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The incorporation of deuterium in organic molecules has widespread applications in medicinal chemistry and materials science 1,2 . For example, the deuterated drugs austedo 3 , donafenib 4 and sotyktu 5 have been recently approved. There are various methods for the synthesis of deuterated compounds with high deuterium incorporation 6 . However, the reductive deuteration of aromatic hydrocarbons-ubiquitous chemical feedstocks-to saturated cyclic compounds has rarely been achieved. Here we describe a scalable and general electrocatalytic method for the reductive deuteration and deuterodefluorination of (hetero)arenes using a prepared nitrogen-doped electrode and deuterium oxide (D 2 O), giving perdeuterated and saturated deuterocarbon products. This protocol has been successfully applied to the synthesis of 13 highly deuterated drug molecules. Mechanistic investigations suggest that the ruthenium-deuterium species, generated by electrolysis of D 2 O in the presence of a nitrogen-doped ruthenium electrode, are key intermediates that directly reduce aromatic compounds. This quick and cost-effective methodology for the preparation of highly deuterium-labelled saturated (hetero)cyclic compounds could be applied in drug development and metabolism studies., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

The selective cross-coupling of two alkyl electrophiles to construct complex molecules remains a challenge in organic synthesis 1,2 . Known reactions are optimized for specific electrophiles and are not amenable to interchangeably varying electrophilic substrates that are sourced from common alkyl building blocks, such as amines, carboxylic acids and halides 3-5 . These limitations restrict the types of alkyl substrate that can be modified and, ultimately, the chemical space that can be explored 6 . Here we report a general solution to these limitations that enables a combinatorial approach to alkyl-alkyl cross-coupling reactions. This methodology relies on the discovery of unusually persistent Ni(alkyl) complexes that can be formed directly by oxidative addition of alkyl halides, redox-active esters or pyridinium salts. The resulting alkyl complexes can be isolated or directly telescoped to couple with a second alkyl electrophile, which represent cross-selective reactions that were previously unknown. The utility of this synthetic capability is showcased in the rapid diversification of amino acids, natural products, pharmaceuticals and drug-like building blocks by various combinations of dehalogenative, decarboxylative or deaminative coupling. In addition to a robust scope, this work provides insights into the organometallic chemistry of synthetically relevant Ni(alkyl) complexes through crystallographic analysis, stereochemical probes and spectroscopic studies., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Asymmetric catalysis enables the synthesis of optically active compounds, often requiring the differentiation between two substituents on prochiral substrates 1 . Despite decades of development of mainly noble metal catalysts, achieving differentiation between substituents with similar steric and electronic properties remains a notable challenge 2,3 . Here we introduce a class of Earth-abundant manganese catalysts for the asymmetric hydrogenation of dialkyl ketimines to give a range of chiral amine products. These catalysts distinguish between pairs of minimally differentiated alkyl groups bound to the ketimine, such as methyl and ethyl, and even subtler distinctions, such as ethyl and n-propyl. The degree of enantioselectivity can be adjusted by modifying the components of the chiral manganese catalyst. This reaction demonstrates a wide substrate scope and achieves a turnover number of up to 107,800. Our mechanistic studies indicate that exceptional stereoselectivity arises from the modular assembly of confined chiral catalysts and cooperative non-covalent interactions between the catalyst and the substrate., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Heteroarenes are ubiquitous motifs in bioactive molecules, conferring favourable physical properties when compared to their arene counterparts 1-3 . In particular, semisaturated heteroarenes possess attractive solubility properties and a higher fraction of sp 3 carbons, which can improve binding affinity and specificity. However, these desirable structures remain rare owing to limitations in current synthetic methods 4-6 . Indeed, semisaturated heterocycles are laboriously prepared by means of non-modular fit-for-purpose syntheses, which decrease throughput, limit chemical diversity and preclude their inclusion in many hit-to-lead campaigns 7-10 . Herein, we describe a more intuitive and modular couple-close approach to build semisaturated ring systems from dual radical precursors. This platform merges metallaphotoredox C(sp 2 )-C(sp 3 ) cross-coupling with intramolecular Minisci-type radical cyclization to fuse abundant heteroaryl halides with simple bifunctional feedstocks, which serve as the diradical synthons, to rapidly assemble a variety of spirocyclic, bridged and substituted saturated ring types that would be extremely difficult to make by conventional methods. The broad availability of the requisite feedstock materials allows sampling of regions of underexplored chemical space. Reagent-controlled radical generation leads to a highly regioselective and stereospecific annulation that can be used for the late-stage functionalization of pharmaceutical scaffolds, replacing lengthy de novo syntheses., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

