Total Synthesis of Carbonolide

Nicolaou s carbonolide synthesis is also based on the coupling of the C -Cio (172) and C11-C15 (174) segments, and the macrolactonization by the intramolecular Horner-Emmons reaction (Nicolaou method). 

The ester 169 was converted into 170 through a Michael type three-carbon extension. The carboxylic acid 172 was derived from 170 through the ketophos-phonate 171. The C11-C15 segment 174 was prepared from (R)-3-hydroxy-butyric acid (173). Esterification of 172 with 174 using DCC and DMAP gave 175, which was converted into 176 through an intramolecular Horner-Emmons reaction. The lactone 176 was transformed to the Tatsuta intermediate 163. 

Abstracted with permission from J. Org. Chem., 1994,59, 3113 1994 American Chemical Society 

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Since ketene is probably the intermediate of the Wolff rearrangement, the choice of solvents dictates the nature of the product. Indeed, water gave carboxylic acids, whereas alcohols or amines led to esters and amides, respectively. These combinations have been applied to the synthesis of more complex molecules. For example, the total synthesis of carbonolide B, a 16-membered macrolide antibiotic, relied on Amdt-Eistert homologation. In this sequence, a protected furanuronic acid was transformed to the corresponding a-diazoketone, which was then converted to its homologous carboxylic ester. The reaction was achieved using catalytic amounts of silver benzoate and excess of triethylamine in methanol (Scheme 3.4).11... 

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