Trypanosoma protozoan parasites are the causative agents of Chagas disease and sleeping sickness, two neglected tropical diseases where there is an urgent need for improved treatments and the evaluation of promising drug leads like the actinoallolides. Enabled by the highly stereocontrolled aldol reactions of three chiral ketone building blocks, an efficient first total synthesis of the potent anti‐trypanosomal macrolide (+)‐actinoallolide A has been achieved in 17 steps and 8 % overall yield. Our convergent route features an adventurous ring‐closing metathesis to form the requisite trisubstituted (8E)‐alkene in the 12‐membered macrolactone, followed by the controlled installation of the labile transannular hemiacetal. Late‐stage diversification then provides ready access to the congeneric (+)‐actinoallolides B–E.
Trypanosoma protozoanparasites are the causative agents of Chagas disease and sleeping sickness,t wo neglected tropical diseases where there is an urgent need for improved treatments and the evaluation of promising drug leads like the actinoallolides.E nabled by the highly stereocontrolled aldol reactions of three chiral ketone building blocks,a ne fficient first total synthesis of the potent anti-trypanosomal macrolide (+ +)-actinoallolide Ah as been achieved in 17 steps and 8% overall yield. Our convergent route features an adventurous ring-closing metathesis to form the requisite trisubstituted (8E)-alkene in the 12-membered macrolactone,f ollowed by the controlled installation of the labile transannular hemiacetal. Late-stage diversification then provides ready access to the congeneric (+ +)-actinoallolides B-E.
The actinoallolides are a family of polyketide natural products isolated from the bacterium Actinoallomurus fulvus. They show potent biological activity against trypanosomes, the causative agents of the neglected tropical diseases...
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