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iso-epoxy-amphidinolide N Pt. I   

10 May 2006 5,728 views 7 Comments


Nicolaou, Bulger and Brenzovich OBC, 2006, Advance Articles. DOIs: 10.1039/b602020h, 10.1039/b602021f

Two papers in OBC this week from the Nicolaou labs, concerning the synthesis of the related structures iso-epoxy-amphidinolide N and des-epoxy-caribenolide I. In another two part discussion, we’ll consider their initial strategy, and a further, more successful attempt.

Their initial synthesis relied upon a late-stage epoxidation, as the allylic epoxide was deemed too sensitive to survive even a standard deprotection. Thus, taking that back to the exocyclic alkene, they were left with a possible enyne metathesis – either ring-closing or in a acyclic cross-metathesis fashion. The other obvious disconnection is the ester, which, again, could be ring-closing in a yamaguichi sense.

Disconnection of the pyran moiety to a masked 1,3-dihydroxyketone was then proposed, used technology developed by Enders:


They then tried to couple this advanced fragment in a cross-metathesis, but were unable to perform this as either an alkene or enyne metathesis. Thus, they performed the esterifcation mentioned above, and then attempted an enyne RCM, which, unfortunately, again failed.

A second synthesis, aiming at inserting this diene moiety via a either a Sonagashira or Stille coupling also failed. However, much was learnt in these routes, and a synthesis of the related iso-epoxy-amphidinolide N was successful, and will be discussed tomorrow.

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  • scared_anonym says:

    1. I never read Nicolaou’ syntheses, because a) they are boring, long and have those horrible schemes from compound A -> compound B via those “a-z” steps. So you have to go all the way down to the scheme and imagine those 20 steps in your head to understand how they got from one product to another. I just find it annoying. And also I just do not see an exciting new (means really NEW, cutting edge chemistry) chemistry there as they always claim.

    b) Workforce….I understand that the main goal is to be the ‘first’, but I mean seriously 3 PEOPLE on this molecule, what do they do? As I figured 3rd one was bringing starting materials as can be seen from 2 papers. But still 2 would be more than enough, and also it would be more educative for them. Same for CP molecule…Matt Shair 2 people, Fukuyama 2 people, Nicolaou…hehe guess? 7 PEOPLE! I say this is ridiculous! What can 7 people do there?

    But…whatever, whoever has money can do whatever he wants ;)

  • Tot. Syn. says:

    Yeah, but the exciting stuff is always the BIG stuff in KCN’s work. Stuff like that ring closure. Even though the methodology isn’t very different to the literature, the execution is interesting, and its failure even more so.

  • anon says:

    On any molecule in K.C.’s group, one or two people do the front work, and the rest of the crew does scale up / optimization of earlier steps. People in that lab work hard. You can question this strategy, but at the end of the day, K.C. gets synthetic questions answered in a timely fashion, whereas others working in smaller teams frequently have to wait for scale-up.

    The work of Nicolaou is much like that of any other large synthetic group — the efforts in the lab are directed by the students and not the PI. Danishefsky has had some short and elegent efforts… he’s also had some long, mind-numbingly steppy ones. You can’t blame the boss… you have to blame the student(s)… or even the molecule. Sometimes well crafted synthetic plans degrade into unforeseen functional group manipulations, and when you’re at step 25, it’s hard to justify rewriting the route to avoid a protecting group or oxidation state change. Especially if your time in the lab is coming to an end and you need publications for whatever you’re doing next. Look at Wender’s synthesis of Resiniferatoxin… the route has some beautiful steps in it, but at the same time, the end of the synthesis degrades into annoying manipulations. Shit happens. That doesn’t take anything away from the work… just that good plans don’t always work out on paper.

  • scared_anonym says:

    Resiniferatoxin-very complicated molecule, tough one… This is what differs people, same molecule made by corey and shibasaki…in corey’s case no shit happened :) route is short and efficient. When you answer chemistry question you always should ask yourself “is this a cutting edge chemistry question?”

  • NoName says:

    as EJ acknowledged in the paper, corey’s synthesis took full advantage of earlier studies (still very clever, though); shibasaki’s one is more independent, i guess.

    that’s why lot of people gave more credit to the first synthesis (maybe more money, too); you’ll never know what kind of shit would happen.

  • sdsd says:

    well…anytime you do research you take advantage of your earlier studies

  • insider says:

    to set the record straight, from my understainding, Bulger and Brenzovich were pretty collaborative on this effort, swapping off the “lead” and “scaleup” roles. Usually in the KCN labs with a grad student and postdoc(s) the grad student does the lead and and postdoc does the scaleup. In this case Bulger was a postdoc and Brenzovich was a grad student, but the “typical” KCN roles were not used. The project was picked up after another grad student failed to complete the project (if you look in other articles on the same compound there’s another name), and much of the synthetic route had to be reworked in a short period of time.