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.

The structural complexity and biological importance of macrolide natural products has inspired the development of innovative strategies for their chemical synthesis. With their dense stereochemical content, high level of oxygenation...

The diverse and complex structures of polyketide natural products have stimulated the imagination of synthetic chemists for decades. Captivated by their often impressive biological activities and their dazzling array of stereochemically-rich motifs, we have been motivated to achieve their efficient and stereocontrolled total synthesis. This review captures snapshots from our thirty-year foray into the total synthesis of 18 polyketide natural products, detailing the unique challenges, discoveries and revelations made en route to eventual success. Notably, crucial to each of these campaigns was the judicious application of highly selective aldol reactions to iteratively configure the densely oxygenated stereoclusters that characterise this fascinating class of bioactive natural products.

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...