A Unified Total Synthesis of the Actinoallolides, a Family of Potent Anti‐Trypanosomal Macrolides

Abstract

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.

Metathesis Reactions in Natural Product Fragments and Total Syntheses

“…Paterson and co‐workers accomplished the total synthesis of actinoallolides A−E 537 – 541 (Scheme 81). These are polyketides with a 12‐membered macrolactone linked to a long alkyl chain, isolated from the endophytic actinomycete Actinoallomurus fulvus MK10‐036 and possess a strong profile against Trypanosoma protozoan parasites [262] . In this synthetic strategy, they employed an RCM protocol as the key transformation to construct the 12‐membered macrolactone.…”

Conquering peaks and illuminating depths: developing stereocontrolled organic reactions to unlock nature's macrolide treasure trove

“…It was proposed to initially disassemble the lactone linkage and macrocyclic alkene in 178 to reveal C1-C8 alkene 179 and C9-C21 alkene 180. 75 We envisaged an adventurous ring-closing olefin metathesis (RCM) to install the highlighted trisubstituted This journal is © The Royal Society of Chemistry 2021 E-alkene. However, this ''do or die'' key step was perceived as a high-risk, high-reward manoeuvre due to the lack of examples in constructing comparable medium-ring systems.…”

Applications of Yamaguchi Method to Esterification and Macrolactonization in Total Synthesis of Bioactive Natural Products

“…According to the estimation of the World Health Organisation 8 million people are currently infected. [69] Since all present drug treatments are suffered from severe side effects, there is an urgent requirement for more promising medicines, including those inspired by natural products. [70] Complex polyketides actinoallolides were obtained from a cultured broth of the endophytic actinomycete Actinoallomurus fulvus MK10-036 [71] and they display potent activity against Trypanosoma protozoan parasites, while they are not able to exhibit toxicity against the MRC-5 human cell line.…”

“…In 2019, the first total synthesis of the potent anti-trypanosomal macrolides (+)-actinoallolides A-E was completed by Paterson from ethyl ketone (18) involving Yamaguchi method between the two complex fragments acid (21) and the alcohol ( 19). [69] The synthesis of the acid fragment (21) initiated from (S)-lactic acid and the preparation of the side chain fragment ( 19) started from the ethyl ketone (18), accessible in three steps from (R)-Roche ester. Next, esterification using Yamaguchi method took place between acid fragment (21) and the alcohol (19) to produce C13 ester in 99 % yield and it was then subjected to a "do or die" RCM-based strategy to afford 12-membered macrolactone (22) with desired E-alkene (Scheme 13).…”

“…With advanced intermediates ( 66) and (68) available, the authors proceeded to finish the total synthesis of (À )-enigmazole A (70). Esterification of ( 66) with (68) under Yamaguchi conditions [7] occurred to furnish crucial ester (69) in the presence of the TCBC and DMAP in toluene in 96 % yield (Scheme 21). Finally, bioactive secondary metabolite (À )-enigmazole A (70) was obtained from ester (69) over several steps; the total synthesis of (À )-enigmazole A (70) was accomplished in 29 steps (longest linear sequence) from readily available (R)-Roche ester.…”