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Over the past years, Pd(II)-catalyzed oxidative couplings have enabled the construction of molecular scaffolds with high structural diversity via C–C, C–N and C–O bond-forming reactions. In contrast to the use of stoichiometric amounts of more common oxidants, such as metal salts (Cu and Ag) and benzoquinone derivatives, the use of molecular oxygen for the direct or indirect regeneration of Pd(II) species presents itself as a more viable alternative in terms of economy and sustainability. In this review, we describe recent advances on the development of Pd-catalyzed oxidative cyclizations/functionalizations, where molecular oxygen plays a pivotal role as the sole stoichiometric oxidant.1 Introduction2 Oxidative C–C and C–Nu Coupling2.1 Intramolecular Oxidative C–Nu Heterocyclization Reactions2.1.1 C–H Activation2.1.2 Wacker/Aza-Wacker-Type Cyclization2.1.3 Tandem Wacker/Aza-Wacker and Cyclization/Cross-Coupling Reactions2.2 Intermolecular Oxidative C–Nu Heterocoupling Reactions2.3 Intramolecular Oxidative (C–C) Carbocyclization Reactions2.4 Intermolecular Oxidative C–C Coupling Reactions2.4.1 Cyclization Reactions2.4.2 Cross-Coupling Reactions2.4.3 Homo-Coupling Reactions3 Aerobic Dehydrogenative Coupling/Functionalization4 Oxidative C–H Functionalization5 Summary

A two-step procedure for the preparation of cyclopropanecarboxaldehyde-1,1-diester from a γ,δ-epoxyester and its synthetic versatility are described herein. The epoxide ring-opening/cyclopropanation process occurs in the presence of Mg(ClO4)2 under heating, resulting in cyclopropanemethanol-1,1-diester in 65% yield. A mild TEMPO-mediated oxidation of this substrate readily generated the corresponding aldehyde in 75% yield, which was applied in the one-pot synthesis of four cyclopropylidene-γ-lactams and three δ-lactams. In addition, vinylcyclopropanes were obtained through the Wittig reaction of the aldehyde with phosphonium salts and used as precursors for tetrahydrofurans.

A method for the transition-metal-free direct C–H arylation of unactivated arenes is developed with aryl bromides as substrates and 8-hydroxyquinoline as an efficient promoter. A variety of biaryl compounds with structural diversity are obtained in moderate to high yields. Mechanistic studies reveal that the reaction proceeds via a homolytic­ aromatic substitution pathway.

General routes for the synthesis of 1,3-oxazin-4-ones are discussed, with particular attention paid to recent developments in the field. The syntheses of amine functionalised cyclopropyl carbinols via a hydride-mediated reduction of various 5-chloroethyl-1,3-oxazin-4-enones in moderate to good yield are disclosed. This new method provides an opportunity to access greater structural diversity within these useful synthetic building blocks.

The identification of new bioactive small molecules is increasingly reliant upon the synthesis and screening of chemical libraries. The extent of structural diversity and the proportion of unique scaffolds in a library are commonly acknowledged to be the most important factors in determining its success in identifying new biologically relevant compounds. Particularly important in this respect are macrocycles, which display unique physicochemical attributes and are used in many clinical applications. Despite these advantages, macrocycles remain under-represented in many contemporary screening collections, predominantly due to their synthetic intractability. Diversity-oriented­ synthesis is a powerful method for the construction of deliberately diverse collections of small molecules, and many research groups are working to apply its principles to the synthesis of structurally and functionally diverse macrocyclic libraries. In this short review we introduce why macrocycles are promising chemotypes in screening libraries, especially for challenging biological targets such as protein–protein interactions, and we review a collection of strategies developed in our laboratory for the diversity-oriented synthesis of macrocycle libraries. We analyse a selection of the macrocycle collections generated using these approaches and conclude with our perspective on future directions of the field. 1 Introduction 1.1 Chemical Libraries in Drug Discovery and Chemical Biology 1.2 Macrocycles in Screening Collections 1.3 Diversity-Oriented Synthesis 2 Build/Couple/Pair 2.1 Strategy Overview 2.2 Typical B/C/P Strategies 2.3 Advanced B/C/P Strategies 2.4 Two-Directional Synthesis 3 Alternative Approaches to Macrocycle Library Synthesis 4 Discussion and Concluding Remarks

A highly efficient method for the synthesis of spiropyrazolone derivatives with structural diversity has been established via a facile three-component 1,3-dipolar cycloaddition of aldehydes, amino ester, and unsaturated pyrazolones. This protocol is applicable to a variety of unsaturated pyrazolones and aldehyde-derived azomethine ylides, providing an easy access to spiropyrazolone-based tetrahydro­pyrroles with structural diversity in high yields (up to 97%).

