Chemical synthesis articles within Nature Chemistry

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  • Article |

    Chiral sulfur pharmacophores are crucial in drug discovery, but the controlled synthesis of sulfinamides with stereogenic-at-sulfur(IV) centres is a long-standing challenge. Now a method for the catalytic asymmetric synthesis of sulfinamides and sulfinate esters has been developed that features the acyl transfer sulfinylation of diverse nucleophiles, including aromatic amines and alcohols, using chiral 4-arylpyridine N-oxides as catalysts.

    • Tao Wei
    • , Han-Le Wang
    •  & Hai-Ming Guo

  • Article |

    Fusicoccane diterpenoids are complex natural products with intricate tricyclic skeletons and intriguing biological activities. Now a chemoenzymatic strategy has been developed for modularly synthesizing a number of compounds from the family. This approach combines de novo skeletal construction and hybrid C–H oxidations, allowing the synthesis of ten different natural products.

    • Yanlong Jiang
    •  & Hans Renata

  • Article |

    A robust organometallic platform is developed for stoichiometric cross-couplings of common aryl and alkyl electrophiles under a single set of conditions. Inexpensive and persistent organonickel complexes are prepared by electrolysis and implemented in the diversification of drug-like molecules with high reliability from a diverse set of alkyl precursors.

    • Long P. Dinh
    • , Hunter F. Starbuck
    •  & Christo S. Sevov

  • Research Briefing |

    The precision synthesis of cyclic polymers with ultrahigh molar mass (UHMM) and circularity is challenging. Now, a method that involves superbase-mediated living linear-chain growth followed by macromolecular cyclization triggered by protic quenching enables the on-demand production of UHMM cyclic polymers with a narrow dispersity and closed-loop chemical recyclability.

  • Article |

    Phenols and their derivatives are ubiquitous in nature and important within the chemical industry. Their properties are linked to their substitution patterns, but meta-isomers are underrepresented due to the difficulty of their synthesis. Now we address this challenge by describing a 1,2-transposition of phenols that enables a formal para- to meta-isomerization.

    • Simon Edelmann
    •  & Jean-Philip Lumb

  • Article
    | Open Access

    Enantioconvergent reactions convert both enantiomers of a racemic starting material into a single enantioenriched product. All currently known enantioconvergent processes necessitate the loss or partial loss of the racemic substrate’s stereochemical information. Now, an alternative approach has been developed that proceeds with full retention of the racemic substrate’s configuration.

    • Steven H. Bennett
    • , Jacob S. Bestwick
    •  & Andrew L. Lawrence

  • Article
    | Open Access

    Radical polymerizations yield polymers that cannot easily be degraded. The co-polymerization of cyclobutene-based monomers with conventional vinyl monomers has now been shown to result in co-polymers with cyclobutane mechanophores in their backbone, which facilitate on-demand degradation through a combination of mechanical activation and hydrolysis. This approach offers a promising avenue for the degradation of all-carbon-bond-backbone polymers.

    • Peng Liu
    • , Sètuhn Jimaja
    •  & Nico Bruns

  • Article |

    Chiral 1,2-benzazaborines are promising isosteres of naphthalene, but rarely explored due to the lack of efficient synthetic methods. Now, the copper-catalysed enantioselective hydroboration of alkenes with 1,2-benzazaborines has been developed, providing a general platform for the atom-economic and efficient construction of diverse chiral 1,2-benzazaborine compounds bearing a 2-carbon-stereogenic centre or allene skeleton.

    • Wanlan Su
    • , Jide Zhu
    •  & Qiuling Song

  • Article
    | Open Access

    Despite the widespread utility of ruthenium catalysts, many protocols for their use require high temperatures or light irradiation. Now, the synthesis of an air- and moisture-stable ruthenium precatalyst has been reported. This versatile catalyst drives an array of transformations and enables rapid screening and optimization of reactions, revealing previously unknown in situ generated ruthenium complexes.

