Natural products from the human microbiome: an emergent frontier in organic synthesis and drug discovery.

Often referred to as the "second genome", the human microbiome is at the epicenter of complex inter-habitat biochemical networks like the "gut-brain axis", which has emerged as a significant determinant of cognition, overall health and well-being, as well as resistance to antibiotics and susceptibility to diseases. As part of a broader understanding of the nexus between the human microbiome, diseases and microbial interactions, whether encoded secondary metabolites (natural products) play crucial signalling roles has been the subject of intense scrutiny in the recent past. A major focus of these activities involves harvesting the genomic potential of the human microbiome via bioinformatics guided genome mining and culturomics. Through these efforts, an impressive number of structurally intriguing antibiotics, with enhanced chemical diversity vis-à-vis conventional antibiotics have been isolated from human commensal bacteria, thereby generating considerable interest in their total synthesis and expanding their therapeutic space for drug discovery. These developments augur well for the discovery of new drugs and antibiotics, particularly in the context of challenges posed by mycobacterial resistance and emerging new diseases. The current landscape of various synthetic campaigns and drug discovery initiatives on antibacterial natural products from the human microbiome is captured in this review with an intent to stimulate further activities in this interdisciplinary arena among the new generation.

A protocol for directly accessing geminal C-4 diarylated pyrazol-5(4H)-ones via tandem C-H aryne insertion and their inceptive neurobiological evaluation.

Geminal C-4 diarylation of substituted pyrazol-5(4H)-ones with in situ generated arynes as the aryl source has been achieved in a one-flask operation. All the newly accessed C4-gem-diarylated pyrazolone entities were found to be non-cytotoxic with varying AChE enzyme inhibitory activities and BBB permeability attributes that augur well for further advancement towards CNS therapeutics for untreatable disorders.

One-Pot Synthesis of Functionally Enriched Benzo[b]fluorenones: An Eco-Friendly Embedment of Diverse 1-Indanones into o-Bis-Ynones.

An efficient, base-promoted, one-pot, metal-free, open-flask synthesis of diverse, functionally enriched benzo[b]fluoren-11-ones has been discovered, and wide applicability of this exceptionally simple protocol with green flavors has been scoped. This synthesis proceeds via an unanticipated, tandem, double-aldol condensation between in situ-generated 1-indanone dianions and o-bis-ynones to furnish benzo[b]fluoren-11-ones harboring as many as six variegated substituents on their tetracyclic framework. This methodology has also been amplified to access heterocyclic analogues 2- and 4-azabenzo[b]fluorenones of benzo[b]fluoren-11-ones and extended to mixed linear-angular annulated pentacyclic dibenzo[a,h]fluoren-13-one.

Direct Two Carbon Ring Expansion of 1-Indanones with Ynones: An Eco-Friendly, One-Flask Approach to Functionally Enriched 5H-Benzo[7]annulenes.

Direct 2C-ring expansion of 1-indanones with ynones to 5H-benzo[7]annulenes has been observed, and its generality has been gauged (19 examples). Overall, this simple and convenient cascade process to 5H-benzo[7]annulenes involves engagement of 1-indanone with two ynone moieties with formation of three new C-C σ-bonds, cleavage of C-C σ-bond, and concurrent functionality amplification. The resulting seven-membered ring, laced with an opportunistic disposition of four proximal functional groups, offers avenues for their further productive interplay. Our new approach embraces many green and eco-friendly features.

Diversified Stitching of Ynones with Oxindole-3-oxy acrylates: One-Flask Spiro-annulation Protocol toward Assorted 3H/5H-Spiro[furan-2,3'-indolin]-2'-ones.

Spiroannulation of oxindole-3-oxy acrylates with ynones involving two overlapping, base differentiated cascades has been observed. Initial exposure of ynones and oxindole 3-oxy acrylates to K2CO3 triggered a tandem Michael-Michael cascade to deliver a pair of spiroannulated diastereomers. Further exposure to LiHMDS led to deep restructuring through a second multistep cascade involving stereoselective recreation of the C3 quaternary center to furnish 3H-spiro[furan-2,3'-indolin]-2'-ones with functional amplification and scrambling. This new scaffold can be directly accessed in a one-flask operation from ynones and oxindole-3-oxy acrylates.

Indeno-Annulation of o-Formyl-Ynones, o-Bis-Ynones, and p-Bis-o-Formyl-Ynones with Dimethyl Acetone-1,3-Dicarboxylate: One Flask Cascade Synthesis of Functionally Endowed 9-Fluorenols and Indeno[1,2-b]fluorenols.

A mild, scalable, one-pot access to multifunctional 9-fluorenols from o-formyl-ynones and o-bis-ynones on reaction with dimethylacetone-1,3-dicarboxyate through tandem Michael addition-Aldol condensation cascade has been conceptualized and executed. The scope and utility of this synthetic approach have been further amplified for one-pot entry into functionally enhanced, higher order fluorenols like pentacyclic indeno[1,2-b]fluorene-6,12-diols and further to indeno[1,2-b]fluorene-6,12-diones through the implementation of "double indeno-annulation" tactic on p-bis-o-formyl ynones and dimethylacetone-1,3-dicarboxylate. Besides several green attributes, the current approach is also compatible with the emerging time and energy economy features and is a swift gateway to build complexity.

