Efficient and Modular Synthesis of New Structurally Diverse Functionalized [n]Paracyclophanes by a Ring‐Distortion Strategy

With the goal of synthesizing new [n]paracyclophanes, the expansion of the scope of a strategy originally disclosed by Winterfeldt et al., was investigated. This approach involves sequential Diels–Alder/retro‐Diels–Alder reactions, the applications of which have been constrained so far to steroid derivatives. An efficient access to new functionalized [9]‐, [10]‐, and [16]paracyclophanes, including original cage architectures, was developed from readily available building blocks using thermal electrocyclization and a cycloaddition/cycloreversion sequence as the key steps.     

Synthesis of chiral building blocks for cephalostatin analogues

The present paper describes the synthesis of 5‐azido‐6‐ketones (14) and 6‐hydroxy‐5‐ketone (20) from Hajos Wiechert ketone as chiral building blocks for cephalostatin analogues. The synthesis of symmetric cephalostatin analogue from 6‐hydroxy‐5‐ketone has also been reported. The characterization of the each synthesized compounds was carried out by IR, ¹H‐NMR, ¹³C‐NMR and High resolution Mass Spectrometry.     

Synthetic Study of (−)‐Norzoanthamine: Construction of the ABC Ring Moiety

Throw your hat in the ring : A highly diastereoselective synthesis of the ABC rings of (?)‐norzoanthamine has been achieved starting from the (?)‐Hajos–Parrish ketone (see scheme). Three asymmetric quaternary carbon centers on the C ring were constructed by a 1,4‐addition, and an intramolecular Diels–Alder reaction provided a trans‐decalin scaffold on the AB rings.

     

Chiral Recognition and Separation by Chirality‐Enriched Metal–Organic Frameworks

Endowed with chiral channels and pores, chiral metal–organic frameworks (MOFs) are highly useful; however, their synthesis remains a challenge given that most chiral building blocks are expensive. Although MOFs with induced chirality have been reported to avoid this shortcoming, no study providing evidence for the ee value of such MOFs has yet been reported. We herein describe the first study on the efficiency of chiral induction in MOFs using inexpensive achiral building blocks and fully recoverable chiral dopants to control the handedness of racemic MOFs. This method yielded chirality‐enriched MOFs with accessible pores. The ability of the materials to form host–guest complexes was probed with enantiomers of varying size and coordination and in solvents with varying polarity. Furthermore, mixed‐matrix membranes (MMMs) composed of chirality‐enriched MOF particles dispersed in a polymer matrix demonstrated a new route for chiral separation.     

Palladium‐Catalyzed Intramolecular Trost–Oppolzer‐Type Alder–Ene Reaction of Dienyl Acetates to Cyclopentadienes

A new approach to the synthesis of highly substituted cyclopentadienes, indenes, and cyclopentene‐fused heteroarenes by means of the Pd‐catalyzed Trost–Oppolzer‐type intramolecular Alder–ene reaction of 2,4‐pentadienyl acetates is described. This unprecedented transformation combines the electrophilic features of the Tsuji–Trost reaction with the nucleophilic features of the Alder–ene reaction. The overall outcome can be perceived as a hitherto unknown “acid‐free” iso‐Nazarov‐type cyclization. The versatility of this strategy was further demonstrated by the formal synthesis of paucifloral F, a resveratrol‐based natural product.     

Rhodium(I)‐Catalyzed Regiospecific Dimerization of Aromatic Acids: Two Direct C?H Bond Activations in Water

2,2′‐Diaryl acids are key building blocks for some of the most important and high‐performance polymers such as polyesters and polyamides (imides), as well as structural motifs of MOFs (metal–organic frameworks) and biological compounds. In this study, a direct, regiospecific and practical dimerization of simple aromatic acids to generate 2,2′‐diaryl acids has been discovered, which proceeds through two rhodium‐catalyzed C H activations in water. This reaction can be easily scaled up to gram level by using only 0.4–0.6 mol % of the rhodium catalyst. As a proof‐of‐concept, the natural product ellagic acid was synthesized in two steps by this method.     

