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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.

Medicinal Chemistry

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

Catalysis for Bioactive Compounds

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

Total Synthesis

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

Drug 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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications

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.

Article | Open Access | | Nature Communications