Acid-Catalyzed Decomposition of <i>O</i>‑Silylated α‑Diazo-β-hydroxy Esters: Access to Mixed Monosilyl Acetals

Acid-catalyzed decomposition of diazocarbonyl compounds triggers a wide range of transformations leading to synthetically useful building blocks with high diversity. In this field, the chemistry of α-diazo-β-hydroxy ester substrates is largely dominated by migration processes. We describe herein a new approach to original mixed monosilyl acetals from O-protected α-diazo-β-hydroxy-β-aryl esters and alcohols, catalyzed by trimethylsilyl trifluoromethanesulfonate (TMSOTf). The ratio between these original mixed acetals, the symmetric acetals, and the migration products fluctuates depending on the catalyst, the nature of the alcohols, and the substituent on the aromatic ring. Fifty-six examples are reported herein with yields up to 71% and diastereoselectivity up to 6:1. Such mixed monosilyl acetals constitute a synthetic equivalent of α-substituted β-oxoesters with high potential for further transformations

Synthetic Variants of Mycolactone Bind and Activate Wiskott–Aldrich Syndrome Proteins

Mycolactone is a complex macrolide toxin produced by <i>Mycobacterium ulcerans</i>, the causative agent of skin lesions called Buruli ulcers. Mycolactone-mediated activation of neural (N) Wiskott–Aldrich syndrome proteins (WASP) induces defects in cell adhesion underpinning cytotoxicity and disease pathogenesis. We describe the chemical synthesis of 23 novel mycolactone analogues that differ in structure and modular assembly of the lactone core with its northern and southern polyketide side chains. The lactone core linked to southern chain was the minimal structure binding N-WASP and hematopoietic homolog WASP, where the number and configuration of hydroxyl groups on the acyl side chain impacted the degree of binding. A fluorescent derivative of this compound showed time-dependent accumulation in target cells. Furthermore, a simplified version of mycolactone mimicked the natural toxin for activation of WASP in vitro and induced comparable alterations of epithelial cell adhesion. Therefore, it constitutes a structural and functional surrogate of mycolactone for WASP/N-WASP-dependent effects

Synthetic Variants of Mycolactone Bind and Activate Wiskott–Aldrich Syndrome Proteins

Mycolactone is a complex macrolide toxin produced by <i>Mycobacterium ulcerans</i>, the causative agent of skin lesions called Buruli ulcers. Mycolactone-mediated activation of neural (N) Wiskott–Aldrich syndrome proteins (WASP) induces defects in cell adhesion underpinning cytotoxicity and disease pathogenesis. We describe the chemical synthesis of 23 novel mycolactone analogues that differ in structure and modular assembly of the lactone core with its northern and southern polyketide side chains. The lactone core linked to southern chain was the minimal structure binding N-WASP and hematopoietic homolog WASP, where the number and configuration of hydroxyl groups on the acyl side chain impacted the degree of binding. A fluorescent derivative of this compound showed time-dependent accumulation in target cells. Furthermore, a simplified version of mycolactone mimicked the natural toxin for activation of WASP in vitro and induced comparable alterations of epithelial cell adhesion. Therefore, it constitutes a structural and functional surrogate of mycolactone for WASP/N-WASP-dependent effects