Rhodium(I)‐Catalyzed Regiospecific Dimerization of Aromatic Acids: Two Direct CH Bond Activations in Water

2,2′‐Diaryl acids are key building blocks for some of the most important and high‐performance polymers such as polyesters and polyamides (imides), as well as structural motifs of MOFs (metal–organic frameworks) and biological compounds. In this study, a direct, regiospecific and practical dimerization of simple aromatic acids to generate 2,2′‐diaryl acids has been discovered, which proceeds through two rhodium‐catalyzed C? H activations in water. This reaction can be easily scaled up to gram level by using only 0.4–0.6 mol % of the rhodium catalyst. As a proof‐of‐concept, the natural product ellagic acid was synthesized in two steps by this method.     

Metal‐Free Route for the Synthesis of 4‐Acyl‐1,2,3‐Triazoles from Readily Available Building Blocks

Functionalized 1,2,3‐triazole heterocycles have been known for a long time and hold an extraordinary potential in diverse research areas ranging from medicinal chemistry to material science. However, the scope of therapeutically important 1‐substituted 4‐acyl‐1H‐1,2,3‐triazoles is much less explored, probably due to the lack of synthetic methodologies of good scope and practicality. Here, we describe a practical and efficient one‐pot multicomponent reaction for the synthesis of α‐ketotriazoles from readily available building blocks such as methyl ketones, N,N‐dimethylformamide dimethyl acetal, and organic azides with 100 % regioselectivity. This reaction is enabled by the in situ formation of an enaminone intermediate followed by its 1,3‐dipolar cycloaddition reaction with an organic azide. We effectively utilized the developed strategy for the derivatization of various heterocycles and natural products, a protocol which is difficult or impossible to realize by other means.     

Design and Synthesis of New Biprivileged Molecular Scaffolds: Indolo‐Fused Benzodiazepinyl/quinoxalinyl benzimidazoles

The present article describes the design and synthesis of new biprivileged molecular scaffolds with diverse structural features. Commercially available, simple heterocyclic building blocks such as 4‐fluoro‐3‐nitrobenzoic acid, 2‐chloro‐3‐nitrobenzoic acid, and indoline were utilized for the synthesis of the novel heterocycles. Pictet–Spengler‐type condensation was used as a key step to construct tetracyclic indolo‐benzodiazepines and indolo‐quinoxalines linked with substituted benzimidazoles. Analysis of single crystals of representative compounds showed that these molecular skeletons have the potential to present various substituents with distinct three‐dimensional orientations.     

A Three‐Minute Synthesis and Purification of Ibuprofen: Pushing the Limits of Continuous‐Flow Processing

In a total residence time of three minutes, ibuprofen was assembled from its elementary building blocks with an average yield of above 90 % for each step. A scale‐up of this five‐stage process (3 bond‐forming steps, one work‐up, and one in‐line liquid–liquid separation) provided ibuprofen at a rate of 8.09 g h^?1 (equivalent to 70.8 kg y^?1) using a system with an overall footprint of half the size of a standard laboratory fume hood. Aside from the high throughput, several other aspects of this synthesis expand the capabilities of continuous‐flow processing, including a Friedel–Crafts acylation run under neat conditions and promoted by AlCl₃, an exothermic in‐line quench of high concentrations of precipitation‐prone AlCl₃, liquid–liquid separations run at or above 200 psi to provide solvent‐free product, and the use of highly aggressive oxidants, such as iodine monochloride. The use of simple, inexpensive, and readily available reagents thus affords a practical synthesis of this important generic pharmaceutical.     

Total Synthesis of (+)‐Neomarinone

The first total synthesis of (+)‐neomarinone has been achieved by following a concise and convergent route using methyl (R)‐lactate and (R)‐3‐methylcyclohexanone as chiral building blocks. Key steps of the synthesis are the stereocontrolled formation of the two quaternary stereocenters by diastereoselective 1,4‐conjugate addition and enolate alkylation reactions, and the construction of the furanonaphthoquinone skeleton by regioselective Diels–Alder reaction between a 1,3‐bis(trimethylsilyloxy)‐1,3‐diene and a bromoquinone. The synthesis proves the relative and absolute stereochemistry of natural neomarinone.     

