Synthetic Studies Towards Anthracimycin

Abstract

Anthracimycin (9) is a macrocyclic natural product isolated from a Streptomyces strain (CNH365) collected off the coast of Santa Barbara (USA) in 2013. Anthracimycin (9) displayed potent antibiotic activity against a panel of important bacterial strains, including MRSA (ATCC 12709, MIC 0.0625 μg/mL) and B. anthracis (UM23C1-1, MIC 0.031 μg/mL) through an as yet undetermined mechanism of action. Additionally, 9 is also a novel mTOR inhibitor, suppressing proliferation of cancer stem cells in hepatocellular carcinoma cell lines. Anthracimycin (9) possesses a highly rigid, 14-membered macrocyclic structure, bearing a 1,3-E,Z-diene fragment, a hydrogen bonded 1,3-dicarbonyl motif and an appended trans-decalin ring system. The complex molecular architecture, potent biological activity and unknown mode of action makes 9 an interesting target for chemical synthesis and presents a unique chemical scaffold for drug discovery. It was envisaged that 9 could be assembled from three key intermediates; phosphonate (S)-84, ester 86 and decalin fragment 243. These fragments could be unified sequentially by an aldol reaction, vinylogous Horner-Wittig reaction and macrolactonisation. An IMDA cycloaddition was selected as an efficient method of constructing 243, and the synthesis and IMDA reactivity of four distinct precursors, namely ester (R)-199, aldehyde 99, ketone 226 and chiral auxiliary-bearing 242 were investigated. Precursor 242, bearing an Evans oxazolidinone auxiliary was reacted successfully to afford an IMDA adduct possessing the same stereochemical configuration as the natural product (9). It was envisaged that 9 could be assembled from three key intermediates; phosphonate (S)-84, ester 86 and decalin fragment 243. These fragments could be unified sequentially by an aldol reaction, vinylogous Horner-Wittig reaction and macrolactonisation. An IMDA cycloaddition was selected as an efficient method of constructing 243, and the synthesis and IMDA reactivity of four distinct precursors, namely ester (R)-199, aldehyde 99, ketone 226 and chiral auxiliary-bearing 242 were investigated. Precursor 242, bearing an Evans oxazolidinone auxiliary was reacted successfully to afford an IMDA adduct possessing the same stereochemical configuration as the natural product (9). Function-oriented synthesis (FOS) studies towards structurally simplified analogues of 9 were conducted, whereby the trans-decalin ring system of 9 was replaced with cyclohexene fragments obtained through a Diels-Alder cycloaddition reaction. These fragments enabled investigation of methods required for constructing the macrocycle of 9. In particular, a Mukaiyama aldol reaction of aldehyde 334a with bis-silyl enol ether 346 was envisaged to construct the tricarbonyl motif (strategy A). The subsequent vinylogous Horner-Wittig reaction of aldehyde 362a and phosphonate (S)-84 proved problematic, thus the order of fragment coupling was revised. Strategy B emphasised 1,3-E,Z-diene synthesis prior to tricarbonyl installation, through the vinylogous Horner-Wittig reaction. Subsequent enolate alkylation of ketone 396a with acid chloride 428 delivered late-stage intermediate 386a, however, the final macrocyclisation step ultimately proved unsuccessful. Given the problematic macrocyclisation, an alternative coupling strategy involving an intramolecular Stille coupling was attempted on linear fragment 444, which was assembled through coupling of carboxylic acid 445 and amine 446. Gratifyingly, 444 underwent smooth macrocyclisation to provide 14-membered macrocycle 443, bearing resemblance to anthracimycin (9) through the configuration of the 1,3-E,Z-diene unit and an appended aromatic ring in place of the trans-decalin ring system. These studies served as a proof-of-concept for this coupling strategy towards simplified analogues of 9 and will inform the end game strategy in the ongoing total synthesis of 9.