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| - Total Synthesis of Rutamycin B and Oligomycin C
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| - The asymmetric synthesis of the macrolide antibiotics (+)-rutamycin B (1) and (+)-oligomycin C(2) is described. The approach relied on the synthesis and coupling of the individual spiroketalfragments 3a and 3b with the C1−C17 polyproprionate fragment 4. The preparation of the spiroketalfragments was achieved using chiral (E)-crotylsilane bond construction methodology, which allowedthe introduction of the stereogenic centers prior to spiroketalization. The present work details thesynthesis of the C19−C28 and C29−C34 subunits as well as their convergent assembly throughan alkylation reaction of the lithiated N,N-dimethylhydrazones 6 and 8 to afford the individuallinear spiroketal intermediates 5a and 5b, respectively. After functional group adjustment, theseadvanced intermediates were cyclized to their respective spiroketal-coupling partners 40 and 41.The requisite polypropionate fragment was assembled in a convergent manner using asymmetriccrotylation methodology for the introduction of six of the nine-stereogenic centers. The use of threeconsecutive crotylation reactions was used for the construction of the C3−C12 subunit 32. AMukaiyama-type aldol reaction of 35 with the chiral α-methyl aldehyde 39 was used for theintroduction of the C12−C13 stereocenters. This anti aldol finished the construction of the C3−C17 advanced intermediate 36. A two-carbon homologation completed the construction of thepolypropionate fragment 38. The completion of the synthesis of the two macrolide antibiotics wasaccomplished by the union of two principal fragments that was achieved with an intermolecularpalladium-(0) catalyzed cross-coupling reaction between the terminal vinylstannanes of theindividual spiroketals 3a and 3b and the polypropionate fragment 4. The individual carboxylicacids 46 and 47 were cyclized to their respective macrocyclic lactones 48 and 49 under Yamaguchireaction conditions. Deprotection of these macrolides completed the synthesis of the rutamycin Band oligomycin C.
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