Thursday, December 10, 2009

Reaction of the Week #1 - Schmidt reaction

I intended this to come out at least a week ago, but with the holiday season seems to come family crises and deaths.

So. The Schmidt reaction.  Its seminal publication came in 1923 It's pretty commonly known, and very similar to the Curtius and the Hofmann rearrangements taught in undergraduate organic II.  It can transform a carboxylic acid into an amine one carbon shorter, an aldehyde into a nitrile (generally aromatic aldehydes), or a ketone into an amide or lactam (depending on the starting material) with the addition of HN3, hydrazoic acid, in acidic conditions (the first few times I looked at it my brain saw NH3, so watch out).  Other groups that may react with HN3 are nitriles, imines, diimides, some alkenes, and alcohols, according to the Kürti and Czakó text, as well as any other acid-sensitive groups.

The intramolecular version appears in the literature frequently.  An alternative electrophile to those listed above (and the acid-to-carboxonium shown in the mechanism) is a leaving group, such as an iodide, triflate, tosylate or nosylate.  A recent JACS Communication by Kapat and coworkers at the University of Berne (Switzerland) used an acid-free version of this variation that produced great enantioselectivity of a natural product from tree frog skin, (-)-indolizidine 167B.  (This target is fairly attractive for the challenge of that particular stereocenter; a quick Google search will show you quite a few other approaches.) This is the TOC graphical be honest the colors are what made me check it out.

The full synthesis is detailed below. There was a few interesting reactions so I wrote the synthesis out stepwise.  Copper-catalyzed asymmetric allylic substitution with a Grignard reagent enantioselectively installed a t-butoxypropyl group.  The terminal alkene then underwent carboazidation - which is a really neat reaction, though at first glance the reagents looked like some gen. chem. magic.  Reduction of the ester to the alcohol which was tosylated and then reduced resulted in the desired propyl side chain.  The t-butyl ether was cleaved under mild Lewis acidic conditions to produce the free primary alcohol.   Note the box with various deprotection conditions for t-butyl ethers (the group is generally installed with isobutene in the presence of acid).

The last few steps where the Schmidt comes in are as follows:

The free alcohol is converted to the triflate, which is nucleophilically attacked by the azide anion.  A 1,2-alkyl shift ejects nitrogen gas, and reduction of the iminium product results in 98% ee, 79% yield of the natural product. 

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Constructive criticism welcome; criticism for judgement's sake, not.