Illogical Nucleophiles

Abstract Compounds with a 1,2-, 1,4- and 1,6-dioxygen pattern and related bifunctional structures are presented. Disconnection of the internal bonds results in illogical synthons because of the mismatch of charges in the patterns with an even number of C atoms between the functional groups. Three-membered heterocyclic rings are presented as an important class of illogical nucleophiles in the retrosyn-thesis of the 1,2-difunctional pattern. Retrosynthesis of the 1,6-dicarbonyl pattern by reconnection and rctro-Birch reduction of the aromatic building block is related to chemoselective Birch reduction and ozonolysis in the synthetic route. The retrosynthesis and synthesis of salbutamol and asymmetric synthesis of —)-frontalin are presented. 

Since disconnection of any of the C-C bonds of a dissonant system leads to two fragments of identical reactivity (either nucleophilic or electrophilic), in the synthetic direction the reactivity of one of the two fragments must be inverted (see 5.1, "illogical disconnections"). Another possibility, however, is to oxidise or to reduce the resulting fragments to radical species. 

The obvious disconnection on a 1,4-dicarbonyl compound gives us a logical nucleophilic synthon (an enolate anion) A but an illogical electrophilic synthon B ... 

Disconnection of an a-hydroxy carboxylic acid results in an illogical synthon a carboxylic acid moiety that is nucleophilic at the carbonyl carbon. 

The disconnection of a y-hydroxy carbonyl at the alpha carbon seems illogical because it is different from the aldol disconnection of a P-hydroxy carbonyl. The alpha carbon is the nucleophile as expected, but the electrophilic synthon has a positive charge not on the same carbon as the hydroxyl, but on the adjacent carbon. This reactivity can be achieved by using an epoxide ring, because when a nucleophile attacks an epoxide, the hydroxyl group of the product is on the carbon next to the carbon that was attacked. 

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