An Approach to Functionally Embellished o-Alkynylbenzoates or Furan-3(2H)-ones from Diynones and DMAD: Controlled Divergence and Product Selectivity.

The discovery of reaction regime controlled product diversification in a one-pot reaction between diynones and dimethyl-1,3-acetonedicarboxylate (DMAD) to selectively furnish either functionally unique pentasubstituted o-alkynylbenzoates or fully substituted furan-3(2H)-ones is delineated. The potential of these two versatile platforms to enter new utilitarian chemical space has also been explored.

In Situ-Generated Ammonia Mediates Deep Restructuring of o-Bis-Ynones through a Cascade Process: One-Pot Synthesis of 2-Azafluorenones.

One-pot synthesis of 2-azaflorenones from readily accessed o-bis-ynones through Michael addition, orthogonal aldol reaction, dehydrative isomerization, and a 6-endo-dig-cyclization cascade, triggered by in situ-generated ammonia in the presence of a Cu(I) catalyst, has been discovered and its generality scoped. A few selected reactions of a prototypical 2-azafluorenone have been explored for functionality augmentation in its core structure. Overall, this operationally convenient 2-azafluorenone synthesis involves the formation of five new bonds (3 C-N and 2 C-C) in one pot and embodies many green and sustainable features; notably, the reagent ammonia is subsumed into the reactant o-bis-ynones with atom economy, and the only by-product is water.

Recursive Anion-Triggered Tandem Reactions of ortho-Bis-ynones: Tunable Synthesis of 1-Indenones and Cyclopenta[a]inden-8(2H)-ones.

Recursive anion-mediated activation of o-bis-ynones sets off a Michael addition-aldol reaction-dehydrative rearrangement cascade, leading to the one-pot synthesis of 1-indenones via orthogonal interplay between the two ortho-ynone moieties. Repeating the recursive anion engagement with the 1-indenones unfolded access to a functionally embellished cyclopenta[a]inden-8(2H)-one core and its spiroannulated analogues either directly or stepwise through tandem 1,6-Michael-type addition-6π electrocyclization and an in situ oxidation sequence.

Tandem Michael-anti-Michael Addition-Mediated Orthogonal Strapping of Diynones: Regioselective Spirocyclopentannulation of Oxindoles and Pyrazolones and DFT Validation.

An efficient protocol involving the transformation of sequentially generated recursive anions from heterocyclic precursors to orthogonally strap diynones through one pot transition-metal-free spirocyclopentannulation has been devised, employing oxindoles and pyrazolones as prototypical platforms. Insights into these regioselective tandem Michael-anti-Michael processes have been gleaned through DFT calculations.

Stitching Ynones with Nitromethanes: Domino Synthesis of Functionally Enriched Benzofurans and Benzothiophenes.

A convenient one-pot benzannulation of regioisomeric 2- or 3-substituted furan and thiophene ynones with a range of nitromethanes has been discovered to directly access densely and diversely functionalized benzofurans and benzothiophenes. In this protocol, the nitro group in nitromethanes functions as recursive carbanion activator to setup tandem Michael addition-6π-electrocyclization, and its eventual sacrificial elimination facilitates aromatization and overall benzannulation. This benzannulation was also explored with furan/thiophene based o-halo ynones wherein a Michael addition-SNAr process operates and nitromethanes leave their imprint to deliver nitro substituted benzo-furans and -thiophenes.

Re-imagining Priorities for Chemistry: A Central Science for "Freedom from Fear and Want".

Human security, defined as "freedom from want and fear and freedom to live in dignity", provides an overarching concept to address threats to human security dimensions such as health, food, economics, the environment and sustainable development, while placing the individual at the centre of attention. Chemistry is central to addressing these challenges, but surprisingly its role and contributions to human security have hitherto not been explicitly set out. This article situates chemistry in the human security framework, highlighting areas where chemistry knowledge, methods and products are vital. It underscores three complementary facets: 1) chemistry contributes to many dimensions of human security, but needs to do much more in the light of oncoming global challenges; 2) the human security framing illuminates areas where chemistry itself needs to adapt to contribute better, by intensification of current approaches and/or by building or strengthening chemistry tools, skills and competencies; and 3) repositioning as central to human security affords chemistry a powerful opportunity to refresh itself as a science for the benefit of society-and it will need to engage more directly and dynamically at the interface of science, society and policy in order to do so.

Conceptualization and Synthesis of the First Inosito-Inositol (Decahydroxydecalin, DHD): In†silico Binding to ß-Amyloid Protein.

