Heterocyclic Mechanisms – Isopyrodysinoic acid
Every Thursday morning at Sydney we have a problem session attended by all organic chemistry staff, PhD and Honours students. Part of these sessions always involves running through mechanisms and syntheses on our perpetually spotless blackboards. This is a useful exercise, and usually the simplest questions bring up the most interesting points for discussion.
Recently, one of our graduate students, Kaitlin, challenged the other teams to devise a synthesis of a recently-isolated natural product isopyrodysinoic acid. (One of the reasons Kaitlin chose a “new” molecule is that the question circumvents the repetition of a literature answer. Incredibly “isopyrodysinoic” is a one-word Googlewhack, or at least it was until this post.)
Another of our students, Fargol, wrote up a synthesis on the board for about an hour, and towards the end got to a molecule containing fragment 1. She suggested that in the presence of heat and acid this molecule would cyclise to 2, which is probably true. There was some discussion of how this transformation is possible – Fargol drew the direct displacement of the protonated alcohol by the amide, which probably would not happen. This is quite an interesting step, requiring a different mechanism. I know how I would do it. Suggestions? This would make a good advanced chem question for next year.
mattoddchem, 
Heiko, and 
Shankar are discussing. 
Intermolecular 
Shankar 5:39 am on December 9, 2009 Permalink |
I am not sure if am too late to respond (lot of catching up to do!). You are correct in that simple protic acid will not do. My suggestion is to make imide and then followed by Mitsunobu and my alternative suggestion (more speculative) is to pull off some sort of intramolecular “Ritter reaction” that delivers the amide from the corresponding “ene-nitrile”.
mattoddchem 6:23 am on December 9, 2009 Permalink |
I would guess that protic acid would be fine – but that the mechanism is not a direct displacement. I’d start with an extended tautomerisation of the s/m that makes the C-OH carbon sp2 (as an enol), as the first step. Then I’d tautomerise again to give a C=O before the NH2 finally attacks. See what I mean?
Heiko 6:50 am on December 15, 2009 Permalink |
i would say that instead of forming the amide a lactone would be formed! the oxygen should be much more nucleophilic than the nitrogen which would give after aqueous work-up the lactone… i would transform the amide into a bis-TMS-imide (described in the Corey synthesis of Tamiflu) and then mesylate the alcohol… this should give directly the lactam…
mattoddchem 12:06 pm on December 17, 2009 Permalink |
No, I don’t think so. If we’re warming with some acid, as is so often the case in heterocyclic chemistry, we’ll be under thermodynamic control, so whether one thing is more nucleophilic than another is less important. I also don’t think that you’d need anything other than acid – that’s the point. I’ll post the mechanism separately just as soon as I’ve got my inbox below 100 emails.