

    impressive.

  • anon says:

    barcelona: Baran reported 50 % yield, with the remaining mass being recovered s.m., and he was using RaNi, which isn’t exactly the most even-tempered and reliable of reagents…

  • Ron says:

    Reading the SI reveals that a lot of the products in the synthethic scheme seem to be quite unstable and should be used immediately – hence why there are several yields over a few steps.

  • a-non says:

    Could the reason why the Kumada process dominates be because generally for Hiyama couplings the silyl group must be activated (pentavalent Si usually with F-)? At least that’s what the link implied…

  • InfMP says:

    yeah i think kumada conditions are quite different.

    So anyway, I read the whole supporting info. Awesome synthesis. when working on large scale early in a synthesis, doing several steps in a row without chromatographic event is a huge plus, and so it’s no surprise they carry through several steps.
    Fascinating is that they might have had to work in shifts (nicolaou/baran minotaur anyone?). Some compounds were only stable for the moment and had to be carried through several steps on the spot.

    As for the last step, Baran is very honest. If you think that is a solid 50%, you read it wrong.”Ra Ni was washed with H2O (3 × 5mL), sat. aq. Rochelle’s salt (3 × 5 mL), H2O (5 × 5 mL), MeOH (3 × 5 mL), and H2O again (3 ×
    5 mL, all supernatants were removed with pipette)”
    They clear state that it is Roughly 1mg product, and roughly 1mg start.
    (ca. 1 mg) and (+)-cortistatin A (ca. 1 mg, ca. 50%; ca. 100% brsm).
    I swear if i could do my methodlogy project on brsm….

  • PotStirrer says:

    Can anyone provide a reasonable explanation why the beta-gamma unsaturated enone is formed instead of the alpha-beta unsaturated enone in going from 7 to 8?

  • Pete says:

    Potstirrer…I was surprised at that too. Selective elimination seems (very) surprising, but in the grand scheme of things, It doesn’t matter as the next step is enolization/triflation. Whether they do it from the shown intermediate or have to form the extended enolate, they are still ‘ok.’

    I wonder if they were surprised when that happened and just took the material on anyways…?

  • milkshake says:

    I suppose the originally-produced enone is conjugated but SOCl2+pyridine system is also causing enolisation of the CO with C=C shift. If the workup was mild enough C=C did not get a chance to shift back so the conjugated ClSO-enolate hydrolysis produced beta-gamma product.
    If I remember correctly TMS-Cl with NEt3 and some added ZnCl2 can also do this kind of elimination, providing TMS-O-dienes.

  • Jose says:

    How in the world does Baran find this many person-lab hours??

    http://pubs.acs.org/doi/pdf/10.1021/ja806981k

  • texasboy says:

    I would hate to be in that lab. did you see massadine supporting? like 80 pages with a table of contents. too much information.

  • Tot. Syn. says:

    Too much information? There’s no such thing!! It’s supporting information – it’s not bedtime reading material. Would you rather the converse? The utter dismay of finding the reaction you want in a tet. lett., with no experimental or SI?

  • Bandit says:

    here here paul, respect to those who make a serious effort over sup inf for the sake of others not just cos it is required

  • recordings says:

    Are there any sites where organic lecture recordings are posted for the public usage? Thanks.

  • ch3mical says:

    Not sure about other UC’s but you should search

    http://podcast.ucsd.edu/

  • Undergrad senior says:

    @ Jose- If this gives you an idea, a recent visit to a prestigous total synthesis lab on the West Coast revealed that they work 8-12 meaning 8 in the morning to 12 at night as they said, with a 20 personnel program one can imagine such a feat being imaginable.

  • Vik says:

    I would love to work 8-12 on weekdays with a 6h group meeting on saturday and total rest on sunday would be an ideal postdoc time (2h)..eeh.

  • Vik says:

    should be…postdoc time (2 years)..

  • optional says:

    I have a simple question for all you hardcore synthetic organic chemists who work 8 am to 12 am.
    Are you folks 100% efficient for the enitre 15 hours of the day? Could you have accomplished the same amount of work in 10 efficient working hours? Cause if I organize my things well, and plan a day ahead, I believe that I can do it.