When searching for the ideal molecule to fill a particular functional role (for example, a medicine), the difference between success and failure can often come down to a single atom 1 . Replacing an aromatic carbon atom with a nitrogen atom would be enabling in the discovery of potential medicines 2 , but only indirect means exist to make such C-to-N transmutations, typically by parallel synthesis 3 . Here, we report a transformation that enables the direct conversion of a heteroaromatic carbon atom into a nitrogen atom, turning quinolines into quinazolines. Oxidative restructuring of the parent azaarene gives a ring-opened intermediate bearing electrophilic sites primed for ring reclosure and expulsion of a carbon-based leaving group. Such a 'sticky end' approach subverts existing atom insertion-deletion approaches and as a result avoids skeleton-rotation and substituent-perturbation pitfalls common in stepwise skeletal editing. We show a broad scope of quinolines and related azaarenes, all of which can be converted into the corresponding quinazolines by replacement of the C3 carbon with a nitrogen atom. Mechanistic experiments support the critical role of the activated intermediate and indicate a more general strategy for the development of C-to-N transmutation reactions., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Modern retrosynthetic analysis in organic chemistry is based on the principle of polar relationships between functional groups to guide the design of synthetic routes 1 . This method, termed polar retrosynthetic analysis, assigns partial positive (electrophilic) or negative (nucleophilic) charges to constituent functional groups in complex molecules followed by disconnecting bonds between opposing charges 2-4 . Although this approach forms the basis of undergraduate curriculum in organic chemistry 5 and strategic applications of most synthetic methods 6 , the implementation often requires a long list of ancillary considerations to mitigate chemoselectivity and oxidation state issues involving protecting groups and precise reaction choreography 3,4,7 . Here we report a radical-based Ni/Ag-electrocatalytic cross-coupling of substituted carboxylic acids, thereby enabling an intuitive and modular approach to accessing complex molecular architectures. This new method relies on a key silver additive that forms an active Ag nanoparticle-coated electrode surface 8,9 in situ along with carefully chosen ligands that modulate the reactivity of Ni. Through judicious choice of conditions and ligands, the cross-couplings can be rendered highly diastereoselective. To demonstrate the simplifying power of these reactions, concise syntheses of 14 natural products and two medicinally relevant molecules were completed., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Research in the field of asymmetric catalysis over the past half century has resulted in landmark advances, enabling the efficient synthesis of chiral building blocks, pharmaceuticals and natural products 1-3 . A small number of asymmetric catalytic reactions have been identified that display high selectivity across a broad scope of substrates; not coincidentally, these are the reactions that have the greatest impact on how enantioenriched compounds are synthesized 4-8 . We postulate that substrate generality in asymmetric catalysis is rare not simply because it is intrinsically difficult to achieve, but also because of the way chiral catalysts are identified and optimized 9 . Typical discovery campaigns rely on a single model substrate, and thus select for high performance in a narrow region of chemical space. Here we put forth a practical approach for using multiple model substrates to select simultaneously for both enantioselectivity and generality in asymmetric catalytic reactions from the outset 10,11 . Multisubstrate screening is achieved by conducting high-throughput chiral analyses by supercritical fluid chromatography-mass spectrometry with pooled samples. When applied to Pictet-Spengler reactions, the multisubstrate screening approach revealed a promising and unexpected lead for the general enantioselective catalysis of this important transformation, which even displayed high enantioselectivity for substrate combinations outside of the screening set., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Macrocycles represent attractive candidates in organic synthesis and drug discovery. Since 2014, nineteen macrocyclic drugs, including three radiopharmaceuticals, have been approved by FDA for the treatment of bacterial and viral infections, cancer, obesity, immunosuppression, etc. As such, new synthetic methodologies and high throughput chemistry (e.g., microwave-assisted and/or solid-phase synthesis) to access various macrocycle entities have attracted great interest in this chemical space. This article serves as an update on our previous review related to macrocyclic drugs and new synthetic strategies toward macrocycles ( Molecules , 2013 , 18 , 6230). In this work, I first reviewed recent FDA-approved macrocyclic drugs since 2014, followed by new advances in macrocycle synthesis using high throughput chemistry, including microwave-assisted and/or solid-supported macrocyclization strategies. Examples and highlights of macrocyclization include macrolactonization and macrolactamization, transition-metal catalyzed olefin ring-closure metathesis, intramolecular C-C and C-heteroatom cross-coupling, copper- or ruthenium-catalyzed azide-alkyne cycloaddition, intramolecular S N Ar or S N 2 nucleophilic substitution, condensation reaction, and multi-component reaction-mediated macrocyclization, and covering the literature since 2010.

