Alexandros L. Zografos

Total Synthesis of Diverse Carbogenic Complexity within the Resveratrol Class from a Common Building Block

Although biomimetic approaches have proven capable of converting resveratrol (1) concurrently into many of the more complex oligomers produced by plants throughout the world (such as 2-10), methods to access single members of the family have proven far more difficult to identify. Herein is described a strategy-level solution based on the use of a common building block, one distinct from Natures starting material, that can participate in a variety of highly selective, reagent-controlled reaction cascades. These endeavors have led to the controlled synthesis of 25 natural products and analogues, molecules whose architectures encompass nearly all the carbogenic diversity of the resveratrol family.

Accessing the structural diversity of pyridone alkaloids: concise total synthesis of rac-citridone A.

A unique route to the structural diversity of pyridone alkaloids is described based on the concept of a common synthetic strategy. Three different core structure analogues corresponding to akanthomycin, septoriamycin A, and citridone A have been prepared by using a highly selective and novel carbocyclization reaction.

“Common synthetic scaffolds” in the synthesis of structurally diverse natural products

Selected natural products have long been considered as desirable targets for total synthesis due to their unique biological properties and their challenging structural complexity. Laboratory synthesis of natural compounds usually relies on target-oriented synthesis, involving the production, isolation and purification of successive intermediates, requiring multiple steps to arrive to the final product. A far more economical approach using common synthetic scaffolds that can be readily transformed through biomimetic-like pathways to a range of structurally diverse natural products has been evolved in the last decade, leading synthesis to new directions. This tutorial review critically presents the hallmarks in this field.

Designed spiro-bicyclic analogues targeting the ribosomal decoding center.

The bacterial ribosome represents the confirmed biological target for many known antibiotics that interfere with bacterial protein synthesis. Aminoglycosides represent a lead paradigm in RNA molecular recognition and constitute ideal starting points for the design and synthesis of novel RNA binders. Previous rational design approaches of RNA‐targeting small molecules have been mainly concentrated on direct functionalization of aminoglycosidic substructures. Herein, we successfully designed and synthesized rigid spirocyclic scaffolds locked in a predicted ribosome‐bound “bioactive” conformation. These analogues are able to mimic many of the interactions of the natural products for the A‐site, as proven by their obtained binding affinities. The development of an optimized approach for their synthesis and their potential to inhibit protein production in vitro are presented. Our results could be further utilized for the development of analogues with improved antibiotic profiles.

Non-natural Elemane as the “Stepping Stone” for the Synthesis of Germacrane and Guaiane Sesquiterpenes

The synthesis of hydroxyelemane 5 from (R)-carvone and its utilization as a common synthetic scaffold to produce structurally diverse germacrane and guaiane sesquiterpenes are described. A highly enantio- and stereoselective biomimetic tandem oxy-Cope/ene rearrangement was used as the key reaction to access the 10-membered macrocyclic core of germacranes and the condensed 5-7 carbocycles of guaiane sesquiterpenes. Additionally, reactions of furanoguaianes under acidic or oxidizing reagents have been investigated, and preliminary results of these conversions are presented.

Electrocyclization of Oxatrienes in the Construction of Structurally Complex Pyranopyridones

Application of a tandem Knoevenagel/6π-electrocyclization sequence is able to produce highly substituted pyranopyridones from moderate to high yields in a one-step reaction. High diasteroselectivity is observed in some cases and was rationalized on the basis of the thermodynamic control of the evidenced reversibility of a 6π-electrocyclization reaction. Numerous examples are provided establishing a novel entry in natural product-like structures of pyranopyridone alkaloids.