Previously unknown entities in the form of 1,2,3,4,5,6,7,8,9,10-decahydroxydecalins (DHDs) have been conceptualized and the first member of this class, an inosito-inositol, has been synthesized from aromatic hydrocarbon naphthalene following a flexible strategy that is amenable to diversity creation. The DHD accessed here has been subjected to preliminary in silico evaluation with Aß and may hold some promise in Alzheimer's disease therapeutics.

Orthogonal Strapping of o-Haloaryl Ynones with Pyrazolones: A One-Pot, Domino Process toward Spiropyrazolones.

A new class of spiroannulated pyrazolone scaffolds have been assembled from diverse o-haloaryl ynones and ß-bromoalkenyl ynones via base mediated, one-pot, metal free, orthogonal strapping (tethering) mediated by the recursive anion(s) derived from pyrazolones. These convenient, preparatively useful transformations proceed through either a tandem Michael addition-intramolecular SNAr reaction or a tandem Michael addition-intramolecular AdNE process to furnish a range of pharmacophoric, diverse, spiroannulated pyrazolones from readily accessible precursors.

Macrocyclization via C-H functionalization: a new paradigm in macrocycle synthesis.

The growing emphasis on macrocycles in engaging difficult therapeutic targets such as protein-protein interactions and GPCRs via preferential adaptation of bioactive and cell penetrating conformations has provided impetus to the search for de novo macrocyclization strategies that are efficient, chemically robust and amenable to diversity creation. An emerging macrocyclization paradigm based on the C-H activation logic, of particular promise in the macrocyclization of complex peptides, has added a new dimension to this pursuit, enabling efficacious access to macrocycles of various sizes and topologies with high atom and step economy. Significant achievements in macrocyclization methodologies and their applications in the synthesis of bioactive natural products and drug-like molecules, employing strategic variations of C-H activation are captured in this review. It is expected that this timely account will foster interest in newer ways of macrocycle construction among practitioners of organic synthesis and chemical biology to advance the field.

Blocking the Hype-Hypocrisy-Falsification-Fakery Pathway is Needed to Safeguard Science.

In chemistry and other sciences, hype has become commonplace, compounded by the hypocrisy of those who tolerate or encourage it while disapproving of the consequences. This reduces the credibility and trust upon which all science depends for support. Hype and hypocrisy are but first steps down a slippery slope towards falsification of results and dissemination of fake science. Systemic drivers in the contemporary structure of the science establishment encourage exaggeration and may lure the individual into further steps along the hype-hypocrisy-falsification-fakery continuum. Collective, concerted intervention is required to effectively discourage entry to this dangerous pathway and to restore and protect the probity and reputation of the science system. Chemists must play and active role in this effort.

Living Messages from Chemistry Icons: Legacies with Contemporary Relevance.

Beyond individual scientific virtuosity and creativity that leading figures in chemistry have displayed, they have sometimes conveyed wider messages of significance beyond their own professional specialization. They include insights into broader aspects of science, society or the ways of the world. On the other hand, the words, attitudes and actions of eminent chemists from former times have not always presented good models for others to follow, whether judged by their own contemporary or our present standards. Both positive and negative lessons may convey to us something about humanity in general or the nature of our current predicaments and challenges. In an era when science is more necessary than ever to help meet oncoming global challenges, yet the principles and results of science are irrationally questioned, it is particularly relevant to re-connect with the broad insights and messages that can be derived from examining the thoughts and deeds of chemistry icons from the past.

Synthesis of Quinolines and Isoquinolines via Site-Selective, Domino Benzannulation of 2- and 3-Chloropyridyl Ynones with Nitromethane.

An approach of general applicability to diverse quinolines and isoquinolines via a tactic that utilizes the recursive anion from nitromethane as a 1C-connector to stitch easily and appropriately crafted pyridyl ynones through a transition-metal-free, tandem Michael addition-SNAr process is delineated. The straightforwardness, one-pot operation, and good yields mark this methodology for wider exploitation in targeting more embellished quinolines and isoquinolines and complex platforms embodying these moieties.

The Need for Cultural Competence in Science: A Practical Approach to Enhancing Equality, Diversity, and Inclusion.

"The entire field of science needs to enhance its performance with regard to equality, diversity, and inclusion …" Read more in the Editorial by S. A. Matlin, V. W. W. Yam et al.

Synthesis of the Polyoxygenated Cyclohexanoid Core of Bioactive Glycosides Xylosmin and Flacourtosides E and F.

A flexible synthesis of the carbocyclic core present in glycosides xylosmin and flacourtosides E and F, natural products exhibiting antimalarial and antiarboviral activities, has been accomplished. Our approach emanates from the Diels-Alder adduct of cyclopentadiene and MOM-protected 2-hydroxymethyl- p-benzoquinone and takes advantage of the stereochemical propensity of the norbornyl-fused scaffolds to generate the dense oxy-functionalization pattern with stereocontrol, enroute to a racemic synthesis of the carbocyclic core present in the aforementioned bioactive materials. This effort augurs well for exploring chemical diversity space around their scaffold.