Azabicycloalkenes as synthetic intermediates--synthesis of azabicyclo[X.3.0]alkane scaffolds

A general method to synthesize functionalized azabicyclo[X.3.0]alkane scaffolds 5 is reported. Key intermediates are azabicycloalkenes such as 1 and 2, which are acylated with unsaturated carboxylic acids and subsequently submitted to tandem olefin metathesis. The resulting bicyclic heterocycles are versatile intermediates for different dipeptide mimetics and can be used as intermediates for natural products with indolizidine scaffolds or analogues thereof. [reaction: see text].     

Copper‐Catalyzed Enantioselective Allylboration of Alkynes: Synthesis of Highly Versatile Multifunctional Building Blocks

The first copper‐catalyzed enantioselective allylboration of alkynes is reported. The method employs a multitasking chiral NHC‐Cu catalyst and provides access to densely functionalized molecules from simple starting materials with excellent levels of chemo‐, regio‐, and enantioselectivity. These multifunctional products display highly versatile reactivity as shown by the synthesis of a variety of non‐racemic molecular scaffolds. DFT calculations were conducted to gain insight into the high selectivity levels of this catalytic process.     

Enantioselective synthesis of erythro-4-deoxyglycals as scaffolds for target- and diversity-oriented synthesis: new insights into glycal reactivity

An efficient, enantioselective synthesis of erythro-4-deoxyglycals has been developed using asymmetric aldehyde allylation and tungsten-catalyzed alkynol endo-cycloisomerization as the key steps. These versatile synthetic scaffolds have been elaborated to a variety of products using stereoselective transformations that are complementary to those available using the corresponding threo glycals. This work has provided valuable insights into the relationships between glycal structure and reactivity. In addition, a new diene-forming side reaction during tungsten-catalyzed alkynol cycloisomerization has been discovered.     

Rapid Assembly of Functionalised Spirocyclic Indolines by Palladium‐Catalysed Dearomatising Diallylation of Indoles with Allyl Acetate

Herein, we report the application of allyl acetate to the palladium‐catalysed dearomatising diallylation of indoles. The reaction can be carried out by using a readily available palladium catalyst at room temperature, and can be applied to a wide range of substituted indoles to provide access to the corresponding 3,3‐diallylindolinines. These compounds are versatile synthetic intermediates that readily undergo Ugi reactions or proline‐catalysed asymmetric Mannich reactions. Alternatively, acylation of the 3,3‐diallylindolinines with an acid chloride or a chloroformate, followed by treatment with aluminium chloride, enables 2,3‐diallylindoles to be prepared. By using ring‐closing metathesis, functionalised spirocyclic indoline scaffolds can be accessed from the Ugi products, and a dihydrocarbazole can be prepared from the corresponding 2,3‐diallylindole.     

Polyketide Cyclizations for the Synthesis of Polyaromatics

The folding and cyclization of poly‐β‐carbonyl chains controlled by the intricate enzymatic polyketide synthase machinery results in a remarkable diversity of aromatic natural products. Synthetic methods that allow for the preparation of highly reactive polyketide chains while governing their folding in ensuing cyclizations likewise lead to versatile divergent preparations of aromatic scaffolds valuable for numerous applications. Although biomimetic polyketide cyclizations have repeatedly been applied in the total synthesis of polyphenol natural products, their utility for the preparation of the broad range of polyaromatic architectures has yet to reach its full potential. This Minireview highlights some of the virtues of applying polyketide logic to the retrosynthetic analysis of polycyclic aromatic scaffolds, the increasing accessibility of precursors, and the potential of small‐molecule catalysts for controlling polyketide cyclizations to provide polyaromatic scaffolds.     

Direct amination of γ-halo-β-ketoesters with anilines

The direct amination of α-haloacetoacetates with anilines is described. Compared to existing methods, this simple protocol provides an attractive strategy to prepare diverse γ-anilino-β-ketoesters in one step. Good to excellent yields of the amination products were obtained under robust conditions, providing versatile and useful scaffolds.     

Benzannulation of arynes with dimethylacetonedicarboxylates via an insertion-fragmentation-Dieckman-aromatization cascade: Expeditious entry to naphthoresorcinols and binaphthoresorcinols

Aryne insertions into 1,3,5-tricarbonyl bearing dimethylacetonedicarboxylate (DMAD) proceeds through a 4-step cascade process to eventuate in a versatile one pot synthesis of functionally embellished naphthoresorcinols. Functional group amplifications and transformations on these entities have been explored with the intent to apply them for natural products syntheses and to access other interesting scaffolds.     

