Studies towards the Total Synthesis of Amycolamicin: A Chiral Auxiliary‐Based Diels‐Alder Approach towards the Decalin Core

Abstract

The stereoselective synthesis of (1S,2S,5R)‐5‐((4‐methoxybenzyl)oxy)‐2‐methyl‐8‐methylene‐1,2,4a,5,6,7,8,8a‐octahy‐dronaphthalene‐1‐carboxylic acid (2) is described, which comprises the bicyclic core structure of the natural product amycolamicin (1). The bicyclic ring‐system was established via an intramolecular Diels‐Alder reaction of a triene carrying a SuperQuat chiral auxiliary. The latter could be readily removed by methanolysis in excellent yield, which allowed for effective conversion of a hydroxy group at C(1) into the methylene group present in the natural product. The intramolecular Diels‐Alder reaction could also be performed with a triene incorporating a classical, phenylalanine‐derived Evans auxiliary, but the removal of the latter from the initial Diels‐Alder product was hampered by competing attack of nucleophiles on the endocyclic carbonyl group in the oxazolidinone ring. Acid 2 could be converted into an acyl cyanide that features as a key advanced intermediate in one of the three total syntheses of amycolamicin reported to date.

Formal synthesis of kibdelomycin and derivatisation of amycolose glycosides

“…ESI † ) we had to postpone the introduction of the methylene group until after the decalin formation. We opted for Davies' SuperQuat auxiliary for the following Diels–Alder reaction, after many attempts to remove an Evans auxiliary had failed after successful Diels–Alder reaction and in accordance with the results of Frossard et al 19 Unlike most who use AlMeCl 2 as a catalyst for the IMDA, we had better results when heating triene 16 in toluene at 80 °C over 3 d which afforded octalin 15 with 43% yield besides some separable undesired cis -octalin. Quantitative removal of the TES-protecting group with HF pyridine complex left the alcohol 50 which had its auxiliary cleaved off with sodium methoxide to give hydroxyester 51 with 90% yield.…”

Evans’ Chiral Auxiliary‐Based Asymmetric Synthetic Methodology and Its Modern Extensions

“…[28] In 2022, Altmann and coworkers elaborated the stereoselective synthesis of carboxylic acid 23 (Scheme 6). [29] It comprises the trans-decalin core of amycolamicin (24) isolated from the soil actinomycete Amycolatopsis sp. MK575-fF5, showed a competitive inhibitor of the ATPase activity of bacterial DNA gyrase B (GyrB) and topoisomerase IV (ParE) and shows broadspectrum activity against Gram-positive bacteria.…”