Chemical synthesis has been described as a central science. Its practice provides access to the chemical structures of known and/or designed function. In particular, human health is greatly impacted by synthesis that enables advancements in both basic science discoveries in chemical biology as well as translational research that can lead to new therapeutics. To support the chemical synthesis needs of investigators across campus, the Vanderbilt Institute of Chemical Biology established a chemical synthesis core as part of its foundation in 2008. Provided in this Review are examples of synthetic products, known and designed, produced in the core over the past 10 years.

New drugs introduced to the market are privileged structures having affinities for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates, provide insight into molecular recognition and simultaneously function as leads for the design of future medicines. This review is part of a continuing series presenting the most likely process-scale synthetic approaches to 40 NCEs approved for the first time anywhere in the world in 2019.

Non-canonical amino acid derivatives are an attractive scaffold for novel drug candidates. Among the methods used to prepare this motif, the asymmetric Mannich-type reaction of α-imino carboxylic acid derivatives is a preeminent strategy because a wide variety of non-canonical amino acids can be accessed by changing only the nucleophile. Preparing the common substrate is difficult, however, which makes this method problematic. We developed a convenient method for synthesizing common substrates using MnO 2 -mediated oxidation of stable precursors. Peptides bearing non-canonical amino acids are another attractive synthetic target. We propose a new approach for synthesizing non-canonical amino acid-containing peptides by directly applying various organic reactions to peptidic substrates. Using hydrophobic anchor-supported peptides, we directly applied ring-closing metathesis and asymmetric Friedel-Crafts reactions to peptidic substrates. We also developed a novel recyclable organocatalyst according to the nature of the hydrophobic anchor tagged compound.

This review describes the progress of the last decade on the synthesis of substituted benzofurans, which are useful scaffolds for the synthesis of numerous natural products and pharmaceuticals. In particular, new intramolecular and intermolecular C-C and/or C-O bond-forming processes, with transition-metal catalysis or metal-free are summarized. (1) Introduction. (2) Ring generation via intramolecular cyclization. (2.1) C7a-O bond formation: (route a). (2.2) O-C2 bond formation: (route b). (2.3) C2-C3 bond formation: (route c). (2.4) C3-C3a bond formation: (route d). (3) Ring generation via intermolecular cyclization. (3.1) C7a-O and C3-C3a bond formation (route a + d). (3.2) O-C2 and C2-C3 bond formation: (route b + c). (3.3) O-C2 and C3-C3a bond formation: (route b + d). (4) Benzannulation. (5) Conclusion.

The hydrogen isotopes deuterium (D) and tritium (T) have become essential tools in chemistry, biology and medicine 1 . Beyond their widespread use in spectroscopy, mass spectrometry and mechanistic and pharmacokinetic studies, there has been considerable interest in incorporating deuterium into drug molecules 1 . Deutetrabenazine, a deuterated drug that is promising for the treatment of Huntington's disease 2 , was recently approved by the United States' Food and Drug Administration. The deuterium kinetic isotope effect, which compares the rate of a chemical reaction for a compound with that for its deuterated counterpart, can be substantial 1,3,4 . The strategic replacement of hydrogen with deuterium can affect both the rate of metabolism and the distribution of metabolites for a compound 5 , improving the efficacy and safety of a drug. The pharmacokinetics of a deuterated compound depends on the location(s) of deuterium. Although methods are available for deuterium incorporation at both early and late stages of the synthesis of a drug 6,7 , these processes are often unselective and the stereoisotopic purity can be difficult to measure 7,8 . Here we describe the preparation of stereoselectively deuterated building blocks for pharmaceutical research. As a proof of concept, we demonstrate a four-step conversion of benzene to cyclohexene with varying degrees of deuterium incorporation, via binding to a tungsten complex. Using different combinations of deuterated and proteated acid and hydride reagents, the deuterated positions on the cyclohexene ring can be controlled precisely. In total, 52 unique stereoisotopomers of cyclohexene are available, in the form of ten different isotopologues. This concept can be extended to prepare discrete stereoisotopomers of functionalized cyclohexenes. Such systematic methods for the preparation of pharmacologically active compounds as discrete stereoisotopomers could improve the pharmacological and toxicological properties of drugs and provide mechanistic information related to their distribution and metabolism in the body.

