Macrolactonization Macrosphelide

INOC was successfully employed in the total synthesis of the 16-membered macrolactone (+)-macrosphelide B 53. Interestingly, the cycloaddition of nitrile oxide generated in situ from 51 was more stereoselective in dioxane than in CH2CI2 (dr 10 1 vs 2 1). The major isomer was then converted into 53 by reductive N-0 bond cleavage, dehydration and MEM deprotection <05OL3159>. 

Carbonylative macrolactonization is also possible. Takahashi and coworkers successfully prepared a library of macrosphelide targets using solid phase synthesis under Pd(0) catalysis (Scheme 2.5). By using the split-and-pool technique, 122 compounds were synthesized [15]. 

Chemoselective carbonylation of a vinyl iodide 34 with alcohol containing a vinyl bromide moiety 35 has been successfully employed for the solid-phase synthesis of a macrosphelide precursor 36 [43]. After the 4-methoxyphenylmethyl (MPM) group was removed, the palladium-catalyzed carbonylative macrolactonization of the vinyl bromide 37 achieved the synthesis of the macrosphelide-supported derivative 38 (Scheme 9.13). The combinatorial synthesis of a 122-member macrosphelide library has been performed by the three-component strategy based on the palladium-catalyzed chemoselective carbonylation/macrolactonization reaction. 

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