    • Gillian McArthur
    • , Jamie H. Docherty
    •  & Igor Larrosa

  • Article
    | Open Access

    α-Amino acids possessing β-stereocentres are difficult to synthesize. Now, an iridium-catalysed protocol allows the direct upconversion of simple alkenes and glycine derivatives to give β-substituted α-amino acids with exceptional levels of regio- and stereocontrol. The reaction design is based on exploiting the native directing ability of a glycine-derived N–H unit to facilitate enolization of the adjacent carbonyl.

    • Fenglin Hong
    • , Timothy P. Aldhous
    •  & John F. Bower

  • News & Views |

    Chiral amines possessing a stereogenic carbon atom bearing three carbon substituents and one nitrogen substituent are challenging structural motifs to prepare enantioselectively. Now, such motifs have been accessed in high enantiopurities by asymmetric Cu-catalysed propargylic amination using sterically confined ligands.

    • Joshua D. Sieber

  • Article |

    Enantioenriched α-disubstituted α-ethynylamines are valuable synthons to chiral α-tertiary amines and azacycles, but their facile access remains challenging. Now, sterically confined pyridinebisoxazoline ligands have been developed to facilitate highly enantioselective Cu(I)-catalysed propargylic amination of both aliphatic and aryl ketone-derived propargylic carbonates to give α-tertiary ethynylamines. Related tandem sequences are reported to synthesize quaternary azacycles.

    • Zheng Zhang
    • , Ying Sun
    •  & Jian Zhou

  • Article
    | Open Access

    The insertion of metal atoms and heteroaromatic units provides a way to tune the optical, electronic and magnetic properties of graphene nanoribbons. Now the synthesis of a porphyrin-fused graphene nanoribbon with a narrow bandgap and high charge mobility has been achieved, and this material used to fabricate field-effect and single-electron transistors.

    • Qiang Chen
    • , Alessandro Lodi
    •  & Harry L. Anderson

  • Article |

    The rapid generation of molecular complexity from a given molecular scaffold is crucial to drug discovery and development. Now the chemodivergent molecular editing of indoles using fluoroalkyl carbenes has been developed to modularly access four different types of fluorine-containing N-heterocyclic compound with high molecular complexity.

    • Shaopeng Liu
    • , Yong Yang
    •  & Xihe Bi

  • Perspective |

    Although generally perceived as an old-fashioned and unselective tool to build molecules, the photochemistry community is now re-discovering the power of UV light and is using key mechanistic information to develop new catalytic processes driven by visible light. This Perspective discusses the progress and impact of UV light in organic synthesis.

    • Giulio Goti
    • , Kavyasree Manal
    •  & Luca Dell’Amico

  • Article |

    Developing a generalizable method for blocking and rescuing tryptophan (Trp) interactions would enable the gain-of-function manipulation of various Trp-containing proteins but has so far been challenging. Now a genetically encoded N1-vinyl-caged Trp capable of rapid and bioorthogonal decaging enables site-specific activation of Trp on a protein of interest within living cells.

    • Yuchao Zhu
    • , Wenlong Ding
    •  & Peng R. Chen

  • Article |

    The preparation of 14C-labelled compounds is a crucial step in pharmaceutical development but typically requires using toxic, radioactive gases. Now a broadly applicable functional group metathesis reaction has been developed that forms 14C-labelled carboxylic acids in one pot, without added gases, via dynamic exchange with an easily handled carboxylic acid 14C source.

    • R. Garrison Kinney
    • , José Zgheib
    •  & Bruce A. Arndtsen

  • Research Briefing |

    Covalent protein conjugation facilitates the study of biological processes and the synthesis of therapeutic biomacromolecules. A method that uses vinyl thianthrenium reagents for the site-selective formation of highly reactive episulfonium species on proteins is demonstrated. These in situ-formed intermediates react with diverse nucleophiles, providing access to protein conjugates in one step without purification.

  • News & Views |

    Molecules containing a chiral S(VI) moiety have found extensive applications in drug design and organic synthesis, despite a lack of diverse asymmetric methods for their creation. Now, a ligand-mediated process has enabled the production of enantioenriched S(VI)–F motifs, providing a foundation for further stereospecific elaborations.

    • Patrick R. Melvin

  • Article |

    The mechanism for the oxidative addition of aryl halides to nickel(0)–phosphine complexes was proposed over four decades ago. Now, this elementary reaction, which occurs during common cross-coupling reactions, has been re-examined. Both one- and two-electron pathways occur, and their relative contribution depends on the electronic properties of the reaction partners.