Multicomponent reactions are relied on in both academic and industrial synthetic organic chemistry owing to their step- and atom-economy advantages over traditional synthetic sequences 1 . Recently, bicyclo[1.1.1]pentane (BCP) motifs have become valuable as pharmaceutical bioisosteres of benzene rings, and in particular 1,3-disubstituted BCP moieties have become widely adopted in medicinal chemistry as para-phenyl ring replacements 2 . These structures are often generated from [1.1.1]propellane via opening of the internal C-C bond through the addition of either radicals or metal-based nucleophiles 3-13 . The resulting propellane-addition adducts are then transformed to the requisite polysubstituted BCP compounds via a range of synthetic sequences that traditionally involve multiple chemical steps. Although this approach has been effective so far, a multicomponent reaction that enables single-step access to complex and diverse polysubstituted drug-like BCP products would be more time efficient compared to current stepwise approaches. Here we report a one-step three-component radical coupling of [1.1.1]propellane to afford diverse functionalized bicyclopentanes using various radical precursors and heteroatom nucleophiles via a metallaphotoredox catalysis protocol. This copper-mediated reaction operates on short timescales (five minutes to one hour) across multiple (more than ten) nucleophile classes and can accommodate a diverse array of radical precursors, including those that generate alkyl, α-acyl, trifluoromethyl and sulfonyl radicals. This method has been used to rapidly prepare BCP analogues of known pharmaceuticals, one of which is substantially more metabolically stable than its commercial progenitor.

Frequently referred to as the 'magic methyl effect', the installation of methyl groups-especially adjacent (α) to heteroatoms-has been shown to dramatically increase the potency of biologically active molecules 1-3 . However, existing methylation methods show limited scope and have not been demonstrated in complex settings 1 . Here we report a regioselective and chemoselective oxidative C(sp 3 )-H methylation method that is compatible with late-stage functionalization of drug scaffolds and natural products. This combines a highly site-selective and chemoselective C-H hydroxylation with a mild, functional-group-tolerant methylation. Using a small-molecule manganese catalyst, Mn(CF 3 PDP), at low loading (at a substrate/catalyst ratio of 200) affords targeted C-H hydroxylation on heterocyclic cores, while preserving electron-neutral and electron-rich aryls. Fluorine- or Lewis-acid-assisted formation of reactive iminium or oxonium intermediates enables the use of a mildly nucleophilic organoaluminium methylating reagent that preserves other electrophilic functionalities on the substrate. We show this late-stage C(sp 3 )-H methylation on 41 substrates housing 16 different medicinally important cores that include electron-rich aryls, heterocycles, carbonyls and amines. Eighteen pharmacologically relevant molecules with competing sites-including drugs (for example, tedizolid) and natural products-are methylated site-selectively at the most electron rich, least sterically hindered position. We demonstrate the syntheses of two magic methyl substrates-an inverse agonist for the nuclear receptor RORc and an antagonist of the sphingosine-1-phosphate receptor-1-via late-stage methylation from the drug or its advanced precursor. We also show a remote methylation of the B-ring carbocycle of an abiraterone analogue. The ability to methylate such complex molecules at late stages will reduce synthetic effort and thereby expedite broader exploration of the magic methyl effect in pursuit of new small-molecule therapeutics and chemical probes.

The field of flow chemistry has garnered considerable attention over the past 2 decades. This Perspective highlights many recent advances in the field of flow chemistry and discusses applications to the pharmaceutical industry, from discovery to manufacturing. From a synthetic perspective, a number of new enabling technologies are providing more rationale to run reactions in flow over batch techniques. Additionally, highly automated flow synthesis platforms have been developed with broad applicability across the pharmaceutical industry, ranging from advancing medicinal chemistry programs to self-optimizing synthetic routes. A combination of simplified and automated systems is discussed, demonstrating how flow chemistry solutions can be tailored to fit the specific needs of a project.

