Scalable Biomimetic Syntheses of Paeciloketal B, 1-epi-Paeciloketal B, and Bysspectin A.

The first total synthesis of the benzannulated 5,5-spiroketal natural products paeciloketal B and 1-epi-paeciloketal B has been achieved in 10 linear steps employing a biomimetic spiroketalization. This approach also furnished the related natural product bysspectin A from the same putative biosynthetic precursor as the paeciloketals. Alternatively, bysspectin A could be accessed in only six steps using an improved route. This scalable and efficient synthesis affords insight into the biosynthesis of these natural products in nature.

The Synthesis and Bioactivity of the Marine Macrolide Callyspongiolide.

Callyspongiolide, a macrolide natural product with a conjugated diene-ynic side chain, has garnered significant attention from the synthetic community since its isolation from a sea sponge in 2013. Herein, the approaches that have been applied to this bioactive natural product to date are reviewed. These synthetic endeavors have established the absolute stereochemistry of this molecule and allowed further investigation into its promising caspase-independent bioactivity, while also contributing to the wider field of macrolide synthesis.

Molecules derived from the extremes of life: a decade later.

Covering: Early 2008 until the end of 2019Microorganisms which survive (extreme-tolerant) or even prefer (extremophilic) living at the limits of pH, temperature, salinity and pressure found on earth have proven to be a rich source of novel structures. In this update we summarise the wide variety of new molecules which have been isolated from extremophilic and extreme-tolerant microorganisms since our original 2009 review, highlighting the range of bioactivities these molecules have been reported to possess.

The Total Synthesis of the Bioactive Natural Product Plantazolicin†A and Its Biosynthetic Precursor Plantazolicin†B.

Herein, we describe our full investigations into the synthesis of the peptide-derived natural product plantazolicin A, a compound that demonstrates promising selective activity against the causative agent of anthrax toxicity, and its biosynthetic precursor plantazolicin B. This report particularly focuses on the challenging preparation of the arginine containing thiazole fragment, including the development of a robust, high yielding procedure that avoids the use of sulfurating agents. Extensive studies on the design of a coherent protecting group strategy and the establishment of a step-efficient dicyclization/oxidation approach allowed high levels of convergence for the construction of the oxazole fragments. This has led to a unified, highly convergent synthesis for both plantazolicin A and B.

Synthesis of Natural and Unnatural Cyclooligomeric Depsipeptides Enabled by Flow Chemistry.

Flow chemistry has been successfully integrated into the synthesis of a series of cyclooligomeric depsipeptides of three different ring sizes including the natural products beauvericin (1 a), bassianolide (2 b) and enniatin C (1 b). A reliable flow chemistry protocol was established for the coupling and macrocyclisation to form challenging N-methylated amides. This flexible approach has allowed the rapid synthesis of both natural and unnatural depsipeptides in high yields, enabling further exploration of their promising biological activity.

Total syntheses of linear polythiazole/oxazole plantazolicin A and its biosynthetic precursor plantazolicin B.

Plantazolicin A, a linear decacyclic natural product, exhibits desirable selective activity against the causative agent of anthrax toxicity. The total synthesis of plantazolicin A and its biosynthetic precursor plantazolicin B was successfully achieved by an efficient, unified, and highly convergent route featuring dicyclizations to form 2,4-concatenated oxazoles and the mild synthesis of thiazoles from natural amino acids. This report represents the first synthesis of plantazolicin B and includes the first complete characterization data for both natural products.

The rapid synthesis of oxazolines and their heterogeneous oxidation to oxazoles under flow conditions.

A rapid flow synthesis of oxazolines and their oxidation to the corresponding oxazoles is reported. The oxazolines are prepared at room temperature in a stereospecific manner, with inversion of stereochemistry, from ß-hydroxy amides using Deoxo-Fluor®. The corresponding oxazoles can then be obtained via a packed reactor containing commercial manganese dioxide.

Formal synthesis of berkelic acid: a lesson in α-alkylation chemistry.

The full details of our enantioselective formal synthesis of the biologically active natural product berkelic acid are described. The insertion of the C-18 methyl group proved challenging, with three different approaches investigated to install the correct stereochemistry. Our initial Horner-Wadsworth-Emmons/oxa-Michael approach to the berkelic acid core proved unsuccessful upon translation to the natural product itself. However, addition of a silyl enol ether to an oxonium ion, followed by a one-pot debenzylation/spiroketalisation/thermodynamic equilibration procedure, afforded the tetracyclic structure of the berkelic acid core as a single diastereoisomer.

An enantioselective formal synthesis of berkelic acid.

An enantioselective formal synthesis of berkelic acid is described. The key step involves a late-stage silyl enol ether addition to a benzannulated oxonium ion with subsequent spiroketalization leading to construction of the tetracyclic core. Thermodynamically controlled equilibration under acidic conditions affords the desired spiroketal configuration as a single diastereoisomer.

A flexible asymmetric synthesis of the tetracyclic core of berkelic acid using a Horner-Wadsworth-Emmons/oxa-Michael cascade.

The one-pot Horner-Wadsworth-Emmons/oxa-Michael cascade followed by spiroketalisation affords the tetracyclic benzannulated spiroketal core of berkelic acid, an extremophile natural product with selective activity against ovarian cancer.

Molecules derived from the extremes of life.

In order to survive extremes of pH, temperature, salinity and pressure, organisms have been found to develop unique defences against their environment, leading to the biosynthesis of novel molecules ranging from simple osmolytes and lipids to complex secondary metabolites. This review highlights novel molecules isolated from microorganisms that either tolerate or favour extreme growth conditions.

Anti-Helicobacter pylori activity of derivatives of the phthalide-containing antibacterial agents spirolaxine methyl ether, CJ-12,954, CJ-13,013, CJ-13,102, CJ-13,104, CJ-13,108 and CJ-13,015.

The naturally occurring phthalide-containing antibiotics spirolaxine methyl ether, CJ-12,954, CJ-13,013, CJ-13,015, CJ-13,102, CJ-13,103, CJ-13,104 and CJ-13,108, have been reported to exhibit anti-H. pylori activity. However, the exact stereochemistry of spirolaxine methyl ether, CJ-12,954 or CJ-13,013, contributing to this observed activity has not been confirmed. The anti-H. pylori activity of several analogues of spirolaxine methyl ether, CJ-12,954 and CJ-13,013 of defined stereochemistry together with the anti-H. pylori activity of several indole analogues of the simpler phthalide-containing antibiotics CJ-13,102, CJ-13,104, CJ-13,108 and CJ-13,015 is reported herein. A 1:1 mixture of spiroacetals 5b and 6b in which the phthalide substituent exhibited (3R)-stereochemistry was sixty times more active than the corresponding 1:1 mixture of spiroacetals with (3S)-stereochemistry. Notably, the unnatural (2''S)-diastereomer of spirolaxine methyl ether exhibited more potent anti-H. pylori activity than the natural product spirolaxine methyl ether. The 4,6-dimethoxyindoles 9, 10, 11 and 13 were all found to be less active than their parent compounds 1, 2, 3 and 4, respectively. Chain-shortened 4,6-dimethoxyindole analogue 12 of CJ-13,108 3 and 4,6-dimethoxyindole-spiroacetal 13 exhibited weak anti-H. pylori activity thus providing future opportunity for drug discovery programs.