  • Liquidcarbon says:

    That’s a good question. I myself tend to come in late (noon-ish) and leave around midnight or later.

    The thing is — it’s hard to plan far ahead, unless you’re doing something familiar and repititive like scaling up. Otherwise you rarely know exactly how long will it take for a reaction to complete or how long will it take to purify the product.

  • anonymous says:

    most of often , the time is gone in reading and in purifications. If you’ve some undergrads, then they occupy half of your time.

  • joel says:

    I’ve worked in a number of top academic labs over the last 10 years and have met very few people who *consistently* work 80+ hours per week. But there are certainly a lot of individuals, PIs and whole research groups who say they do—loudly for everyone to hear.
    The people who are telling the truth are typically strong-minded enough to keep their hours to themselves.

    In any case, working long hours is nothing to brag about if you don’t have significant publications/patents in the end.

    Also, those of you who take 2 hour academic lunches ought to subtract that from your total hours.

  • optional says:

    Yup. Show up to work at 8 am feeling shitty and tired and your eyes like half open..sip through a cup of coffee or red-bull until 9 am while doing intellectual masturbation on whats to be done……then flame dry and cool your flasks for another half hour and its 9:30. Then set-up the reaction and read ASAP’s, and occasionally doing TLC’s or GLC analysis and yes, not forgetting to comment on the Totallysynthetic.com, and of course, if you are a guy (boy), then the NFL or MLB or NBA games from the previous night and for the upcoming day or week have to be discussed thoroughly including playoff implications. Perhaps, at 11 am, sip through another cup of caffeine and long behold, its lunch time. Spend one hour for lunch. Now, If the reaction finished, spend another hour for quech, work-up and evaporation, and another two hours for purification, evaporation, and NMRs. Its 3 pm and yes, you feel the need to be rewarded, and so, perhaps a stroll through the department with your buddies checking out who is hot and who is not, including undergrads…for another hour and then contemplate on whether to set up another reaction and also thinking about what to eat for dinner. Well, dinner happens to come by faster than the next flame drying of the rb’s. Dinner’s over at 6 pm and because you are a motivated person you set up another reaction and do your stuff for the next 6 hours and dont notice the slack. By midnight, you can say to your self, I came at 8 am and now, I am leaving at mid-night and so I have worked 16 hours. Yippy ye!!!!

  • chinstrap says:

    I find it amusing how the comments fill up faster sometimes for related “off topic” stuff like this.

    For me, I am doing my PHD in europe and we work alot too, not anything like the west cost though, around 55 hrs weekly (plus daily travel time as the subway, tramway get you there) with saturdays sometimes and things get down alright.

    Working for a big guy with 80 hours weekly, effficient or not, and group meeting on saturdays doesn’t seem to leave much time for actually living your life. Of course at the end of the thesis if you have worked hard, PUBLISHED WELL and the boss respects your efforts, it would be worth it; but having a life away from the push and shove of lab is important for your personal well-being. As I am living in a moderately socialist country there are upsides to having some proper labor laws in effect.

  • Boiling Stone says:

    Wow optional, that really hits the nail on the head for a lot of people I know. In my personal experience, the divide between people from the top schools and the rest of the world is far more based on ego and ambition than on any great difference in ability or creativity. I have met some of the most insecure people at the somewhat famous chemistry department I work at now, and some of the smartest at my undergrad institution, which I doubt almost any poster on this message board has even heard of.

  • InfMP says:

    “checking out who is hot and who is not, including undergrads…” haha my favorite part.

    I hate people who brag about their hours (though some good people do it by accident sometimes). I try very hard and go out of my way to not keep track of mine so that i can’t be like that. Some days im really efficient and sometimes not.

    The number of hours that you spend away from your apt has NO relation. I could spend all of tomorrow at home and work on paper work, but hardcore graduate lab etiquette states i gotta be at the lab, even if im not doing reactions.

  • Cat Herder says:

    Long hours are certainly a part of working on a synthetic project (no matter how efficient you are). However, they are not something to celebrate. It seems to me that people who brag about their hours are totally missing the point of what they are doing.