    • Christina N. Pierson
    •  & John F. Hartwig

  • Article |

    Chirality is an intrinsic property in unsymmetric three-dimensional molecular assembly, contributing to the utility of the corresponding process and the resulting scaffolds. Now, on the sulfur(VI) hub, a three-step sequential ligand-exchange method has been established with precise stereocontrol, enabling the enantioselective synthesis of optically active S(VI) functional molecules.

    • Zhiyuan Peng
    • , Shoujun Sun
    •  & Bing Gao

  • Article
    | Open Access

    Achieving selectivity control in allylic arylations is a long-standing challenge in catalysis. Now a rhodium-catalysed system demonstrates chemo-, regio- and enantioselectivity, enabling Suzuki–Miyaura-type arylation with racemic, non-symmetrical, acyclic allylic systems; chelation is speculated to facilitate oxidative addition and enable both enantiomers of the starting material to converge onto a single product.

    • Violeta Stojalnikova
    • , Stephen J. Webster
    •  & Stephen P. Fletcher

  • Article
    | Open Access

    Complexes of iron in high oxidation states play a pivotal role as active intermediates in numerous catalytic processes. Now, using a multimethod approach on a single molecular system, it has been shown that a stable high-valent Fe(VI) nitride can be converted to a reactive, superoxidized, heptavalent Fe(VII) nitride.

    • Martin Keilwerth
    • , Weiqing Mao
    •  & Karsten Meyer

  • Article |

    While saturated N-heterocycles are widespread motifs in drug discovery, the seven-membered ring azepane is highly underrepresented. Now nitroarenes have been validated as competent substrates for azepane synthesis through conversion into singlet nitrenes for ring enlargement via N insertion and hydrogenolysis. This enables a highly versatile access towards polysubstituted azepanes in just two steps.

    • Rory Mykura
    • , Raquel Sánchez-Bento
    •  & Daniele Leonori

  • News & Views |

    Directional interactions and three-dimensional functional groups are crucial to medicinal compounds. Consequently, new functional groups require stereocontrolled synthetic methods. Now, an enantiopure building block provides controlled and divergent access to valuable sulfonimidoyl functional groups.

    • James A. Bull

  • Article |

    The stereochemical control and bifunctional manipulation of chiral sulfur functional groups is a long-standing challenge. Now, an enantiopure bench-stable S(VI) fluoride exchange reagent enables the asymmetric synthesis of sulfoximines, sulfonimidamides and sulfonimidoyl fluorides. The bifunctional nature of this reagent provides a practical method for the introduction of S(VI) functionality.

    • Shun Teng
    • , Zachary P. Shultz
    •  & Justin M. Lopchuk

  • Article
    | Open Access

    Skeletal editing enables diversification of compounds not possible by applying peripheral editing strategies. Now, a catalyst-free atom-pair swap strategy for pyridine editing has been developed via one-pot sequential dearomatization, cycloaddition and rearomative retrocyclization. Benzenes and naphthalenes with precisely installed functional groups are produced, and the mild conditions enable late-stage skeletal diversification of pyridine cores.

    • Qiang Cheng
    • , Debkanta Bhattacharya
    •  & Armido Studer

  • Article |

    The lack of effective methods for mirror-image (d-) protein sequencing hampers the development of mirror-image biology systems and related applications. Now, total chemical synthesis of mirror-image trypsin enables the sequencing of long d-peptides and d-proteins, which may facilitate applications of d-peptides and d-proteins as potential therapeutic and informational tools.

    • Guanwei Zhang
    •  & Ting F. Zhu

  • Article
    | Open Access

    Single-electron-mediated difunctionalizations of internal olefins allow the simultaneous formation of two contiguous Csp3-stereocentres. Here, we describe enantioenriched arylsulfinylamides as all-in-one reagents for the efficient asymmetric, intermolecular aminoarylation of alkenes. Mechanistic studies revealed an interesting dichotomy in the initiation of the reaction depending on the olefin redox potential.

