Total synthesis and study of 6-deoxyerythronolide B by late-stage C–H oxidation

Abstract

Among the frontier challenges in chemistry in the 21st century are the interconnected goals of increasing synthetic efficiency and diversity in the construction of complex molecules. C—H Oxidation reactions, particularly when applied at late-stages of complex molecule syntheses, hold special promise for achieving both these goals. Here we report a late-stage C—H oxidation strategy in the total synthesis of 6-deoxyerythronolide B (6-dEB), the aglycone precursor to the erythromycin antibiotics. An advanced intermediate is cyclized to the 14-membered macrocyclic core of 6-dEB using a late-stage (step 19 of 22) C—H oxidative macrolactonization reaction that proceeds with high regio-, chemo-, and diastereoselectivity (>40:1). A chelate-controlled model for macrolactonization predicted the stereochemical outcome of C—O bond formation and guided the discovery of conditions for synthesizing the first diastereomeric 13-epi-6-dEB precursor. Overall, this C—H oxidation strategy affords a highly efficient and stereochemically versatile synthesis of the erythromycin core.

Synthesis, Structure, and Catalytic Studies of Palladium and Platinum Bis-Sulfoxide Complexes

“…[15][16][17][18][19][20] Successful examples where the only chelating moieties are sulfoxides are still sporadic. [21][22][23][24][25][26][27][28] Complexes of bissulfoxide ligands with palladium and platinum are known, 22,[29][30][31][32][33][34] but there are not many reports of them being used successfully in catalysis. The only examples reported are from the groups of Shibasaki 22 and White, 33 using palladium bissulfoxides.…”

“…[21][22][23][24][25][26][27][28] Complexes of bissulfoxide ligands with palladium and platinum are known, 22,[29][30][31][32][33][34] but there are not many reports of them being used successfully in catalysis. The only examples reported are from the groups of Shibasaki 22 and White, 33 using palladium bissulfoxides. Following the success of bissulfoxide ligands developed in our laboratory in Rh catalysis, [23][24][25] we decided to study complexes of these ligands with palladium and platinum, with the goal of using them in catalysis.…”

O desafio da ativação das ligações C-H em síntese orgânica

“…51 Recentemente, a viabilidade de aplicação desta reação, baseada na ativação de ligação C-H alílica, foi demonstrada na síntese do produto natural 6-desoxieritronolídeo B, 52 um precursor dos antibióticos do tipo eritromicina, a partir de um intermediário avançado, obtido após 18 etapas (Esquema 13).…”

Transition Metal Catalyzed Approaches to Lactones Involving CO Bond Formation

“…Interestingly, upon addition of tetrabutylammonium fluoride as an additive, the opposite diastereomer was favored (1: 1.3) due to disruption of the Pd chelate intermediate [110]. The authors reasoned that the …”