Synthetic Approaches to Anti‐Inflammatory Macrolactones of the Oxacyclododecindione Type

Abstract

Various synthetic approaches to the oxacyclododecindione‐type macrolactones, known for their potent anti‐inflammatory activity, are presented. These include an attempted carbonylative ring closure, a hydroacylation route, and an approach by ring‐closing metathesis and double bond isomerization, as well as a strategy including ring‐closing metathesis/unsaturation. The last route allowed the preparation of a bioactive analogue of the recently described 14‐deoxyoxacyclododecindione.

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

“…Various strategies such as carbonylative cross-coupling, ringclosing metathesis/isomerization, ring-closing metathesis/ hydrogenation/unsaturation as well as hydroacylation to construct the 12-membered core of the oxacyclododecindione-type macrolactones turned out to be unsuccessful, 3 the main reason for this being the steric hindrance imposed by the 10methyl group. In contrast, an intramolecular Friedel-Crafts acylation at a later stage turned out to be a suitable key step for the synthesis of this compound class.…”

“…1,2 These compounds exhibit potent anti-inflammatory and anti-fibrotic activities in cell culture experiments and in an in vivo mouse model of systemic lupus erythematosus (SLE) and may serve as lead structures for therapeutics against chronic inflammatory and/or fibrotic diseases like asthma, rheumatoid arthritis, SLE or cancer. 3 Since 4-dechloro-14-deoxyoxacyclododecindione (1), 14-deoxyoxacyclododecindione (2) and oxacyclododecindione (3) can only be obtained in minute amounts by fermentation of the producer strain, we herein report the first total synthesis of lactones (±)-1 and (±)-2. 3 Since 4-dechloro-14-deoxyoxacyclododecindione (1), 14-deoxyoxacyclododecindione (2) and oxacyclododecindione (3) can only be obtained in minute amounts by fermentation of the producer strain, we herein report the first total synthesis of lactones (±)-1 and (±)-2.…”

A surprising switch in absolute configuration of anti-inflammatory macrolactones

“…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).…”

Twelve‐membered macrolactones: privileged scaffolds for the development of new therapeutics

“…Given the results of further experimentation in mouse models, OCDD has gained momentum as a possible lead compound for discovery of novel therapeutics for Lupus disease . Driven by the interesting and potentially useful bioactivity of this family, the Opatz group has endeavored to devise synthetic routes to the OCDDs, and has also generated analogs to begin probing SAR information . Interestingly, their synthesis of deoxa‐OCDD ( 90 ) and dechloro‐deoxa‐OCDD ( 91 ) (Scheme ) did not employ the most commonly used methods of ring closure, that is, macrolactonization or RCM.…”