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A New Route to Spiro Heterocycles

SnAP scheme-thumbFor fans of saturated nitrogen heterocycles (and there are many in med-chem), this paper is well worth a look. It’s from Jeffrey Bode’s group at the ETH in Zürich (authors of a recent review in this area), and it’s another version of their “SnAP” chemistry, tin-mediated conditions for ring formation. Bode and coauthor Woon-Yew Siau report a variety of interesting compounds, some of which would be rather painful to make by other routes.
No one’s crazy about using tin, but the transformation is too useful to pass up. It seems to work well with a variety of cyclic ketones, for one thing, and can be extended to acyclic trifluormethyl ketones as well. On the heterocycle side, there are a few limitations. Trying it on N-proteced 3-keto pyrrolidines or piperidines, for example, gives low yields (too much diversion into an enamine). I would guess that overcoming this problem is a current research focus in the group. Larger rings than the 7-membered one also don’t form well – not to anyone’s surprise, since those are a pain under most conditions.
But given the number of useful morpholines, piperazines, and piperidines out there, I’m very glad to have another route to crank them out, particularly with the less-studied quaternary carbons. There’s probably some tin in my future, darn it all.

9 comments on “A New Route to Spiro Heterocycles”

  1. Anonymous says:

    There was a good movie called “Pushing Tin”, but I don’t think it was about heterospirocyclothingies, or whatever.

  2. An Old Chemist says:

    Spirocyclic compounds have not been much exploited in med chem. I hope that based on this versatile route, now a lot of hitherto unknown spirocyclic templates will be commercially available for med chems to explore, in various disease areas. Spirocyclics bind in a way that can not be attained by any other template. They can also be made non-chiral by using appropriate substitutents. I worked with a series of spirocyclics which exhibited good oral bioavailablity.

  3. WDR says:

    What drives the dislike of tin, as opposed to other metals that might be used in organic reactions?

  4. An Old Chemist says:

    @3: Tin compounds are very difficult to get rid off from your reaction products. Chromatographies do not work well. D.P.Curran has developed Fluorous reagents for getting rid of tin residues.

  5. JWoods says:

    @3: A lot of alkyltin complexes are highly toxic and have decent bioavailability. It’s the combination of in vivo dosage and efficacy.

  6. Process says:

    @3: GMP. Most engineers would laugh you out of the room if you proposed putting tin in their tank. A lot of glassware, in fact, would be thrown out after Sn contamination if you’re anywhere near a GMP environment. Of course it could be sourced out if that was the only way to make it.

  7. anonymous says:

    I did a lot of stannane work in grad school. All glassware had to go through a bleach bath and then a base bath to clean off the tin. If you skipped a step, you got a face full of organotin vapor when you opened the glassware oven. (Hint: It smells like something that would quickly destroy your liver.)

  8. Anonymous says:

    Yeah, tin really sucks. can they do this by decarboxylative addition to iminium ion or something-then can come from glycine. got to be a better way.

  9. anonymous says:

    Making the iodomethylstannane to make the precursors is no picnic either.

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