The presence of a quaternary centre-a carbon with four other carbons bonded to it-in any given molecule can have a substantial chemical and biological impact. In many cases, it can enable otherwise challenging chemistry. For example, quaternary centres induce large rate enhancements in cyclization reactions-known as the Thorpe-Ingold effect-which has application in drug delivery for molecules with modest bioavailability 1 . Similarly, the addition of quaternary centres to a drug candidate can enhance both its activity and its metabolic stability 2 . When present in chiral ligands 3 , catalysts 4 and auxiliaries 5 , quaternary centres can guide reactions toward both improved and unique regio-, stereo- and/or enantioselectivity. However, owing to their distinct steric congestion and conformational restriction, the formation of quaternary centres can be achieved reliably by only a few chemical transformations 6,7 . For particularly challenging cases-for example, the vicinal all-carbon 8 , oxa- and aza-quaternary centres 9 in molecules such as azadirachtin 10,11 , scopadulcic acid A 12,13 and acutumine 14 -the development of target-specific approaches as well as multiple functional-group and redox manipulations is often necessary. It is therefore desirable to establish alternative ways in which quaternary centres can positively affect and guide synthetic planning. Here we show that if a synthesis is designed such that each quaternary centre is deliberately leveraged to simplify the construction of the next-either through rate acceleration or blocking effects-then highly efficient, scalable and modular syntheses can result. This approach is illustrated using the conidiogenone family of terpenes as a representative case; however, this framework provides a distinct planning logic that is applicable to other targets of similar synthetic complexity that contain multiple quaternary centres.

There is evidence to suggest that increasing the level of saturation (that is, the number of sp 3 -hybridized carbon atoms) of small molecules can increase their likelihood of success in the drug discovery pipeline 1 . Owing to their favourable physical properties, alkylamines have become ubiquitous among pharmaceutical agents, small-molecule biological probes and pre-clinical candidates 2 . Despite their importance, the synthesis of amines is still dominated by two methods: N-alkylation and carbonyl reductive amination 3 . Therefore, the increasing demand for saturated polar molecules in drug discovery has continued to drive the development of practical catalytic methods for the synthesis of complex alkylamines 4-7 . In particular, processes that transform accessible feedstocks into sp 3 -rich architectures provide a strategic advantage in the synthesis of complex alkylamines. Here we report a multicomponent, reductive photocatalytic technology that combines readily available dialkylamines, carbonyls and alkenes to build architecturally complex and functionally diverse tertiary alkylamines in a single step. This olefin-hydroaminoalkylation process involves a visible-light-mediated reduction of in-situ-generated iminium ions to selectively furnish previously inaccessible alkyl-substituted α-amino radicals, which subsequently react with alkenes to form C(sp 3 )-C(sp 3 ) bonds. The operationally straightforward reaction exhibits broad functional-group tolerance, facilitates the synthesis of drug-like amines that are not readily accessible by other methods and is amenable to late-stage functionalization applications, making it of interest in areas such as pharmaceutical and agrochemical research.

The scarcity of precious metals has led to the development of sustainable strategies for metal-catalyzed cross-coupling reactions. The establishment of new catalytic methods using iron is attractive owing to the low cost, abundance, ready availability, and very low toxicity of iron. In the last few years, sustainable methods for iron-catalyzed cross-couplings have entered the critical area of pharmaceutical research. Most notably, iron is one of the very few metals that have been successfully field-tested as highly effective base-metal catalysts in practical, kilogram-scale industrial cross-couplings. In this Minireview, we critically discuss the strategic benefits of using iron catalysts as green and sustainable alternatives to precious metals in cross-coupling applications for the synthesis of pharmaceuticals. The Minireview provides an essential introduction to the fundamental aspects of practical iron catalysis, highlights areas for improvement, and identifies new fields to be explored., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Despite decades of ground-breaking research in academia, organic synthesis is still a rate-limiting factor in drug-discovery projects. Here we present some current challenges in synthetic organic chemistry from the perspective of the pharmaceutical industry and highlight problematic steps that, if overcome, would find extensive application in the discovery of transformational medicines. Significant synthesis challenges arise from the fact that drug molecules typically contain amines and N-heterocycles, as well as unprotected polar groups. There is also a need for new reactions that enable non-traditional disconnections, more C-H bond activation and late-stage functionalization, as well as stereoselectively substituted aliphatic heterocyclic ring synthesis, C-X or C-C bond formation. We also emphasize that syntheses compatible with biomacromolecules will find increasing use, while new technologies such as machine-assisted approaches and artificial intelligence for synthesis planning have the potential to dramatically accelerate the drug-discovery process. We believe that increasing collaboration between academic and industrial chemists is crucial to address the challenges outlined here.

