Total Synthesis of Complex Peptidyl Nucleoside Antibiotics: Asymmetric De Novo Syntheses of Miharamycin B and Its Biosynthetic Precursor

Abstract

Miharamycins belong to a class of peptidyl nucleoside antibiotics with a unique nine-carbon pyranosyl amino acid core and a rare 2-aminopurine moiety. Herein, we report the de novo total synthesis of miharamycin B and its biosynthetic precursor from 3bromofuran and Garner's aldehyde through a modified Achmatowicz reaction. Many challenges were resolved toward the de novo synthesis of miharamycin B, including the introduction of a dense array of functional groups, the stereoselective construction of consecutive stereocenters, dealing with the variability of the anomeric positions, and promoting site-selectivity in the cyclization to form the tetrahydrofuran ring. This de novo synthesis strategy enables efficient preparation of 3'-substituted saccharides, allowing the study of their structure-activity relationships and mode of action, and meets the growing demand for the development of novel antibiotics inspired by miharamycin natural products.

Purine nucleoside antibiotics: recent synthetic advances harnessing chemistry and biology

“…63,65 More recently, the chemical synthesis of miharamycin B (6) and analogues was reported by Wang and Liu. 66 Starting from enantiopure (R)-Garner's aldehyde (49) and 3-bromofuran (50), a 20-step asymmetric de novo approach was designed (Fig. 8b).…”

Expeditious preparation of β-sec-alkyl vicinal amino alcohols used for chiral ligand synthesis

“…1c). 13 Our assumption begins with the addition of a readily accessible primary alkyl Grignard reagent to a N , O -protected l -serine ester 1 to afford dialkyl-decorated tertiary alcohols 2 . 14 Elimination of the hydroxyl group of 2 produces alkenes 3 , then hydrogenation of the alkenes and acid mediated deprotection affords chiral β-2°-alkyl amino alcohols 5 .…”