    • Cédric Hervieu
    • , Mariia S. Kirillova
    •  & Cristina Nevado

  • Article |

    Single-step addition of an aryl ring and a protected amine across an alkene is a succinct route to valuable phenethylamine products, but existing methods suffer from limited scope. Now a family of compounds containing a sulfinamide functional group have been developed to react via electrophilic radicals to yield phenethylamines through an aryl migration with precise stereochemical control.

    • Efrey A. Noten
    • , Cody H. Ng
    •  & Corey R. J. Stephenson

  • Article |

    The synthesis, structure and reactivity of room-temperature-stable [Cp(C6F5)5]+[Sb3F16]− is presented. Coordination of the cyclopentadienyl cation by [Sb3F16]− or C6F6 stabilizes the antiaromatic singlet state in the solid state. Calculated hydride and fluoride ion affinities of the [Cp(C6F5)5]+ cation are higher than those of the tritylium cation [C(C6F5)3]+.

    • Yannick Schulte
    • , Christoph Wölper
    •  & Stephan Schulz

  • News & Views |

    Tetracoordinate boron molecules are the key intermediates in many organoboron-related chemical transformations. Now, using alkynyl tetracoordinate boron species, a nickel-catalysed asymmetric 1,3-metallate shift towards axial chirality has been developed, giving access to various axially chiral alkenes in high efficiency.

    • Li-Qing Ren
    •  & Chuan He

  • Article |

    Enantioselective transformations based on tetracoordinate borons are elusive. Now, an enantioselective nickel-catalysed strategy for the construction of axially chiral alkenes has been reported, via a 1,3-metallate shift of alkynyl tetracoordinate boron species. The reaction uses readily accessible starting materials and a cheap transition-metal catalyst, and the chemoselectivity, regioselectivity and atroposelectivity could be well controlled.

    • Xingxing Ma
    • , Mengwei Tan
    •  & Qiuling Song

  • Article |

    Robust protocols for the synthesis of chiral α-tertiary amino acids remain scarce due to the challenge of constructing congested tetrasubstituted stereocentres. Now a cobalt-catalysed enantioselective aza-Barbier reaction of ketimines with various unactivated alkyl halides has been developed, forming diverse chiral α-tertiary amino esters with high enantioselectivity and excellent functional group tolerance.

    • Xianqing Wu
    • , Hanyu Xia
    •  & Yifeng Chen

  • Article |

    The umpolung functionalization of imines bears vast synthetic potential, but polarity inversion is less efficient compared with the carbonyl counterparts. Now, an alternative strategy exploiting chiral phosphoric acid catalytic aromatization has been developed, affording structures possessing a central chirality or a stereogenic C–N axis with high efficiency and enantiocontrol.

    • Ye-Hui Chen
    • , Meng Duan
    •  & Bin Tan

  • Article |

    Methods for transition-metal-catalysed enantioselective C(sp3)–S bond construction are underdeveloped. Now, by taking advantage of the biomimetic radical homolytic substitution manifold, the copper-catalysed enantioconvergent C(sp3)–S cross-coupling of racemic secondary and tertiary alkyl halides with highly transformable sulfur nucleophiles has been realized. This reaction provides access to an array of α-chiral alkyl organosulfur compounds.

    • Yu Tian
    • , Xi-Tao Li
    •  & Xin-Yuan Liu

  • News & Views |

    Fluoroalkyl fragments are ubiquitous motifs in pharmaceuticals and agrochemicals, but their introduction to a given molecule typically involves expensive or difficult-to-handle reagents. Now, the photocatalysed hydrofluoroalkylation of alkenes has been achieved using simple and readily available fluoroalkyl carboxylic acids.

    • Fabio Juliá

  • News & Views |

    Stereoselective decarboxylative protonation can produce diverse chiral molecules from widely available carboxylic acids. However, general and practical strategies are lacking. Now, a chiral spirocyclic phosphoric acid-catalysed decarboxylation of aminomalonic acids has enabled the modular synthesis of α-amino acids.

    • Xufeng Lin
    •  & Alemayehu Gashaw Woldegiorgis

  • Article
    | Open Access

    Late-stage functionalization of complex drug molecules is challenging. To address this problem, a discovery platform based on geometric deep learning and high-throughput experimentation was developed. The computational model predicts binary reaction outcome, reaction yield and regioselectivity with low error margins, enabling the functionalization of complex molecules without de novo synthesis.

