Perspectives from nearly five decades of total synthesis of natural products and their analogues for biology and medicine

Abstract

This review article summarises a series of total syntheses of natural and designed molecules primarily for biology and medicine. Aspects of new synthetic strategies and methods and optimisation of biological properties are emphasised.

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

“…The resulting great selectivity index [72] (> 20,000 for actinoallolide A (23) creates them a promising class of lead molecules for the success of drugs for the treatment of Chagas disease and sleeping sickness. 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.…”

“…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).…”

“…Moreover, total synthesis is also effective to synthesize rare bioactive natural products in the laboratory as several secondary metabolites are obtained in small quantities from natural sources, especially those from higher plants and marine organisms. [17,18] The field of total synthesis of bioactive natural products has earned momentum in recent years as the demand for rare bioactive secondary metabolites and their analogues is enhancing due to their application in the field of biology and drug discovery and development. [8,19,20] Hence, the primary goal of this review is to summarize the brilliant applications of Yamaguchi method as a central step in the total synthesis of bioactive naturally occurring secondary metabolites and highlights the natural sources, structures, and biological activities of the promising natural products elegantly.…”

Nature's Chemists: The Discovery and Engineering of Phytochemical Biosynthesis

“…These metabolites are often found in low abundance or are produced in rare or slow-growing plant species, which limits the availability and accessibility of the active pharmaceutical agent and impacts market prices. In many cases, these molecules are very complex and are recalcitrant to chemical synthesis, as they contain many chiral centers or polycyclic rings (Nicolaou and Rigol, 2020 ). Even when synthesis is possible, it is not sustainable as it often relies on petrochemical feedstocks and/or environmentally unfriendly production processes (Lechner et al, 2016 ).…”

A look around the West Indies: The spices of life are secondary metabolites

“…Throughout the years, a wide variety of NPs with medicinally relevant bioactivities have been synthesized in academic research labs and pharmaceutical companies around the world. 10 , 11 In many cases, total synthesis was combined with a greater exploration of chemical space through the production of corresponding analogs of target NPs which, themselves, could increase the number of bioactive compounds for therapeutic usage but also ultimately expand understanding of the mechanism of action for their respective NPs. 12 , 13 …”