Synthesis of Bicyclic Proline Derivatives by the Aza‐Cope–Mannich Reaction: Formal Synthesis of (±)‐Acetylaranotin

Herein we suggest an approach to oxygenated bicyclic amino acids based on an aza‐Cope–Mannich rearrangement. Seven distinct amino acid scaffolds analogous to the natural products were prepared on a gram scale with precise control of stereochemistry. Successful implementation of our strategy resulted in the formal synthesis of acetylaranotin.     

Synthesis and antibiofilm activity of a second-generation reverse-amide oroidin library: a structure-activity relationship study

A second-generation library of 2-aminoimidazole-based derivatives incorporating a "reversed amide" (RA) motif in comparison to the marine natural product oroidin were synthesized and subsequently assayed for antibiofilm activity against the medically relevant Gram-negative proteobacteria P. aeruginosa and A. baumannii. Most notably, an in-depth activity profile is reported for the most active subclass of derivatives that bear linear aliphatic chains off the amide bond. Additionally, further structural modifications of the core template, such as removal of the amide bond or substitution with a triazole isostere, resulted in the discovery of analogues with antibiofilm activities that varied with respect to their inhibition and dispersal properties of P. aeruginosa and A. baumannii biofilms.     

A gold-catalyzed entry into the sesquisabinene and sesquithujene families of terpenoids and formal total syntheses of cedrene and cedrol

A concise entry into the bicyclic cyclopropyl ketone derivatives 5 and 6 by way of a gold-catalyzed Ohloff-Rautenstrauch-type enyne cycloisomerization is described. The required substrates were prepared by an asymmetric addition of the branched allylzinc reagent 21 to the alkynyl aldehyde 17 mediated by the deprotonated bisoxazoline (BOX) ligand 22. Compounds 5 and 6 were then converted into a host of different members of the sesquisabina- and sesquithuja families of terpenoids, inter alia with the aid of iron-catalyzed cross-coupling reactions. As the relative and absolute configuration of 5 and 6 could be unambiguously established, the synthetic samples allowed the previously unknown stereostructures of various such terpenoids to be unraveled, including cis-sesquisabinene hydrate (33), 7-epi-sesquithujene (36), sesquisabinene B (37) and epoxy-sesquithujene (45). Moreover, the preparation of 6 also constitutes a formal total synthesis of cedrene (11) and cedrol (12).     

Structural Revisions of a Class of Natural Products: Scaffolds of Aglycon Analogues of Fusicoccins and Cotylenins Isolated from Fungi

The reisolation and structural revision of brassicicene D is described, and inspired us to reassign the core skeletons of brassicicenes C–H, J and K, ranging from dicyclopenta[a,d]cyclooctane to tricyclo[9.2.1.0^3,7]tetradecane using quantum‐chemical predictions and experimental validation strategies. Three novel, highly modified fusicoccanes, brassicicenes L–N, were also isolated from the fungus Alternaria brassicicola, and their structures were unequivocally established by spectroscopic data, ECD calculations, and crystallography. The reassigned structures represent the first class of bridgehead double‐bond‐containing natural products with a bicyclo[6.2.1]undecane carbon skeleton. Furthermore, their stabilities were first predicted with olefin strain energy calculations. Collectively, these findings extend our view of the application of computational predictions and biosynthetic logic‐based structure elucidation to address problems related to the structure and stability of natural products.     

Evolution of a Unified Strategy for Complex Sesterterpenoids: Progress toward Astellatol and the Total Synthesis of (−)‐Nitidasin

Astellatol and nitidasin belong to a subset of sesterterpenoids that share a sterically encumbered trans‐hydrindane motif with an isopropyl substituent. In addition, these natural products feature intriguing polycyclic ring systems, posing significant challenges for chemical synthesis. Herein, the evolution of our stereoselective strategy for isopropyl trans‐hydrindane sesterterpenoids is detailed. These endeavors included the synthesis of several building blocks, enabling studies toward all molecules of this terpenoid subclass, and of advanced intermediates of our initial route toward a biomimetic synthesis of astellatol. These findings provided the basis for a second‐generation and a third‐generation approach toward astellatol that eventually culminated in the enantioselective total synthesis of (?)‐nitidasin. In particular, a series of substrate‐controlled transformations to install the ten stereogenic centers of the target molecule was orchestrated and the carbocyclic backbone was forged in a convergent fashion. Furthermore, the progress toward the synthesis of astellatol is disclosed and insights into some observed yet unexpected diastereoselectivities by detailed quantum‐mechanical calculations are provided.     

Lead Structures for New Antibacterials: Stereocontrolled Synthesis of a Bioactive Muraymycin Analogue

Naturally occurring muraymycin nucleoside antibiotics represent a promising class of novel antibacterial agents. The structural complexity suggests the investigation of simplified analogues as potential lead structures, which can then be further optimized towards highly potent antimicrobials. Herein we report studies on muraymycin‐derived potential lead structures lacking an aminoribose motif found in most naturally occurring muraymycins. We have identified a 5′‐defunctionalized motif to be ideal in terms of stability and chemical accessibility and have synthesized a full‐length muraymycin analogue based on this structure using a novel fully stereocontrolled route. The obtained 5′‐deoxy analogue of the natural product muraymycin C4 showed good inhibitory properties towards the bacterial target protein MraY, sufficient pharmacokinetic stability and no cytotoxicity against human cells, thus making it a promising lead for antibacterial drug development.     

Total Synthesis of Schilancitrilactones B and C

The first total syntheses of schilancitrilactones B and C have been accomplished in 17 steps (longest linear sequence) from commercially available materials. Key steps include an intramolecular radical cyclization to provide the seven‐membered ring, late‐stage iodination, and an intermolecular radical addition reaction to complete the total synthesis.     

Combating Multidrug‐Resistant Bacteria: Current Strategies for the Discovery of Novel Antibacterials

The introduction of effective antibacterial therapies for infectious diseases in the mid‐20th century completely revolutionized clinical practices and helped to facilitate the development of modern medicine. Many potentially life‐threatening conditions became easily curable, greatly reducing the incidence of death or disability resulting from bacterial infections. This overwhelming historical success makes it very difficult to imagine life without effective antibacterials; however, the inexorable rise of antibiotic resistance has made this a very real and disturbing possibility for some infections. The ruthless selection for resistant bacteria, coupled with insufficient investment in antibacterial research, has led to a steady decline in the efficacy of existing therapies and a paucity of novel structural classes with which to replace them, or complement their use. This situation has resulted in a very pressing need for the discovery of novel antibiotics and treatment strategies, the development of which is likely to be a key challenge to 21st century medicinal chemistry.     

Cyclopamine and Hedgehog Signaling: Chemistry,Biology, Medical Perspectives

When Odysseus left the devastated city of Troy after ten years of siege he could not foresee the perils he still had to face. The encounter with the cyclops, a giant with only one eye placed in the middle of its forehead, was doubtlessly one of the creepiest and most dangerous of his adventures. In the end, Odysseus could only escape with the help of a sheep. Whether Homers cyclops was inspired by the observation of terribly malformed neonates remains speculative. However, when sheep herders in Idaho in the middle of the 20th century faced an increasing number of cyclops‐like sheep in their herds, a unique cascade of chemical, biological, and medicinal discoveries was initiated. This Minireview tells this story and shows its impact on modern biomedical research.