Antibiotics Wolff rearrangement

Scheme 10.14 gives some other examples of Wolff rearrangement reactions. Entries 1 and 2 are reactions carried out under the classical silver ion catalysis conditions. Entry 3 is an example of a thermolysis. Entries 4 to 7 are ring contractions done under photolytic conditions. Entry 8, done using a silver catalyst, was a step in the synthesis of macbecin, an antitumor antibiotic. Entry 9, a step in the synthesis of a drug candidate, illustrates direct formation of an amide by trapping the ketene intermediate with an amine. 

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... 

Insertion of carbenoid species into the azetidinone N-H bond is the most straightforward route to 2-oxocarbapenams, and thence to the vast majority of carbapenem antibiotics [186]. Unfortunately, synthesis of the 2-oxopenam 281a (R" = Me) from diazomalonic azetidinyl thioester 323 was abortive [172,187]. The prescribed carbene was generated (rhodium acetate dimer or hv), but it underwent Wolff rearrangement to a ketene. 

The first total synthesis of the antibiotic acanthodoral (1) 118 has been achieved from 3-methyl-2-cyclohexen-l-one in 19 steps in 2.1% overall yield. This synthesis involves the use of a Pd-ene reaction in the presence of CO to form the endocyclic alkene 116, a nonreductive acyl radical cyclization and ring contraction by the Wolff rearrangement of ll ." ... 

The concept of activation of enediyne antibiotics by photolysis of an enediyne chromophore has been developed using a diazo compound. Irradiation of 11-membered enediynes containing an a-diazo-p,p-dicarbonyl fragment leads, via the Wolff rearrangement, to reactive 10-membered structures. Thus, photolysis of 2-diazo-6,7-benzocycloundeca-4,8-diyn-l,3-dione produced the ketoester 3.479 which via enolization undergoes fast cycloaromatization to the reactive diradical 3.480, which in the presence of hydrogen donors produces dihydroanthracene (Scheme 3.17) [245]. 

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