Saturated N-heterocycle rings are common structural motifs of many FDA-approved drugs. Here, the authors show that a metal-free amphoteric diamination of allenes produces valuable six-, seven- and eight-membered N-heterocycles with high diversity and tolerance of functional groups on the ring.
Synthetic and Medicinal Chemistry
The early days of drug discovery and development were lonely: scientists in the 19th century made discoveries often driven by serendipity. Although fortuitous findings continue to happen, we currently rely on the synergistic collaboration across the organic and medicinal chemistry areas for accelerating the rational identification and design of lead compounds.
This collection showcases some of the most recent advances in the multidisciplinary field of discovery and development of bioactive compounds published in Nature Communications. The Medicinal Chemistry tab highlights additions to the med. chem. toolbox. Under Catalysis for Bioactive Compounds we acknowledge advances in homogeneous catalysis that open the door to obtaining bioactive compounds in higher quantity, quality and/or purity. Tying in with that, the Total Synthesis section contains reports on the complete chemical synthesis of natural products, still one of the best sources of drugs and drug leads. Last but not least, the Drug Biosynthesis section showcases some of the most recent discoveries of how Nature synthesizes bioactive compounds and how biocatalytic machinery can be exploited for chemical synthesis.
This collection will be regularly updated with studies published in Nature Communications that advance the field of medicinal and synthetic chemistry.
Diastereo- and enantioselective [3 + 3] cycloaddition of spirocyclopropyl oxindoles using both aldonitrones and ketonitrones
Chiral spirocyclic compounds are important structural motifs for drug discovery. Here, the authors report a synthetic route to spirocycles based on enantioselective cycloaddition of activated spirocyclopropyl oxindoles, which act as donor-acceptor cyclopropanes.
Scalable synthesis enabling multilevel bio-evaluations of natural products for discovery of lead compounds
Isodon diterpenoids, promising anti-cancer agents found in certain tropical plants, are difficult to obtain. Here, the authors developed a synthetic strategy to synthesise several different members of this group, including neolaxiflorin L which emerged from this study as a promising drug candidate.
Facile access to potent antiviral quinazoline heterocycles with fluorescence properties via merging metal-free domino reactions
Heterocycles are ubiquitous in bioactive compounds and routes to different substitution patterns are important to access the full substrate space. Here the authors report a route to 4,5,7,8-substituted antiviral fluorescent quinazolines, to allow cellular uptake visualization without external marker.
Late-stage diversification of natural products is an important starting point for drug discovery. Here, the authors use chiral reagents to perform the regiocontrolled ring expansion of steroid precursors and achieve more than 100 isomerically pure analogs with spatial and functional diversity.
Heteroatom-rich organoboron compounds are promising modulators of enzyme activity. Here, the authors report a library of aminocyanoboronates as serine hydrolases inhibitors with the most potent compound showing in vivo and in vitro nanomolar activity and high selectivity towards human ABHD3 hydrolase.
Spiro compounds contain two or more rings linked together through one common atom. Here the authors provide a method to backfold both rings, producing spiro quasicatenanes, via a strategy of temporarily linking the linear intermediates with covalent bonds.
Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis
Drug resistant tuberculosis (TB) infections are emerging at a high rate, with only few therapeutic options currently available. Here, the authors report synthetic analogues of the natural product sansanmycin that target mycobacterial cell wall biosynthesis and represent potent leads for improved anti-TB treatments.
Flow-based peptide synthesis is a well-established method, yet difficult to combine with native chemical ligation (NCL), the go-to method for peptide cyclization. Here, the authors developed a microfluidic procedure for peptide cyclization within minutes, using NCL and an SEA alkylthioester peptide.
Catalysis for Bioactive Compounds
Axially chiral arylquinazolinones are structural motifs in several natural products and can also act as chiral ligands. Here, the authors show a chiral phosphoric acid-catalysed strategy to access enantiomerically pure arylquinazolinones by efficient transfer of central chirality into axial chirality.
Chiral pyridines are valuable building blocks in medicinal chemistry applications. Here, the authors report the copper-catalysed Lewis acid-assisted asymmetric alkylation of β-substituted alkenyl pyridines with Grignard reagents affording chiral pyridines with excellent enantioselectivity.