Synthesis of biologically active molecules (whether at laboratory or industrial scale) remains a highly appealing area of modern organic chemistry. Nowadays, the need to access original bioactive scaffolds goes together with the desire to improve synthetic efficiency, while reducing the environmental footprint of chemical activities. Long neglected in the field of total synthesis, enantioselective organocatalysis has recently emerged as an environmentally friendly and indispensable tool for the construction of relevant bioactive molecules. Notably, enantioselective Brønsted acid catalysis has offered new opportunities in terms of both retrosynthetic disconnections and controlling stereoselectivity. The present report attempts to provide an overview of enantioselective total or formal syntheses designed around Brønsted acid-catalyzed transformations. To demonstrate the versatility of the reactions promoted and the diversity of the accessible motifs, this Minireview draws a systematic parallel between methods and retrosynthetic analysis. The manuscript is organized according to the main reaction types and the nature of newly-formed bonds., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Chemical C-glycosylation has been well developed to improve stereoselectivity in recent years. Due to its high efficiency to build C-glycosides or O-cyclic compounds, C-glycosylation has found widespread use in the synthesis of biologically active molecules. This review highlights the C-glycosylation methods that have been practised in the total synthesis of natural products and pharmaceuticals in the past decade.

Chemical manufacturing is often done at large facilities that require a sizable capital investment and then produce key compounds for a finite period. We present an approach to the manufacturing of fine chemicals and pharmaceuticals in a self-contained plastic reactionware device. The device was designed and constructed by using a chemical to computer-automated design (ChemCAD) approach that enables the translation of traditional bench-scale synthesis into a platform-independent digital code. This in turn guides production of a three-dimensional printed device that encloses the entire synthetic route internally via simple operations. We demonstrate the approach for the γ-aminobutyric acid receptor agonist, (±)-baclofen, establishing a concept that paves the way for the local manufacture of drugs outside of specialist facilities., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Nitrogen heterocycles represent vital structural motifs in biologically-active natural products and pharmaceuticals. As a result, the development of new, convenient and more efficient processes to N -heterocycles is of great interest to synthetic chemists. Samarium(II) iodide (SmI₂, Kagan's reagent) has been widely used to forge challenging C-C bonds through reductive coupling reactions. Historically, the use of SmI₂ in organic synthesis has been focused on the construction of carbocycles and oxygen-containing motifs. Recently, significant advances have taken place in the use of SmI₂ for the synthesis of nitrogen heterocycles, enabled in large part by the unique combination of high reducing power of this reagent (E 1/2 of up to -2.8 V) with excellent chemoselectivity of the reductive umpolung cyclizations mediated by SmI₂. In particular, radical cross-coupling reactions exploiting SmI₂-induced selective generation of aminoketyl radicals have emerged as concise and efficient methods for constructing 2-azabicycles, pyrrolidines and complex polycyclic barbiturates. Moreover, a broad range of novel processes involving SmI₂-promoted formation of aminyl radicals have been leveraged for the synthesis of complex nitrogen-containing molecular architectures by direct and tethered pathways. Applications to the synthesis of natural products have highlighted the generality of processes and the intermediates accessible with SmI₂. In this review, recent advances involving the synthesis of nitrogen heterocycles using SmI₂ are summarized, with a major focus on reductive coupling reactions that enable one-step construction of nitrogen-containing motifs in a highly efficient manner, while taking advantage of the spectacular selectivity of the venerable Kagan's reagent., Competing Interests: The authors declare no conflict of interest.

Nature provides a valuable resource of medicinally relevant compounds, with many antimicrobial and antitumor agents entering clinical trials being derived from natural products. The generation of analogues of these bioactive natural products is important in order to gain a greater understanding of structure activity relationships; probing the mechanism of action, as well as to optimise the natural product's bioactivity and bioavailability. This chapter critically examines different approaches to generating natural products and their analogues, exploring the way in which synthetic and biosynthetic approaches may be blended together to enable expeditious access to new designer natural products.