Facile Installation of 2‐Reverse Prenyl Functionality into Indoles by a Tandem N‐Alkylation–Aza‐Cope Rearrangement Reaction and Its Application in Synthesis

An unprecedented tandem N‐alkylation–ionic aza‐Cope (or Claisen) rearrangement–hydrolysis reaction of readily available indolyl bromides with enamines is described. Due to the complicated nature of the two processes, an operationally simple N‐alkylation and subsequent microwave‐irradiated ionic aza‐Cope rearrangement–hydrolysis process has been uncovered. The tandem reaction serves as a powerful approach to the preparation of synthetically and biologically important, but challenging, 2‐reverse quaternary‐centered prenylated indoles with high efficiency. Notably, unusual nonaromatic 3‐methylene‐2,3‐dihydro‐1H‐indole architectures, instead of aromatic indoles, are produced. Furthermore, the aza‐Cope rearrangement reaction proceeds highly regioselectively to give the quaternary‐centered reverse prenyl functionality, which often produces a mixture of two regioisomers by reported methods. The synthetic value of the resulting nonaromatic 3‐methylene‐2,3‐dihydro‐1H‐indole architectures has been demonstrated as versatile building blocks in the efficient synthesis of structurally diverse 2‐reverse prenylated indoles, such as indolines, indole‐fused sultams and lactams, and the natural product bruceolline D.     

The Biocatalytic Repertoire of Natural Biaryl Formation

The catalytic and selective construction of carbon–carbon bonds for the generation of complex molecules is one of the most important tasks in organic chemistry. This was clearly highlighted by the 2010 Nobel Prize in Chemistry, which was awarded for the development of Pd‐catalyzed cross‐coupling reactions. The underlying concept of cross‐linking building blocks to generate molecular complexity can also be widely found in natural product biosynthesis. Impressive examples for such natural cross‐coupling reactions are biosynthetic processes for the assembly of biaryl moieties in natural products—highly efficient enzymatic reactions that often achieve synthetically yet unmatched selectivities. This Minireview highlights selected examples that showcase these fascinating biotransformations.     

Nanorattles or Yolk–Shell Nanoparticles—What Are They,How Are They Made,and What Are They Good For?

The development of nanotechnology has led to the design of cutting‐edge nanomaterials with increasing levels of complexity. Although “traditional” solid, uniform nanoparticles are still the most frequently reported structures, new generations of nanoparticles have been constantly emerging over the last several decades. The outcome of this nano‐art extends beyond nanomaterials with alternative compositions and/or morphologies. The current state‐of‐the‐art allows for the design of nanostructures composed of different building blocks that exhibit diverse properties. Furthermore, those properties can be a reflection of either individual features, which are characteristic of a particular building block alone, and/or synergistic effects resulting from interactions between building blocks. Therefore, the unique structures as well as the outstanding properties of nanorattles have attracted increasing attention for possible biomedical and industrial applications. Although these nanoparticles resemble core–shell particles, they have a distinctive feature, which is a presence of a void that provides a homogenous environment for the encapsulated core. In this Review, we give a comprehensive insight into the fabrication of nanorattles. A special emphasis is put on the choice of building blocks as well as the choice of preparation method, because those two aspects further influence properties and thus possible future applications, which will also be discussed.     

In Situ Generation of Chiral N‐Dienyl Lactams in a Multicomponent Reaction: An Efficient and Highly Selective Way to Asymmetric Amidocyclohexenes

Chiral N‐dienyl lactams are crucial building blocks for the synthesis of complex organic compounds. However, their generation is rather challenging. This paper reports on a highly efficient and diastereoselective multicomponent methodology utilizing chiral a mides, a ldehydes, and d ienophiles (AAD reaction). The three components readily react under in situ generation of chiral N‐dienyl lactams which undergo a subsequent Diels–Alder reaction. Different chiral amides have been employed in the standard protocol delivering yields up to 94 %, and selectivities up to 90 % de. Moreover, DFT calculations were performed to explain the obtained selectivities.     

Internally Protected Amino Sugar Equivalents from Enantiopure 1,2‐Oxazines: Synthesis of Variably Configured Carbohydrates with C‐Branched Amino Sugar Units

A stereodivergent synthesis of differently configured C2‐branched 4‐amino sugar derivatives was accomplished. The Lewis acid mediated rearrangement of phenylthio‐substituted 1,2‐oxazines delivered glycosyl donor equivalents that can directly be employed in glycosidation reactions. Treatment with methanol provided internally protected amino sugar equivalents that have been transformed into the stereoisomeric methyl glycosides 28 , ent‐ 28 , 29 , ent‐ 29 and 34 in two simple reductive steps. Reaction with natural carbohydrates or bicyclic amino sugar precursors allowed the synthesis of homo‐oligomeric di‐ and trisaccharides 44 , 46 and 47 or a hybrid trisaccharide 51 with natural carbohydrates. Access to a bivalent amino sugar derivative 54 was accomplished by reaction of rearrangement product 10 with 1,5‐pentanediol. Alternatively, when a protected L ‐serine derivative was employed as glycosyl acceptor, the glycosylated amino acid 60 was efficiently prepared in few steps. In this report we describe the synthesis of unusual amino sugar building blocks from enantiopure 1,2‐oxazines that can be attached to natural carbohydrates or natural product aglycons to produce new natural product analogues with potential applications in medicinal chemistry.     