Electroreduction of CO2 to CO is a potential valorisation pathway of carbon dioxide for fine chemicals production. Here, the authors show a user-friendly device that couples CO2 electroreduction with carbonylation chemistry for up to gram scale synthesis of pharmaceuticals even under atmospheric CO2.
Catalytic asymmetric radical aminoperfluoroalkylation and aminodifluoromethylation of alkenes to versatile enantioenriched-fluoroalkyl amines
Methods for the asymmetric introduction of organofluorine groups are often limited by the lack of variability in the starting materials. Here the authors report an asymmetric radical process for the introduction of fluoroalkyl groups using readily available fluoroalkylated sulfonyl chlorides.
Biologically active compounds often contain a chiral centre in proximity of amine groups. Here, the authors developed a strategy involving asymmetric isomerization of allylic amines, enamine exchange and chemoselective reduction for the one-pot highly enantioselective synthesis of gamma-branched amines.
Transformations with ClCF2H are very limited and normally involve a difluorocarbene intermediate. Here, the authors report a nickel-catalyzed difluoromethylation of aryl chlorides with chlorodifluoromethane via a difluoromethyl radical intermediate and apply the method to the synthesis of marketed pharmaceuticals.
Selective para-functionalization of substituted arenes is a formidable challenge in homogeneous catalysis. Here, the authors achieved the para-selective C-H difluoromethylation of anilides, indolines and tetrahydroquinolines with a ruthenium catalyst in good yields and apply it to the synthesis of bioactive compounds.
Chemical transformation of amides is normally occurring under harsh conditions. Here, the authors report a mild iridium-catalyzed reductive Ugi-type coupling of tertiary amides, isocyanides and (thio)acetic acid or trimethylsilyl azide to give homologous, bioactive amine products.
Peptide-guided functionalization and macrocyclization of bioactive peptidosulfonamides by Pd(II)-catalyzed late-stage C–H activation
Aryl sulfonamides and sultams are important pharmacophores in medicinal chemistry. Here, the authors report a practical palladium-catalyzed C–H activation assisted by amino-acid residues in the substrate leading to arylsulfonamides and bioactive peptidosulfonamide macrocycles.
Avenaol is a potent germination stimulant that can be extracted from black oat. Here, the authors report the total synthesis of avenaol by developing a strategy to access all-cis-substituted cyclopropanes.
Arisandilactone A is a natural product with a complex oxa-bridged tricyclic carbon core, making it a challenging target in total synthesis. Here the authors report an asymmetric total synthesis of its 19-dehydroxy derivative, with homo-Michael and tandem retro-Michael/Michael reactions as key steps.
Due to the vast number of potential isomers, the chemical synthesis of large carbohydrates is challenging. Here the authors report the synthesis of mycobacterial arabinogalactan, a biologically important natural product composed of 92 monosaccharide units, the largest synthetic polysaccharide to date.
[Au]/[Ag]-catalysed expedient synthesis of branched heneicosafuranosyl arabinogalactan motif of Mycobacterium tuberculosis cell wall
Arabinogalactan forms parts of the cellular envelope ofMycobacterium tuberculosis, however due to its size chemical synthesis is a massive task. Here the authors report the synthesis of branched heneicosafuranosyl arabinogalactan fragment by repeated use of a Au/Ag-catalysed glycosylation methodology.
Albomycins are promising drug candidates for the treatment of bacterial infections. Here, the authors describe the total syntheses of albomycins δ1, δ2, and ε, and evaluate their antimicrobial activity, identifying albomycin δ2 as a strong agent against S. pneumoniae and S. aureus infections.
Scalable total synthesis and comprehensive structure–activity relationship studies of the phytotoxin coronatine
Development of comprehensive structure–activity relationships for coronatine has been a major goal in the agrochemical industry. Here, the authors report the gram-scale production and structure–activity relationship of parent coronafacic acid and ultimately rationalise the biological activity of analogues of this phytotoxin.
Gold-catalyzed stereoselective cycloisomerization of allenoic acids for two types of common natural γ-butyrolactones
Gamma-butyrolactones are widespread in Nature, however direct catalytic methods to access them are limited. Here, the authors report a gold-catalyzed cycloisomerization of allenoic acids to acces γ-butyrolactones and apply it to the asymmetric synthesis of xestospongienes E, F, G, and H and other naturally occurring lactones.