    • David F. Nippa
    • , Kenneth Atz
    •  & Gisbert Schneider

  • Article |

    Asymmetric decarboxylation can transform abundant carboxylic acids into valuable chiral molecules but faces major limitations due to the challenging enantiocontrol of proton transfer. Now the use of Brønsted acid catalysis in conjunction with an anchoring group strategy has enabled the decarboxylative protonation of aminomalonic acids to access diverse amino acids.

    • Wei-Feng Zheng
    • , Jingdan Chen
    •  & Zhongxing Huang

  • Article |

    Alkene hydrofluoroalkylation offers a promising route to diverse fluoroalkylated compounds but current methods have limitations, such as needing expensive fluoroalkylating reagents. Now, leveraging iron photocatalysis and hydrogen-atom-transfer catalysis, a hydrofluoroalkylation method has been developed that utilizes feedstock chemicals such as trifluoroacetic acid as direct fluoroalkyl radical precursors, providing a redox-neutral, general protocol to introduce fluoroalkyl moieties.

    • Kang-Jie Bian
    • , Yen-Chu Lu
    •  & Julian G. West

  • News & Views |

    Fluorination strategies are important in assisting the synthesis of pharmaceuticals. Iodine(I/III) catalysis has become particularly useful for installing gem-difluoro groups but is limited to styrenes. Now, the hypervalent iodane-catalysed difluorination of enynes has enabled access to diverse homopropargylic difluorides.

    • Rachel C. Epplin
    •  & Tanja Gulder

  • Article |

    The bicyclo[1.1.1]pentane (BCP) motif has drawn increasing attention recently in drug discovery. Now, a programmable bis-functionalization strategy has been developed to modularly access bridge-substituted BCP scaffolds, based on the inherent chemoselectivity of BCP bis-boronates (3° > 2°). This strategy should enable further structure–activity relationship studies of BCP-containing drug candidates and open the door to unexplored chemical space.

    • Yangyang Yang
    • , Jet Tsien
    •  & Tian Qin

  • Article
    | Open Access

    Hypervalent iodine catalysis remains a powerful method to enable geminal difluoromethylenation of alkenes. However, the scope is mainly limited to styrene derivatives. Now, enynes have been validated as competent substrates where a formal 1,2-shift of the alkyne occurs, thereby enabling highly versatile homopropargylic difluorides to be generated.

    • Zi-Xuan Wang
    • , Keith Livingstone
    •  & Ryan Gilmour

  • Article |

    The reversible N–H activation and catalytic transformations of ammonia are a challenge. Now, a hidden frustrated Lewis pair is shown to activate non-aqueous ammonia thermoneutrally and split the N–H bond reversibly at ambient temperature. The N–H-activated ammonia was also utilized as an atom-economical nitrogen source for catalytic NH3 transfer reactions.

    • Felix Krämer
    • , Jan Paradies
    •  & Frank Breher

  • News & Views |

    Deuterated compounds are used in many applications such as mass-spectrometry standards, drugs or in organic light-emitting diodes. Now, hydrogen-activated homogeneous pincer complex catalysts can be used to perform selective alkene deuteration with the cheapest available deuterium source, D2O.

    • Anika Tarasewicz
    •  & Volker Derdau

  • News & Views |

    Aryl ethers are useful intermediates in organic synthesis and are found in countless biologically active compounds. Now, through palladium/norbornene cooperative catalysis and incorporation of a polarity-reversed N–O reagent as the O-electrophile, an efficient arene methoxylation approach has been successfully developed.

    • Kun Zhao
    •  & Zhenhua Gu

  • Article |

    Merging carbonyls to form an alkene by removing their oxygens is rare, yet synthetically useful, and the selective combination of two different carbonyls is especially challenging. Now, two strategies for cross-metathesis of unbiased carbonyls have been developed. An Fe-catalysed carbene/ylide strategy affords Z-alkenes, while Cr-catalysed gem-di-metals yield E-alkenes.

    • Lumin Zhang
    •  & David A. Nagib

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