  • Tex says:

    It’s not the quantity of hours that is important so much as the quality of the hours in the lab!

  • TWYI says:

    80 hour weeks LOL!

    That’s great if you want to leave Grad school a socially inadequate freak.

    You need to live a life, meet people outside of work and maybe even have a relationship or two.

  • optional says:

    Thank you all for your input. As you see, its ridiculous for people to say that its the “norm” to work 80+ hours. Next time I hear this, I will tell the person to shut the f… up.

  • Liquidcarbon says:

    optional — kind of like that, yep.

    And for the quality — I know a girl who had two kids while in grad school — and finished in 5 years.

  • Undergrad senior says:

    WOW

  • Jose says:

    The whole 80+ hr work week is simply idiotic. At 3pm you think- “well, I have to be here until midnight anyway, so I’ll just run that column after dinner.” etc etc etc. If you just decided to work like an animal from 8am until 6pm, and then GO HOME, overall productivity and sanity would increase. The time in lab vs. productivity plot is a bell curve, with the max around 50 (?) hr a week. Everything else is egotism, and “sword fighting”.

  • HPCC says:

    When I did my Ph. D., I was with the same girl for the whole 5 years (who also was a Ph. D. student). I was a 55-minute drive away from my institution. Which meant I was in the lab from 8h15 till 18h15, roughly. With a 20-minute lunch break. And stayed late only in exceptional cases, and for night classes. Worked half a day on Saturday, then f-ed off for grocery shopping and romantic dinner at home. Hell, I even managed to get married in the process. :D

    What it entailed, for example, is that I was usually taking my coffee break at my desk while reading papers, or while running a column, seriously. Spot a tlc, remove gloves, lab coat, take a few sips, put lab coat back on, analyse tlc. Push 10 more fractions, tlc…

    And got less than a handful of incidences of “complaints about work productivity”.

  • milkshake says:

    Brian Stoltz used to work 6 days a week during his postdoc. He would leave on Friday nights at a reasonable hour – that way he could go out to have a dinner and party. He always took the Saturdays off, then he would come back to the lab on Sundays.

    He said he liked to work on Sundays as there were far fewer people around – and this way he could get some headstart for the following week.

  • Tot. Syn. says:

    Things are of course a bit different in the UK, but a not-dissimilar ethic follows organic synthesis round the globe (like the smell of a lab-mate who’s been raking around in the lab-freezer). In my first year, I was strictly 9-6, with a bit of Saturday morning if the reactions were needy. Second year got a bit later in the evening, and normally a full day on the weekend (on average). Third year, and it all went nuts by the end, with every hour I wasn’t asleep spent in the lab. Those last few months were beyond silly – 9am to 10pm in the lab, and then 11pm to 2am writing the thesis. But I got it done :)

    I also spent a year at UM-St.L in my undergrad, and did the research thing there too. Classes at 9am, lab-classes finished at 11pm (overrunning quite frequently to 12am or later). Research sat somewhere in between, along with tutoring pre-meds. No-way could I have hacked 5 years of that…

    I’m not telling you what I work now… it’s better for me and you that way ;)

  • Jose says:

    HPCC- you wore a lab coat in grad school??? We just set a coke can or coffee mug on the edge of the hood sash- voila! Drink coffee and collect fractions all at once!

  • aa says:

    Jose- HPCC was not your typical grad student… unlike me in my stained shirts with acid burns right through them, he was known to wear collared shirts TUCKED IN to the lab! apparently it has something to do with the province he grew up in hahaha hence the labcoat

  • HPCC says:

    aa: True. But do you not remember the day I wore this pristine white shirt and was taking a few flasks out of the base bath WITHOUT my labcoat, much to the dismay of random people entering the lab. Think her name was Christine… :D

  • The Dutchess says:

    *thinks Tot. Syn. still works too hard, no matter what he says*

  • [...] lust in the last few years, with three previous appearances in these interwebs (Baran, Nicolaou, Shair).  The reasons for both are the same – both have remarkable biological profiles, and both [...]