Domino Reactions for the Synthesis of Anthrapyran-2-ones and the Total Synthesis of the Natural Product (±)-BE-26554A

Abstract

A domino alkyne addition/CO insertion/Nu acylation reaction to a series of novel anthrapyran-2-ones in good to excellent yields is described. In addition, an efficient synthetic sequence involving carbonylation, formation of a β-keto-sulfoxide, and cyclization is presented en route to the antibiotic and antitumor compound (±)-BE-26554A.

The synthesis and biological activity of novel anthracenone-pyranones and anthracenone-furans

“…This series of compounds were prepared through a domino alkyne insertion/carbonylation/Nu-acylation reaction, described in our earlier publication (Scheme 3). 21 We have found in previous investigations approached using palladium mediated domino reactions to be effective for rapid ring formation and sub-structural diversity. [36][37][38][39][40] In most cases under our reaction conditions the regioisomer 24 predominated in favour of compound 25.…”

“…Compounds 4,9,[13][14][15][16]23,[26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] have been prepared and characterised previously. 21 Non-1-yn-3-one (10) was prepared according to the procedure by Braddock et al 52 3.1.1. General procedure for the deprotection of the isopropyl group; Method A TsOHÁH 2 O (1.5 equiv) was added to a magnetically stirred solution or suspension of isopropylether-anthrapyranone in xylene (0.01-0.04 mM) and heated to reflux for 5-20 min monitoring Figure 4.…”

“…19,20 In 2013, we described a racemic synthesis of anthrapyranones through the annulation of a b-keto-sulfoxide and an aldehyde. 21 Interestingly, a recent report on a non-metal mediated synthetic ring forming processes on simple chromones has come to light 22 along with the oxidative alkylation of these ring systems. 23 The varying biological activity of the pluramycin class of compounds, with different substitution at C2, reflects the importance of this region of the molecule.…”

“…21,[27][28][29] Eventually this intermediate 13 was also used en route to the natural product (±)-BE-26554A (4) (Scheme 2). 21 The b-keto-sulfoxide-annulation procedure with propionaldehyde was especially high yielding (81%) which provided the impetus to expand this reaction to other aldehydes. Coupled with the Augustine olefination procedure by Krohn et al, this sequence could provide a range of substituted 4-pyranone derivatives.…”

“…Summary of the final stages of the synthesis of (±)-BE-26554A (4). 21 treating each of the cell lines at a compound concentration of 25 lM. If, in this preliminary assay, the compound was considered potent with a high percentage inhibition (>90% across all cell lines evaluated or >100% against more than two cell lines) and suitably soluble (in the DMSO/water solution), then a more detailed dose response evaluation was conducted.…”