Unnatural Rigid Scaffolds Targeting the Bacterial Ribosome

The bacterial ribosome represents the confirmed biological target for many known aminoglycoside antibiotics, which interfere with bacterial protein synthesis. Crystallographic analyses of ribosomal subunits and domains thereof in complex with antibiotics have demonstrated that these natural products ACHTUNGTRENNUNGinteract almost exclusively with ribosomal RNA components (rRNA), a result that lends support to earlier biochemical ACHTUNGTRENNUNGfindings[3] and emphasizes the importance of RNA as a drug target. 5] Specifically for natural aminoglycosides such as paromomycin, neomycin B, and neamine (Scheme 1), this is accomplished through their interaction with the decoding-site (Asite) ribosomal RNA 6] (Scheme 1) and disruption of the mRNA-decoding fidelity. 8] Despite their undesirable pharmacological profiles and the development of resistance to them, which both limit their antibiotic utility, their capacity to bind with high affinity to the bacterial decoding site and several other RNA targets renders them a leading paradigm in RNA molecular recognition. 14] Therefore, aminoglycosides and fragments thereof constitute ideal starting points for the design and synthesis of novel RNA binders. Rational design approaches toward RNA-targeting small molecules have been previously reported, mainly concentrating on individually functionalized aminoglycosidic structural components, explicitly 2-deoxystreptamine (2-DOS, Scheme 1) and glucosamine, as well as neamine 21] and paromamine. 23] Herein, by employing the principles of structural electrostatic complementarity, we have designed and synthesized small-molecule rigid scaffolds (Scheme 1, A and B) only distantly related to the parent aminoglycoside motif, bearing the required peripheral amino and hydroxyl functionalities in optimized orientations, which maximize the affinity for the biological target, as suggested by their natural ancestors. The biological evaluation of the new synthetic entities in vitro regarding binding affinity and specificity for the decoding-site RNA was also performed, justifying our initial design parameters. Our novel approach was formulated based on two major considerations. First, the flexibility of the glycosidic bond in the natural products, although limited, might be responsible for the target variability demonstrated in their action. Specifically, a comparison of the oligosaccharide conformations recognized by the bacterial ribosome and the enzymes responsible for antibiotic inactivation presents remarkable differences. Thus, new chemical entities locked in the ribosomebound “bioactive” conformation, where the glycosidic bond has been replaced by a rigid quaternary center, were targeted. These molecules should also conserve established contacts ACHTUNGTRENNUNGbetween natural aminoglycosides and the A-site RNA. Specifically, the key characteristic interactions that were mimicked (shown in Figure 1 A and D for neamine) are: 1) the formation of a pseudo base pair with A1408, 2) the contacts with O4 of U1495, 3) the contact with N7 of G1494, and 4) the contacts with the phosphate group of A1492, A1493 and G1494. Consequently, compound 1 (Scheme 1 and Figure 1 B) was modeled into the bacterial A site (see the Supporting Information for computational methods) in its oxa-spiro, rigid scaffold in the orientation shown in Figure 1 B and C. Our design partially overlooked crystallographically suggested considerations Scheme 1. Secondary structure of the bacterial decoding-site internal loop (A site) in 16S rRNA. The four base changes of the eukaryotic sequence are indicated by arrows. The recognition site for the 2-DOS moiety of aminoglycosides is boxed; structures of neomycin B and paromomycin, neamine (neomycin A), paromamine and 2-DOS, and the conformationally restricted analogues (general structures A, B and specific construct 1) designed and synthesized in this study.

Palladium-catalyzed direct alkenylation of 4-hydroxy-2-pyridones

The first direct C-3 alkenylation of N-substituted-4-hydroxy-2-pyridones with unactivated alkenes has been achieved under conventional palladium acetate catalysis. The presented protocol enables the efficient production of functionalized furo[3,2-c]-pyridones-2 when terminal alkenes are utilized and 3-alkenyl-4-hydroxy-2-pyridones when more substituted reaction partners are involved. The mild reaction conditions allow easy, scalable access to pyridone derivatives that resemble core structures isolated from natural alkaloids.

Advances of Phenoxazines: Synthesis, Reactivity and Their Medicinal Applications

Phenoxazines are an important class of heterocycles, which are emerging in the field of medicinal chemistry. They exhibit numerous biological activities, including antiviral, anticancer, anti-Alzheimer, antidiabetic, antioxidant, anti-inflammatory, antibiotic and many more. The present review focuses on the chemistry along with the medicinal applications of the phenoxazine moiety, in order to provide a greater insight for the development of future phenoxazine therapeutics.

Regioselective Ene-Type Allylic Chlorination of Electron-Rich Alkenes by Activated DMSO

A simple protocol involving the activation of DMSO by chlorotrimethysilane is described for the chemoselective chlorination of polyprenoids. The proposed protocol provides a versatile and scalable alternative to existing routes for accessing useful synthetic synthons for the synthesis of complex terpenoids.