Higher fungi are a promising source of new bioactive natural products with great structural diversity, ranging from polyketides to terpenoids and alkaloids. Many of these structures are a challenge for synthetic organic chemists who have been inspired to develop new total syntheses. Nevertheless, reviews covering syntheses of fungal natural products are lacking. One aim of this review is to close this gap and to present a selection of more recent syntheses of fungal secondary metabolites from different structural classes. Secondly, this review intends to demonstrate that there are many more motivations for the synthesis of natural products than to confirm a proposed structure or to report the first total synthesis of a new natural product. Thirdly, this review is intended to stimulate the interest of organic chemists in the synthesis of fungal natural products. 1 History and Importance of (Fungal) Secondary Metabolites 2 Reasons for the Synthesis of Fungal Natural Products 3 Total Syntheses of Selected Fungal Natural Products 3.1 Terpenes 3.1.1 Sesquiterpenes 3.1.1.1 Polyquinanes 3.1.1.2 Drimanes 3.1.2 Diterpenes: Cyathanes 3.1.3 Terpenes Containing a Butenolide Moiety 3.2 Alkaloids 3.3 Natural Products Derived from the Shikimate Pathway 3.3.1 Pulvinic Acid Derivatives and Terphenyl Quinones 3.3.2 Shikimate Pathway Derived Macrolides 3.3.3 Strobilurins 3.4 Aromatic Polyketides 3.4.1 Quinones 3.4.2 Resorcylates and Catechols 3.5 Sugar Derivatives 4 Conclusion and Outlook

An efficient multicomponent reaction of isocyanides, allenoates, and α,β-unsaturated ketones is disclosed, thus providing rapid access for the synthesis of bicyclic skeletons. From a mechanistic standpoint, the present cycloaddition proceeds through cascade cycloaddition followed by hydration and intramolecular cyclization. Several controlled experiments are also conducted to gain further insight into the reaction mechanism; some valuable and interesting findings were observed during this process. To enrich the structural diversity, 3-(2-oxo­ethylene)indolinones (i.e. with an α,β-unsaturated ketone at position 3) were also found to be compatible in this reaction. In addition, this method is also characterized by its broad substrate scope, mild conditions, and high efficiency, which makes it valuable for further application.

A copper complex has been found to catalyze the borylstannylation of alkenes through three-component coupling with a diboron and a tin alkoxide, affording vic-borylstannylalkanes of structural diversity in a regio- and stereoselective manner. The versatility of this borylstannylation has been also demonstrated by employing allenes, leading to the sole formation of borylstannylated products, which have alkenylborane and allylstannane units.

A series of C-10-substituted tabersonine analogues have been synthesized via palladium-catalyzed cross-coupling reactions. To be specific, tabersonine reacted with NIS in TFA to generate the 10-iodotabersonine, which participated in palladium-catalyzed or palladium/copper co-catalyzed cross-coupling reactions, such as Suzuki–Miyaura cross-coupling reaction, Heck reaction, and Sonogashira­ cross-coupling reaction, to afford C-10 tabersonine analogues. These protocols provide the possibility of introducing substituents with structural diversity and complexity into the C-10 of tabersonine for the pharmacological activity screening.

This review presents the recent progress in the chemistry of dimethyl acetylenedicarboxylate (DMAD). The interest in and applications of this powerful reagent with more than 135 years of history have greatly increased in the last 10 years, further proving its versatility. Undoubtedly, DMAD can be a multi-tool in the quest of molecular complexity and diversity. The extreme structural diversity of the products described in this review illustrates the powerful potential of DMAD as a building block in organic synthesis. 1 Introduction 2 Michael Reactions 2.1 Sulfur as Nucleophile 2.2 Nitrogen as Nucleophile 2.3 Oxygen as Nucleophile 2.4 Addition to Carbon–Carbon Double Bonds 3 Cycloaddition Reactions 3.1 Diels–Alder Reactions ([4+2] Cycloadditions) 3.2 1,3-Dipolar Reactions ([3+2] Cycloadditions) 3.3 [2+2] Cycloadditions 3.4 [8+2] Cycloadditions 4 DMAD and the Generation of Zwitterions; Multicomponent Reactions (MCRs) 4.1 Phosphines and Derivatives 4.2 Amines 4.3 Isocyanides 4.4 Carbenes 4.5 Miscellaneous Reactions 5 Conclusion

