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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

  • Nature Communications | Article | open

    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.

    • Zhishi Ye
    • , Sarju Adhikari
    • , Yu Xia
    •  &  Mingji Dai
  • Nature Communications | Article | open

    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.

    • Peng-Wei Xu
    • , Jia-Kuan Liu
    • , Lan Shen
    • , Zhong-Yan Cao
    • , Xiao-Li Zhao
    • , Jun Yan
    •  &  Jian Zhou
  • Nature Communications | Article | open

    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.

    • Lizhi Zhu
    • , Wenjing Ma
    • , Mengxun Zhang
    • , Magnolia Muk-Lan Lee
    • , Wing-Yan Wong
    • , Brandon Dow Chan
    • , Qianqian Yang
    • , Wing-Tak Wong
    • , William Chi-Shing Tai
    •  &  Chi-Sing Lee
  • Nature Communications | Article | open

    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.

    • Felix E. Held
    • , Anton A. Guryev
    • , Tony Fröhlich
    • , Frank Hampel
    • , Axel Kahnt
    • , Corina Hutterer
    • , Mirjam Steingruber
    • , Hanife Bahsi
    • , Clemens von Bojničić-Kninski
    • , Daniela S. Mattes
    • , Tobias C. Foertsch
    • , Alexander Nesterov-Mueller
    • , Manfred Marschall
    •  &  Svetlana B. Tsogoeva
  • Nature Communications | Article | open

    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.

    • Manwika Charaschanya
    •  &  Jeffrey Aubé
  • Nature Communications | Article | open

    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.

    • Joanne Tan
    • , Armand B. Cognetta III
    • , Diego B. Diaz
    • , Kenneth M. Lum
    • , Shinya Adachi
    • , Soumajit Kundu
    • , Benjamin F. Cravatt
    •  &  Andrei K. Yudin

Catalysis for Bioactive Compounds

  • Nature Communications | Article | open

    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.

    • Yong-Bin Wang
    • , Sheng-Cai Zheng
    • , Yu-Mei Hu
    •  &  Bin Tan
  • Nature Communications | Article | open

    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.

    • Ravindra P. Jumde
    • , Francesco Lanza
    • , Tilde Pellegrini
    •  &  Syuzanna R. Harutyunyan
  • Nature Communications | Article | open

    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.

    • Mikkel T. Jensen
    • , Magnus H. Rønne
    • , Anne K. Ravn
    • , René W. Juhl
    • , Dennis U. Nielsen
    • , Xin-Ming Hu
    • , Steen U. Pedersen
    • , Kim Daasbjerg
    •  &  Troels Skrydstrup
  • Nature Communications | Article | open

    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.

    • Jin-Shun Lin
    • , Fu-Li Wang
    • , Xiao-Yang Dong
    • , Wei-Wei He
    • , Yue Yuan
    • , Su Chen
    •  &  Xin-Yuan Liu
  • Nature Communications | Article | open

    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.

    • Zhao Wu
    • , Summer D. Laffoon
    •  &  Kami L. Hull
  • Nature Communications | Article | open

    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.

    • Chang Xu
    • , Wen-Hao Guo
    • , Xu He
    • , Yin-Long Guo
    • , Xue-Ying Zhang
    •  &  Xingang Zhang

Total Synthesis

  • Nature Communications | Article | open

    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.

    • Motohiro Yasui
    • , Rina Ota
    • , Chihiro Tsukano
    •  &  Yoshiji Takemoto
  • Nature Communications | Article | open

    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.

    • Yi-Xin Han
    • , Yan-Long Jiang
    • , Yong Li
    • , Hai-Xin Yu
    • , Bing-Qi Tong
    • , Zhe Niu
    • , Shi-Jie Zhou
    • , Song Liu
    • , Yu Lan
    • , Jia-Hua Chen
    •  &  Zhen Yang
  • Nature Communications | Article | open

    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.

    • Yong Wu
    • , De-Cai Xiong
    • , Si-Cong Chen
    • , Yong-Shi Wang
    •  &  Xin-Shan Ye
  • Nature Communications | Article | open

    Arabinogalactan forms parts of the cellular envelope of Mycobacterium 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.

    • Shivaji A. Thadke
    • , Bijoyananda Mishra
    • , Maidul Islam
    • , Sandip Pasari
    • , Sujit Manmode
    • , Boddu Venkateswara Rao
    • , Mahesh Neralkar
    • , Ganesh P. Shinde
    • , Gulab Walke
    •  &  Srinivas Hotha
  • Nature Communications | Article | open

    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.

    • Zihua Lin
    • , Xiaobo Xu
    • , Sheng Zhao
    • , Xiaohong Yang
    • , Jian Guo
    • , Qun Zhang
    • , Chunmei Jing
    • , Shawn Chen
    •  &  Yun He
  • Nature Communications | Article | open

    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.

    • Mairi M. Littleson
    • , Christopher M. Baker
    • , Anne J. Dalençon
    • , Elizabeth C. Frye
    • , Craig Jamieson
    • , Alan R. Kennedy
    • , Kenneth B. Ling
    • , Matthew M. McLachlan
    • , Mark G. Montgomery
    • , Claire J. Russell
    •  &  Allan J. B. Watson

Drug Biosynthesis

  • Nature Communications | Article | open

    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.

    • Jian-Ming Lv
    • , Dan Hu
    • , Hao Gao
    • , Tetsuo Kushiro
    • , Takayoshi Awakawa
    • , Guo-Dong Chen
    • , Chuan-Xi Wang
    • , Ikuro Abe
    •  &  Xin-Sheng Yao
  • Nature Communications | Article | open

    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.

    • Fabrizio Alberti
    • , Khairunisa Khairudin
    • , Edith Rodriguez Venegas
    • , Jonathan A. Davies
    • , Patrick M. Hayes
    • , Christine L. Willis
    • , Andy M. Bailey
    •  &  Gary D. Foster
  • Nature Communications | Article | open

    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.

    • Junying Ma
    • , Hongbo Huang
    • , Yunchang Xie
    • , Zhiyong Liu
    • , Jin Zhao
    • , Chunyan Zhang
    • , Yanxi Jia
    • , Yun Zhang
    • , Hua Zhang
    • , Tianyu Zhang
    •  &  Jianhua Ju
  • Nature Communications | Article | open

    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.

    • Franziska Leipoldt
    • , Javier Santos-Aberturas
    • , Dennis P. Stegmann
    • , Felix Wolf
    • , Andreas Kulik
    • , Rodney Lacret
    • , Désirée Popadić
    • , Daniela Keinhörster
    • , Norbert Kirchner
    • , Paulina Bekiesch
    • , Harald Gross
    • , Andrew W. Truman
    •  &  Leonard Kaysser
  • Nature Communications | Article | open

    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.

    • Nadine Zumbrägel
    • , Christian Merten
    • , Stefan M. Huber
    •  &  Harald Gröger
  • Nature Communications | Article | open

    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.

    • Fuqiang Ma
    • , Meng Ting Chung
    • , Yuan Yao
    • , Robert Nidetz
    • , Lap Man Lee
    • , Allen P. Liu
    • , Yan Feng
    • , Katsuo Kurabayashi
    •  &  Guang-Yu Yang