Total synthesis of two potent anti-inflammatory macrolactones of the oxacyclododecindione type

Abstract

An esterification/Friedel-Crafts-cyclization approach permitted the first successful synthetic entry into the oxacyclododecindione subclass of the dihydroxyphenylacetic acid lactone-type natural products. This route allowed the preparation of two highly active anti-inflammatory fungal secondary metabolites 14-deoxyoxacyclododecindione and 14-deoxy-4-dechlorooxacyclododecindione as well as their 14-desmethyl analogues.

Total Synthesis and Biological Evaluation of the Anti-Inflammatory (13R,14S,15R)-13-Hydroxy-14-deoxyoxacyclododecindione

“…3,4,10−12 To date, two natural products and 10 synthetic derivatives of the oxacyclododecindione series have been successfully synthesized. 5,9 All of the retrosynthetic approaches followed a strategy based on the key step of an intramolecular Friedel-Crafts acylation (IFCA) at low substrate concentration and low temperature. 5,9,11 Other approaches to the ring closure of the 12-membered lactone, such as carbonylative cross-coupling, hydroacylation, or metathesis reaction, have not proved fruitful.…”

“…5,9 All of the retrosynthetic approaches followed a strategy based on the key step of an intramolecular Friedel-Crafts acylation (IFCA) at low substrate concentration and low temperature. 5,9,11 Other approaches to the ring closure of the 12-membered lactone, such as carbonylative cross-coupling, hydroacylation, or metathesis reaction, have not proved fruitful. 7 The synthesis of 13-hydroxy-14-deoxyoxacyclododecindione (4) commenced with the preparation of the three building esterification and Wittig olefination, followed by the key IFCA.…”

A surprising switch in absolute configuration of anti-inflammatory macrolactones

“…In our previous report on the racemic total synthesis of 4-dechloro-14-deoxyoxacyclododecindione ((±)-3) and 14-deoxyoxacyclododecindione ((±)-4), we found that synthetic (±)-4 was more active on a IL-4/Stat6-dependent and a TGF-β/Smad2/3dependent transcriptional luciferase reporter in transiently transfected HepG2 cells, than the isolated natural product (+)-4. 12,13 There are two possibilities to explain this result; the isolated material had a lower degree of purity, or the unnatural enantiomer (−)-4 is more active than the naturally occurring enantiomer (+)-4. To investigate this issue and to elucidate the absolute configuration of 14-deoxyoxacyclododecindione ((+)-4), a separation of racemic (±)-4 by chiral, preparative HPLC was performed.…”

“…It should be noted that the relative configuration of the two adjacent stereocenters was assigned as (14R*,15S*) by racemic total synthesis of 4-dechloro-14-deoxyoxacyclododecindione (3) and 14-deoxyoxacyclododecindione (4). 12,13 Due to their structural analogy to the macrolactones 1 and 2 the absolute configuration was assumed to be (14R,15S). [12][13][14][15] While (−)-1 and (−)-2 show biological activities in the micromolar range, the secondary metabolites 3-5 exhibit anti-inflammatory and anti-fibrotic activities in cell culture experiments at nanomolar concentrations.…”

“…12,13 Due to their structural analogy to the macrolactones 1 and 2 the absolute configuration was assumed to be (14R,15S). [12][13][14][15] While (−)-1 and (−)-2 show biological activities in the micromolar range, the secondary metabolites 3-5 exhibit anti-inflammatory and anti-fibrotic activities in cell culture experiments at nanomolar concentrations. 2,3 Furthermore, these lactones were successfully used in an in vivo mouse model of systemic lupus erythematosus (SLE).…”