Three‐Component Reactions with (S)‐Methyl Pyroglutamate: An Efficient Way to Diversely Substituted Asymmetric Amidocyclohexenes

Chiral N‐dienyl lactams are crucial building blocks for the synthesis of complex organic compounds. However, their generation is rather challenging. This paper reports the novel one‐pot reaction of (S)‐methyl pyroglutamate as the a mide component with different a ldehydes and d ienophiles (AAD reaction) to give novel chiral 1‐amido‐2‐cyclohexenes. The corresponding N‐dienyl lactams generated in situ undergo subsequent Diels–Alder reactions in good yield and diastereoselectivity. The scope and limitations of the three‐component protocol were investigated. X‐ray and NMR spectroscopic analysis of the products as well as DFT calculations of the intermediates were also performed to explain the observed stereoselectivity and structural features.     

Multistep Continuous‐Flow Synthesis in Medicinal Chemistry: Discovery and Preliminary Structure–Activity Relationships of CCR8 Ligands

A three‐step continuous‐flow synthesis system and its application to the assembly of a new series of chemokine receptor ligands directly from commercial building blocks is reported. No scavenger columns or solvent switches are necessary to recover the desired test compounds, which were obtained in overall yields of 49–94 %. The system is modular and flexible, and the individual steps of the sequence can be interchanged with similar outcome, extending the scope of the chemistry. Biological evaluation confirmed activity on the chemokine CCR8 receptor and provided initial structure–activity‐relationship (SAR) information for this new ligand series, with the most potent member displaying full agonist activity with single‐digit nanomolar potency. To the best of our knowledge, this represents the first published example of efficient use of multistep flow synthesis combined with biological testing and SAR studies in medicinal chemistry.     

The Biosynthesis of the Benzoxazole in Nataxazole Proceeds via an Unstable Ester and has Synthetic Utility

Heterocycles, a class of molecules that includes oxazoles, constitute one of the most common building blocks in current pharmaceuticals and are common in medicinally important natural products. The antitumor natural product nataxazole is a model for a large class of benzoxazole‐containing molecules that are made by a pathway that is not characterized. We report structural, biochemical, and chemical evidence that benzoxazole biosynthesis proceeds through an ester generated by an ATP‐dependent adenylating enzyme. The ester rearranges via a tetrahedral hemiorthoamide to yield an amide, which is a shunt product and not, as previously thought, an intermediate in the pathway. A second zinc‐dependent enzyme catalyzes the formation of hemiorthoamide from the ester but, by shuttling protons, the enzyme eliminates water, a reverse hydrolysis reaction, to yield the benzoxazole and avoids the amide. These insights have allowed us to harness the pathway to synthesize a series of novel halogenated benzoxazoles.     

Base‐Catalyzed Tandem Michael/Dehydro‐Diels–Alder Reaction of α,α‐Dicyanoolefins with Electron‐Deficient 1,3‐Conjugated Enynes: A Facile Entry to Angularly Fused Polycycles

Angularly fused carbocyclic frameworks and their heteroatom‐substituted analogues exist in many natural products that display a broad and interesting range of biological activities. Preparation of polycyclic products by cycloaddition reactions have been the long‐standing hot topic in the synthetic community. Dehydro‐Diels–Alder (DDA) reactions are one class of dehydropericyclic reactions that are derived conceptually by systematic removal of hydrogen atom pairs. A base‐promoted tandem Michael addition and DDA reaction of α,α‐dicyanoolefins with electron‐deficient 1,3‐conjugated enynes was realized in which a DDA reaction takes place between the arylalkynes and electron‐deficient tetrasubstituted olefin. The control experiments support the stepwise anionic reaction pathway rather than the concerted reaction pathway.