Cyrneine diterpenoids represent a biologically important subfamily of cyathane-type diterpenoids. Here, the authors show new key steps to access their 5-6-7-tricyclic core and establish a more step-economic synthesis of cyrneine A and the first synthesis of cyrneine B and glaucopine C in a divergent manner.
Stereodivergent synthesis of vicinal quaternary-quaternary stereocenters and bioactive hyperolactones
Stereodivergent construction of adjacent quaternary-quaternary stereocenters remains a formidable synthetic challenge. Here, the authors report a nickel-catalyzed enantioselective dearomatization Claisen rearrangement leading to vicinal all-carbon stereocentres and apply it to the stereodivergent synthesis of bioactive hyperolactones.
Biosynthesis of helvolic acid and identification of an unusual C-4-demethylation process distinct from sterol biosynthesis
The biosynthetic pathway of fusidane-type antibiotics, such as helvolic acid, is largely undiscovered. Here, the authors investigate the biosynthesis of helvolic acid, thereby determining the sequence of the enzymatic reactions involved in the process and the intermediates formed.
Heterologous expression reveals the biosynthesis of the antibiotic pleuromutilin and generates bioactive semi-synthetic derivatives
Pleuromutilin derivatives are potent antibacterial drugs obtained from Basidiomycete fungi. Here, the authors report the genetic characterisation of the steps involved in pleuromutilin biosynthesis through heterologous expression and generate a semi-synthetic pleuromutilin derivative with enhanced antibiotic activity.
Biosynthesis of ilamycins featuring unusual building blocks and engineered production of enhanced anti-tuberculosis agents
Tuberculosis (TB) remains one of the world’s deadliest communicable diseases, novel anti-TB agents are urgently needed due to severe drug resistance and the co-epidemic of TB/HIV. Here, the authors show that anti-mycobacterial ilamycin congeners bearing unusual structural units possess extremely potent anti-tuberculosis activities.
Warhead biosynthesis and the origin of structural diversity in hydroxamate metalloproteinase inhibitors
Metalloproteinase inhibitors are leads for drug development, but their biosynthetic pathways are often unknown. Here the authors show that the acyl branched warhead of actinonin and matlystatins derives from an ethylmalonyl-CoA-like pathway and the structural diversity of matlystatins is due to the activity of a decarboxylase-dehydrogenase enzyme.
The 3-thiazolidine ring, a pharmaceutically interesting cyclic structural element found e.g. in some antibiotics, is hard to obtain via currently used approaches. Here, the authors developed a straightforward method to efficiently synthesize a variety of defined, pure 3-thiazolidines.
Efficient molecular evolution to generate enantioselective enzymes using a dual-channel microfluidic droplet screening platform
Optimizing an enzyme usually requires testing thousands of variants, thus consuming large amounts of material and time. Here, the authors present a method that allows for measuring two different activities of the same enzyme simultaneously instead of doing two consecutive rounds of screening.
Characterization of a dual function macrocyclase enables design and use of efficient macrocyclization substrates
Cyclic peptide macrocycles are promising anti-cancer and antimicrobial molecules. Here, the authors characterize the structure and catalytic mechanism of the prolyl oligopeptidase B from Basidiomycete fungi, showing that its dual macrocyclase-peptidase activity is crucial for amatoxin macrocyclization.
Biomimetic catalytic transformation of toxic α-oxoaldehydes to high-value chiral α-hydroxythioesters using artificial glyoxalase I
Glyoxalase I converts toxic methylglyoxal to a thioester. Here the authors report a synthetic analogue capable of enantioselectively converting alpha-keto aldehydes to thioesters via formation of a hemithioacetal, giving access to both enantiomers of a range of alpha-hydroxy thioesters.
Biosynthetic pathway for furanosteroid demethoxyviridin and identification of an unusual pregnane side-chain cleavage
Demethoxyviridin is a fungal steroid that inhibits a phosphatidylinositol 3-kinase, an enzyme contributing to tumor progression. Here, the authors elucidate the biosynthetic route that leads to the formation of demethoxyviridin in fungi.