Synthetic efforts on the road to marine natural products bearing 4-O-2,3,4,6-tetrasubstituted THPs: an update.

Scientific literature is inundated with secondary metabolites from marine sources. In this ocean of natural products, the presence of recurring patterns has traditionally led scientists to unravel the biosynthetic mechanisms that naturally yield these products, as well as to imitate Nature to prepare them in the laboratory, especially when promising bioactivities and stimulating molecular architectures are involucrate. For instance, natural products containing multisubstituted oxygenated rings and macrocyclic lactones are recurrently selected as targets for developing total syntheses. Thus, in the last decades a noteworthy number of synthetic works regarding miyakolide, madeirolide A and representative compounds of polycavernosides, lasonolides and clavosolides have come to fruition. Up to now, these families of macrolides are the only marine natural products bearing a tetrasubstituted tetrahydropyran ring with carbon substituents at positions 2, 3 and 6, as well as an oxygen at position 4. Their splendid structures have received the attention of the synthetic community, up to the point of starring in dozens of articles, and even some reviews. This work covers all the synthetic studies towards miyakolide and madeirolide A, as well as the synthetic efforts performed after the previous specialised reviews about lasonolide A, polycavernoside A and clavosolides, published in 2006, 2007 and 2016, respectively. In total, this review summarises 22 articles in which these marine natural products with 4-O-2,3,4,6-tetrasubstituted tetrahydropyrans have the leading role.

Stereoselective Synthesis of Highly Substituted Tetrahydropyrans through an Evans Aldol-Prins Strategy.

A direct and general method for the synthesis of naturally occurring 2,3,4,5,6-pentasubstituted tetrahydropyrans has been developed, employing ß,γ-unsaturated N-acyl oxazolidin-2-ones as key starting materials. The combination of the Evans aldol addition and the Prins cyclization allowed the diastereoselective and efficient generation of the desired oxacycles in two fashions: a one-pot Evans aldol-Prins protocol, in which five new σ bonds and five contiguous stereocenters were straightforwardly generated, and a two-step version, which additionally permitted the isolation of ß,γ-unsaturated alcohol precursors bearing an N-acyl oxazolidin-2-one in the α position. From these alcohols were also obtained halogenated pentasubstituted tetrahydropyrans as well as 2,3,4,5-tetrasubstituted tetrahydrofurans, shedding light on the mechanism of the process. Computational studies were consistent with the experimental findings, and this innovative Evans aldol-Prins strategy was performed for the preparation of a battery of more than 30 densely substituted tetrahydropyrans, unprecedentedly fused to a 1,3-oxazinane-2,4-dione ring, both in a racemic fashion and in an enantiomeric fashion. These novel molecules were successfully submitted to several transformations to permit simple access to a variety of differently functionalized tetrahydropyrans. Most of these unique molecules were evaluated for their antimicrobial activity against Gram-positive and Gram-negative bacteria and the yeast Candida albicans, and some structure-activity relationships were established.