In recent years, there has been an exponential rise in the number of reports describing synthetic methods that utilize catalytic sp 3 and sp 2 C-H bond activation. Many have emerged as powerful synthetic tools for accessing biologically active motifs. Indeed, application to C-C and C-heteroatom bond formation, provides new directives for the construction of new pharmaceutical entities. Herein, we highlight some recent novel C-H activation processes that exemplify the utility of these transformations in medicinal chemistry., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Discovering pharmaceutical candidates is a resource-intensive enterprise that frequently requires the parallel synthesis of hundreds or even thousands of molecules. C-H bonds are present in almost all pharmaceutical agents. Consequently, the development of selective, rapid and efficient methods for converting these bonds into new chemical entities has the potential to streamline pharmaceutical development. Saturated nitrogen-containing heterocycles (alicyclic amines) feature prominently in pharmaceuticals, such as treatments for depression (paroxetine, amitifadine), diabetes (gliclazide), leukaemia (alvocidib), schizophrenia (risperidone, belaperidone), malaria (mefloquine) and nicotine addiction (cytisine, varenicline). However, existing methods for the C-H functionalization of saturated nitrogen heterocycles, particularly at sites remote to nitrogen, remain extremely limited. Here we report a transannular approach to selectively manipulate the C-H bonds of alicyclic amines at sites remote to nitrogen. Our reaction uses the boat conformation of the substrates to achieve palladium-catalysed amine-directed conversion of C-H bonds to C-C bonds on various alicyclic amine scaffolds. We demonstrate this approach by synthesizing new derivatives of several bioactive molecules, including varenicline.

To optimize drug candidates, modern medicinal chemists are increasingly turning to an unconventional structural motif: small, strained ring systems. However, the difficulty of introducing substituents such as bicyclo[1.1.1]pentanes, azetidines, or cyclobutanes often outweighs the challenge of synthesizing the parent scaffold itself. Thus, there is an urgent need for general methods to rapidly and directly append such groups onto core scaffolds. Here we report a general strategy to harness the embedded potential energy of effectively spring-loaded C-C and C-N bonds with the most oft-encountered nucleophiles in pharmaceutical chemistry, amines. Strain-release amination can diversify a range of substrates with a multitude of desirable bioisosteres at both the early and late stages of a synthesis. The technique has also been applied to peptide labeling and bioconjugation., (Copyright © 2016, American Association for the Advancement of Science.)

Biocatalysis offers an alternative approach to conventional chemical processes for the production of single-isomer chiral drugs. Lipases are one of the most used enzymes in the synthesis of enantiomerically pure intermediates. The use of this type of enzyme is mainly due to the characteristics of their regio-, chemo- and enantioselectivity in the resolution process of racemates, without the use of cofactors. Moreover, this class of enzymes has generally excellent stability in the presence of organic solvents, facilitating the solubility of the organic substrate to be modified. Further improvements and new applications have been achieved in the syntheses of biologically active compounds catalyzed by lipases. This review critically reports and discusses examples from recent literature (2007 to mid-2015), concerning the synthesis of enantiomerically pure active pharmaceutical ingredients (APIs) and their intermediates in which the key step involves the action of a lipase.

Quaternary carbon stereocentres-carbon atoms to which four distinct carbon substituents are attached-are common features of molecules found in nature. However, before recent advances in chemical catalysis, there were few methods of constructing single stereoisomers of this important structural motif. Here we discuss the many catalytic enantioselective reactions developed during the past decade for the synthesis of single stereoisomers of such organic molecules. This progress now makes it possible to incorporate quaternary stereocentres selectively in many organic molecules that are useful in medicine, agriculture and potentially other areas such as flavouring, fragrances and materials.

Terpenoids constitute a significant fraction of molecules produced by living organisms that have found use in medicine and other industries. Problems associated with their procurement and adaptation for human use can be solved using chemical synthesis, which is an increasingly economical option in the modern era of chemistry. This article documents, by way of individual case studies, strategies for reducing the time and cost of terpene synthesis for drug discovery. A major trend evident in recent syntheses is that complex terpenes are increasingly realistic starting points for both medicinal chemistry campaigns and large-scale syntheses, at least in the context of the academic laboratory, and this trend will likely penetrate the commercial sector in the near future.

