Carbonolides

The macrolide carbonolide B contains six stereogenic centers at sp3 carbons. Devise a strategy for synthesis of cabonolide B and in particular for establishing the stereochemistry of the C(l)-C(8) segment of the molecule. 

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... 

For a review, in English, of computer-aided conformational design in macrolide synthesis (including carbonolides) see O. Yonemitsu, Yuki Gosei Kagaku Kyokaishi, 1994, 52, 946. 

The closure of large rings via Heck reactions has not received extensive attention. A pioneering example was reported in 1981 by Ziegler and co-workers during a model study for the construction of carbonolide B (100), the aglycone of the antitumor antibiotic carbomycin B (Scheme 6-16) [36]. In this study, vinyl iodide 98 was converted to the 16-membered macrocycle 99 using stoichiometric amounts of a palladium catalyst. Additional... 

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). 

P.G.M. Wuts and S.S. Bigelow [31] synthesized the Cj-Cg segment of carbomycin B, which is identical with that of the Nicolaou carbonolide synthesis, by using allylboronates to secure the four contiguous stereogenic centers from C3 to Cg. 

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