Development of environmental friendly synthetic strategies for Sonogashira cross coupling reaction: An update

Sonogashira cross coupling is a well-known reaction for the formation of carbon–carbon bond. It involves the coupling of aryl halides with terminal alkynes to synthesize versatile functionalized alkyne scaffolds having diverse applications. Many of the natural products and important pharmaceutical drugs can be obtained through this reaction. In this regard, hectic progress has been put by the synthetic chemists to make this cross coupling more effective. This review article discloses mild and environmental friendly reaction conditions of Sonogashira cross coupling developed during 2013–2018.     

Productive Syntheses of Privileged Scaffolds Inspired by the Recognition of a Diels–Alder Pattern Common to Three Classes of Natural Products

Identification of a common Diels–Alder pattern in three classes of bioactive natural products led us to study the synthesis and cycloaddition of a new class of cyclic dienes readily available from β,γ-unsaturated lactams. A practical and readily scalable route to the parent p-methoxybenzyl-protected 6- and 7-membered β,γ-unsaturated lactams was developed. These were readily transformed into the corresponding O-silylated dienes, which were reacted with dimethyl and diethyl fumarate to yield stereoselectively highly functionalized bicyclic adducts. These exhibited unexpected and versatile transformations upon acid hydrolysis depending on the nature of the dienophile substituents and the acid catalyst. All reactions have been performed on multigram quantities. These transformations provide a convenient, economical, and easily scalable pathway for the rapid construction of functionally and stereochemically dense privileged scaffolds for the construction of libraries of natural products-inspired molecules of pharmacological relevance.     

Carbopalladation Cascades Using Carbon–Carbon Triple Bonds: Recent Advances to Access Complex Scaffolds

Alkynes are one of the most versatile functional groups as synthetic handles. They allow for a direct access to partially or fully substituted alkenes through difunctionalization reactions. A prominently utilized transformation for these sequences is the carbopalladation of alkynes, which can be followed by various termination steps such as aromatizations, dearomatizations, cross‐coupling reactions, or pericyclic processes, amongst others. This Minireview provides an overview of the recent literature published in the field of carbopalladation chemistry, both with a focus on methodology as well as its application in the syntheses of complex molecular scaffolds, natural products, and functional molecules.     

Synthesis of new 4-methyl-3-piperidones via an iron-catalyzed intramolecular tandem isomerization–aldolisation process

A new versatile synthesis of 3-piperidones is described, starting from amino acids. It uses, as a key step, an iron carbonyl-mediated intramolecular tandem isomerization–aldolisation reaction. These new heterocycles appear as useful scaffolds for the total synthesis of various types of bioactive molecules.     

Borophosphonate cages: easily accessible and constitutionally dynamic heterocubane scaffolds

A versatile and experimentally facile procedure for the synthesis of borophosphonate cages of the general formula [tBuPO(3)BR'](4) is described. The method involves heating of tert-butylphosphonic acid with a boronic acid in toluene to give borophosphonates in [4+4] condensation reactions. The products display a heterocubane structure with bent P-O-B bridges as evidenced by crystallographic analyses. Scrambling experiments show that the borophosphonate cages are constitutionally dynamic scaffolds with exchange reactions occurring on the hour time scale at room temperature. The cages can be decorated with reactive groups such as aldehydes. Our results demonstrate that borophosphonate cages are interesting building blocks for dynamic covalent chemistry.     

Recent applications of radical cascade reaction in the synthesis of functionalized 1-indenones

1-Indenones are important scaffolds in natural products, biologically active molecules as well as functional materials. Recently, radical cascade cyclization has emerged as an efficient and powerful strategy for the construction of valuable and versatile functionalized 1-indenones. In this review, the recent advances of this rapidly growing area were summarized. The selected examples have been classified according to the type of reaction substrates such as 1,3-diarylpropynones, 2-alkynylbenzonitriles, arylpropynols, 1,5-enynes and 2-alkynylated bromocinnamates.     

Solid-phase synthesis of multiple classes of peptidomimetics from versatile resin-bound aldehyde intermediates

A wide variety of highly substituted lactam containing peptidomimetic scaffolds are prepared by solid-phase synthesis from a single, versatile class of resin-bound aldehyde intermediates (1). These include monocyclics 3, bicyclics 4, tricyclics 5, and tetracyclics 6. The key intermediate 1 is readily synthesized from resin-bound natural or unnatural alpha-amino acids. The synthetic procedures permit the construction of a large diversity of substitution patterns for ready use in combinatorial chemistry. In every case, the release of final products from resin is by a cyclitive cleavage process. Since this depends on successful completion of multiple intermediate synthetic steps, the products are often quite pure, even though previous steps involve only a filtration workup. The mild conditions for many of these synthetic procedures offer the promise of using this chemistry in peptide fragment condensations to produce modified peptides, at either the N-terminus or C-terminus, or as individually assembled peptide segments with a wide variety of conformationally restricted peptidomimetic linkers at the point of juncture.     

