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.

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.

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.

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.

C-H modification of natural products: a minimalist enabling tactic for drug discovery, API processing and bioconjugation.

Intrusion into the C-H chemical space of natural products through the strategic deployment of C-H functionalization reactions could lead to incredibly new molecular diversities with an unforeseen impact on biological functions. Based on this hypothesis, semisynthetic C-H modification of natural products is emerging as a minimalist tactic in natural product based drug discovery. Several examples of C-H modification of natural products, resulting in functional gains in key pharmacological attributes viz. potency, aqueous solubility and DMPK profile, along with opportunities in allied areas such as API processing, bioconjugation, and target deconvolution, continue to surface in the recent literature. The strategy has already recorded commercial success in the development of antineoplastic drugs topotecan and irinotecan and in industrial production of pravastatin, calcitriol and artemisinin. This Feature Article highlights the broad contours of this evolving paradigm at the interface of natural product and synthetic chemistry research to accelerate and widen the scope of natural product-based drug discovery.

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.

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.

Chemistry must respond to the crisis of transgression of planetary boundaries.

Recent assessments alarmingly indicate that many of the world's leading chemicals are transgressing one or more of the nine planetary boundaries, which define safe operating spaces within which humanity can continue to develop and thrive for generations to come. The unfolding crisis cannot be ignored and there is a once-in-a-century opportunity for chemistry - the science of transformation of matter - to make a critical difference to the future of people and planet. How can chemists contribute to meeting these challenges and restore stability and strengthen resilience to the planetary system that humanity needs for its survival? To respond to the wake-up call, three crucial steps are outlined: (1) urgently working to understand the nature of the looming threats, from a chemistry perspective; (2) harnessing the ingenuity and innovation that are central to the practice of chemistry to develop sustainable solutions; and (3) transforming chemistry itself, in education, research and industry, to re-position it as 'chemistry for sustainability' and lead the stewardship of the world's chemical resources. This will require conservation of material stocks in forms that remain available for use, through attention to circularity, as well as strengthening engagement in systems-based approaches to designing chemistry research and processes informed by convergent working with many other disciplines.

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.

A shared future: chemistry's engagement is essential for resilience of people and planet.

Strengthening resilience-elasticity or adaptive capacity-is essential in responding to the wide range of natural hazards and anthropogenic changes humanity faces. Chemistry's roles in resilience are explored for the first time, with its technical capacities set in the wider contexts of cross-disciplinary working and the intersecting worlds of science, society and policy. The roles are framed by chemistry's contributions to the sustainability of people and planet, examined via the human security framework's four material aspects of food, health, economic and environmental security. As the science of transformation of matter, chemistry is deeply involved in these material aspects and in their interfacing with human security's three societal and governance aspects of personal, community and political security. Ultimately, strengthening resilience requires making choices about the present use of resources as a hedge against future hazards and adverse events, with these choices being co-determined by technical capacities and social and political will. It is argued that, to intensify its contributions to resilience, chemistry needs to take action along at least three major lines: (i) taking an integrative approach to the field of 'chemistry and resilience'; (ii) rethinking how the chemical industry operates; and (iii) engaging more with society and policy-makers.

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.

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.

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.

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.

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.

Realigning science, society and policy in uncertain times.

Against a backdrop of rapidly changing social, economic and geopolitical settings and ideologies, the world is facing a wide range of challenges, including in biodiversity, climate, energy, the environment, food, health and water. These can only be addressed by fully harnessing key capacities that science offers. However, there is a crisis of trust in science which affects some sections of society and some policy-makers, impairing the capacity of science to deliver its essential roles. This damaged relationship between science, society and policy has immense health, economic and social consequences and implications for sustainability of the entire planet. Scientists must strive collectively to re-establish trust by society and politicians where it is damaged, and reinforce conviction of science's central importance in underpinning policy. Science's roles must in turn be acknowledged by policies that sustain innovation and freedom to work without political interference or constraints. A well-functioning and trusting relationship between science, society and policy-makers offers a potent means to thwart and mitigate emergent global challenges.

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.

Access to 2-Alkyl/Aryl-4-(1H)-Quinolones via Orthogonal "NH3" Insertion into o-Haloaryl Ynones: Total Synthesis of Bioactive Pseudanes, Graveoline, Graveolinine, and Waltherione F.

An efficient one-pot synthesis of 4-(1H)-quinolones through an orthogonal engagement of diverse o-haloaryl ynones with ammonia in the presence of Cu(I), involving tandem Michael addition and ArCsp2-N coupling, is presented. The substrate scope of this convenient protocol, wherein ammonium carbonate acts as both an in situ ammonia source and a base toward diverse 2-substituted 4-(1H)-quinolones, has been mapped and its efficacy validated through concise total synthesis of bioactive natural products pseudanes (IV, VII, VIII, and XII), graveoline, graveolinine, and waltherione F.