Retron of the Week: Claisen Rearrangement

News flash: retrosynthesis is hard. As a result of this shocking news, and to train myself to recognize transformations that I tend to gloss over, I bring you a new weekly MGW series: RETRON OF THE WEEK.

The 1,4-dicarbonyl can be a tricky retron for a number of reasons. It’s one carbon away from the Michael retron, so it encourages what I like to call “so-damn-close syndrome” (symptoms include cursing, banging head against desk, and staring at molecules trying to will them into possessing extra atoms). The two carbonyl groups also scream enolate alkylation, but good luck getting your hands on the right commercially available alpha-bromoketone and running the reaction with stereocontrol and without side products.

A much easier route to 1,4-dicarbonyls (in the absence of any unsaturated fuctionality) is via the Claisen rearrangement. The retron for this reaction is a 1,4-vinylketone or aldehyde, and 1,4-dicarbonyls can be made from these substrates by ozonolysis. The starting material is a vinyl allyl ether, which with a little heat will undergo a [3,3]-sigmatropic rearrangement to the corresponding 1,4-vinylcarbonyl. The Claisen’s ultimate selling point is its stereospecificity at the new single bond: E,E and Z,Z allyl vinyl ethers give syn products, while E,Z and Z,E stereoisomers lead to anti products. It’s also possible to control the absolute stereochemistry of the product by varying the stereochemistry at the allylic site! See below.Variations on the Claisen rearrangement have centered on the establishment of different kinds of carbonyl groups: amides, esters, acids, etc. The Ireland-Claisen, for example, is the rearrangement of an ester enolate to a 1,4-acid/alkene. Hetero-Claisens form a particularly interesting class of reactions, as they throw imines, phosphonates, and even chromate esters into the mix. A simple but fun problem is the mechanism of this transformation:

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2 Comments

  1. on contrary to unsaturated tertiary alcohols, this secondary alcohol , in my opinion, is oxidized by ordinary esterification/elimination mechanism. do i miss anything?

    Reply

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