Synthesis of heterocycles from arylacetonitriles: Powerful tools for medicinal chemists

Arylacetonitriles are versatile building blocks for the construction of heterocyclic scaffolds in medicinal chemistry. These intermediates are able to engage in a variety of synthetic transformations, giving rise to diverse biologically active structures. This digest focuses on recent applications of this synthetic methodology by drug discovery teams across several disease areas, with an emphasis on different reaction types.     

Recent advances on electrospun scaffolds as matrices for tissue-engineered heart valves

Valvular heart diseases (VHDs) are a major health problem increasing morbidity and mortality worldwide. Currently, treatment of VHDs relies on valve replacement with mechanical or biological valves, which have major drawbacks in terms of durability and the ability to grow, repair and remodel. To this end, tissue-engineered heart valves (TEHVs) have emerged as ideal substitutes. TEHVs are composed of biodegradable, biocompatible and mechanically stable scaffolds that resemble the native valves. These scaffolds are seeded with autologous cells and conditioned in a bioreactor prior to implantation. Scaffolds that have been utilized so far for such application are (i) biological, (ii) synthetic and (iii) cell entrapment in polymerized extra-cellular matrix based scaffolds. Synthetic scaffolds are considered superior over the other two types in terms of controlled mechanical properties and degradation rate. They can be subdivided into porous, hydrogel and fibrous scaffolds. Among the three subcategories, fibrous scaffolds are preferred because they resemble the natural extra-cellular matrix for the native valve. Such scaffolds can be fabricated using phase separation, self-assembly and electrospinning. Electrospinning is a versatile technique for fabricating scaffolds for tissue engineering applications that possess many advantages. Electrospun scaffolds processed using a wide range of synthetic and natural polymers were proven to be promising in terms of mechanical properties comparable to the native valves, fiber diameter within the range of the natural extracellular matrix and good cellular response. However, further investigation in fabricating fibrous scaffolds for tissue-engineered heart valves is still needed. In this review, we discussed electrospun scaffolds as TEHVs matrices, how far they succeeded in meeting the criteria of ideal scaffolds for such application and what the shortage aspects and possible solutions are.     

Scaffold architecture and pharmacophoric properties of natural products and trade drugs: application in the design of natural product-based combinatorial libraries

Natural products were analyzed to determine whether they contain appealing novel scaffold architectures for potential use in combinatorial chemistry. Ring systems were extracted and clustered on the basis of structural similarity. Several such potential scaffolds for combinatorial chemistry were identified that are not present in current trade drugs. For one of these scaffolds a virtual combinatorial library was generated. Pharmacophoric properties of natural products, trade drugs, and the virtual combinatorial library were assessed using a self-organizing map. Obviously, current trade drugs and natural products have several topological pharmacophore patterns in common. These features can be systematically explored with selected combinatorial libraries based on a combination of natural product-derived and synthetic molecular building blocks.     

Access to polyfunctionalized diquinanes, hydrindanes, and decalines via TiCl4 promoted Michael-aldol and Baylis-Hillman reactions

The addition of 0.5 equiv of TiCl(4) to (cyclo)alkanones tethered to α,β-unsaturated ketones afforded polyfunctionalized diquinanes, hydrindanes, and decalines. These products, resulting from a Michael-aldol or a Baylis-Hillman reaction, can be obtained with high or total diastereoselectivity in moderate to high yields. These scaffolds represent interesting building blocks for the synthesis of complex natural products.     

Simple and Expedient Access to Novel Fluorinated Thiazolo- and Oxazolo[3,2-a]pyrimidin-7-one Derivatives and Their Functionalization via Palladium-Catalyzed Reactions

An efficient, versatile, and one-pot method for the preparation of novel fluorinated thiazolo- and oxazolo[3,2-a]pyrimidin-7-ones is described from 2-aminothiazoles or 2-amino-oxazoles and fluorinated alkynoates. This transformation, performed under transition-metal-free conditions, offers new fluorinated cyclized products with good to excellent yields. Moreover, the functionalization of these N-fused scaffolds via the Suzuki-Miyaura and Sonogashira cross-coupling reactions led to the synthesis of highly diverse thiazolo- and oxazolo[3,2-a]pyrimidin-7-ones.     

Simple Synthesis of Versatile Coumarin Scaffolds

We describe an approach using ring‐closing metathesis (RCM) to synthesize versatile coumarin derivatives that present appropriate substitutions both at the aromatic and at the α,β‐unsaturated lactone ring. The obtained compounds can be used as molecular scaffolds suitable for further diversifications through a combinatorial approach.