Terminal, monosubstituted alkenes are ideal prospective starting materials for organic synthesis because they are manufactured on very large scales and can be functionalized via a broad range of chemical transformations. Alkenes also have the attractive feature of being stable in the presence of many acids, bases, oxidants and reductants. In spite of these attributes, relatively few catalytic enantioselective transformations have been developed that transform aliphatic α-olefins into chiral products with an enantiomeric excess greater then 90 per cent. With the exception of site-controlled isotactic polymerization of α-olefins, none of these catalytic enantioselective processes results in chain-extending carbon-carbon bond formation to the terminal carbon. Here we describe a strategy that directly addresses this gap in synthetic methodology, and present a single-flask, catalytic enantioselective conversion of terminal alkenes into a number of chiral products. These reactions are facilitated by a neighbouring functional group that accelerates palladium-catalysed cross-coupling of 1,2-bis(boronates) relative to non-functionalized alkyl boronate analogues. In tandem with enantioselective diboration, this reactivity feature transforms alkene starting materials into a diverse array of chiral products. We note that the tandem diboration/cross-coupling reaction generally provides products in high yield and high selectivity (>95:5 enantiomer ratio), uses low loadings (1-2 mol per cent) of commercially available catalysts and reagents, offers an expansive substrate scope, and can address a broad range of alcohol and amine synthesis targets, many of which cannot be easily addressed with current technology.

Macrocyclic scaffolds are commonly found in bioactive natural products and pharmaceutical molecules. So far, a large number of macrocyclic natural products have been isolated and synthesized. The construction of macrocycles is generally considered as a crucial and challenging step in the synthesis of macrocyclic natural products. Over the last several decades, numerous efforts have been undertaken toward the synthesis of complex naturally occurring macrocycles and great progresses have been made to advance the field of total synthesis. The commonly used synthetic methodologies toward macrocyclization include macrolactonization, macrolactamization, transition metal-catalyzed cross coupling, ring-closing metathesis, and click reaction, among others. Selected recent examples of macrocyclic synthesis of natural products and druglike macrocycles with significant biological relevance are highlighted in each class. The primary goal of this review is to summarize currently used macrocyclic drugs, highlight the therapeutic potential of this underexplored drug class and outline the general synthetic methodologies for the synthesis of macrocycles.

Oxa-Michael reactions, i.e. addition reactions of oxygen nucleophiles to conjugated systems, have traditionally received much less attention from the scientific community compared to the addition of carbon nucleophiles to conjugate acceptor systems (Michael reaction). This was mainly due to lack of reactivity and selectivity of these reactions. Within the last few years however, there has been a remarkable increase in publications focussing on method development as well as applications to natural product synthesis. This tutorial review discusses instructive examples that have substantially broadened the scope of oxa-Michael reactions., (This journal is © The Royal Society of Chemistry 2012)

New drugs are introduced to the market every year and each represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the synthesis of 15 NCEs that were launched anywhere in the world in 2010., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

In this account, a rapid retrosynthesis-based scoring method for the assessment of synthetic accessibility of drug-like molecules, called RASA (Retrosynthesis-based Assessment of Synthetic Accessibility) is devised. RASA first constructs a synthesis tree for the target molecule based on retrosynthetic analysis; in this process a series of strategies are suggested for limiting combinatorial explosion of the synthesis tree. A scoring function (RASA-score) for the assessment of synthetic accessibility is then proposed based on the optional effective synthetic routes, the complexity of reaction, and the difficulty of separation/purification associated with the most favorable synthetic route. The contributions of individual components are calibrated by linear regression analysis based on the synthetic accessibility estimates of a training set (100 compounds) given by a group of medicinal chemists (G1). Two external test sets (TS1 and TS2), whose synthetic accessibility estimates were given by the group G1 medicinal chemists and another group (G2) of medicinal chemists (from literature), respectively, were adopted for the evaluation of RASA. The correlation coefficient between the calculated RASA-score values and the estimated scores by medicinal chemists for TS1 is 0.807 and that for TS2 is 0.792, which demonstrate the validity and reliability of RASA. The validity and reliability as well as the high speed of RASA and its capability of suggesting synthetic routes enable it a useful tool in drug discovery.