Due to their structural diversity, elegant polycyclic molecular architecture, and biological activity, the indole alkaloids have been investigated by organic chemists over the last century. The first akuammiline alkaloid, echitamine, was isolated in 1875 and first described in 1880. Owing to the exceptional structure of akuammiline alkaloids, it was not until 125 years later that the first successful total synthesis was accomplished. This review will give an overview of this class of alkaloids, pinpointing its structural characteristics and showcasing the completed total syntheses. Furthermore, an overview of the structural diversity is given. 1 Introduction 2 Structural Analysis 3 Biosynthesis 4 Completed Total Syntheses 4.1 (±)-Vincorine 4.2 (–)-Vincorine 4.3 (±)-Aspidophylline A 4.4 (+)-Scholarisine A 5 Conclusion

A facile and efficient one-pot synthesis of substituted thieno[2,3-b]pyridines has been developed. Treatment of enaminones, such as 2-acetyl-3-(dimethylamino)propenamides and -propenoates, with 2-cyanothioacetamide in the presence of potassium carbonate in N,N-dimethylformamide at 80 degrees C followed by addition of methylene-active bromides at room temperature provided, via intramolecular cyclization, 2,3,5,6-tetrasubstituted thieno[2,3-b]pyridines in yields of 78-90%. This protocol, which combines construction and modification of the thieno[2,3-b]pyridine ring, increases the structural diversity of the final products from readily available materials.

Catalytic nucleophilic addition to the carbon-nitrogen doublebond of an imino group in an asymmetric fashion provides a directconnective and attractive route to enantioenriched N-protected amineswith structural diversity. In the last decades, significant achievementshave been made in the field of catalytic enantioselective reactionsinvolving the use of α-amido sulfones as in situ equivalentsof activated imines. These, in combination with diverse nucleophiles,are used to prepare optically pure amines or N-protected amides.This review focuses on the recent advances in the synthetic applicationsof α-amido sulfones as reactive precursors of imines inthe asymmetric addition of organometallic reagents, Mannich-,aza-Henry, Strecker, and other asymmetric nucleophilic additionreactions. 1 Introduction 2 Asymmetric Mannich-Type Reactions 2.1 Phase-Transfer-Catalyzed Mannich Reactions 2.2 Bifunctional Organocatalyzed Mannich Reactions 3 Catalytic Enantioselective Addition of Organometallic Reagents- 4 Catalytic Enantioselective Aza-Henry Reactions 5 Asymmetric Strecker Reactions 6 Miscellaneous Reactions 7 Summary and Outlook

A two-step synthesis of 3-(N-substituted aminomethyl)-5-(N-substituted imino)-2,3-dihydro-imidazo[1,2-a]pyridines is reported. Starting from 3-bromomethyl-5-chloro-2,3-dihydroimidazo[1,2-a]pyridine, the synthesis comprises two consecutive reactions with primary amines. The products are derived from a three-dimensional molecular scaffold and may therefore be useful in medicinal chemistry in the search for small molecules that can adapt optimally to the three-dimensional binding sites of biological targets. The present synthesis is also particularly suitable for the preparation of combinatorial libraries since primary amines are commercially available in great structural diversity. Moreover, the second step is selective for primary amines, which means that secondary amino groups can be introduced into the products without the need for protection.

A new family of chiral diazaphospholidines is readily accessible by phosphorylating commercially available (S)-1,1'-binaphthyl-2,2'-diamine. NMR spectroscopy, mass spectrometry and X-ray crystallographic analysis reveal their unique structures. In preliminary studies these novel monodentate P-ligands were tested in Rh-catalyzed hydrogenation and hydroformylation (31% ee) reactions. The modular nature of the ligands allows for further structural diversity.

Neolignans, dehydrodimers of phenylpropenes, are important natural products with high structural diversity and various biological properties. Several diastereo- and enantioselective synthesis of neolignans have been developed in the past, either specific for each of the various neolignan skeletons or randomized. This review summarizes the efforts towards the synthesis of chiral neolignans, racemic and optically active, and provides a brief outlook for future developments.