Bicyclic Skeleton Research Articles

Catalytic Asymmetric Synthesis of the anti‐COVID‐19 Drug Remdesivir

AbstractThe catalytic asymmetric synthesis of the anti‐COVID‐19 drug Remdesivir has been realized by the coupling of the P‐racemic phosphoryl chloride with protected nucleoside GS441524. The chiral bicyclic imidazole catalyst used is crucial for the dynamic kinetic asymmetric transformation (DyKAT) to proceed smoothly with high reactivity and excellent stereoselectivity (96 % conv., 22:1 SP:RP). Mechanistic studies showed that this DyKAT is a first‐order visual kinetic reaction dependent on the catalyst concentration. The unique chiral bicyclic imidazole skeleton and carbamate substituent of the catalyst are both required for the racemization process, involving the phosphoryl chloride, and subsequent stereodiscriminating step. A 10 gram scale reaction was also conducted with comparably excellent results, showing its potential for industrial application.

Catalytic Asymmetric Synthesis of the anti-COVID-19 Drug Remdesivir.

The catalytic asymmetric synthesis of the anti-COVID-19 drug Remdesivir has been realized by the coupling of the P-racemic phosphoryl chloride with protected nucleoside GS441524. The chiral bicyclic imidazole catalyst used is crucial for the dynamic kinetic asymmetric transformation (DyKAT) to proceed smoothly with high reactivity and excellent stereoselectivity (96 % conv., 22:1 SP :RP ). Mechanistic studies showed that this DyKAT is a first-order visual kinetic reaction dependent on the catalyst concentration. The unique chiral bicyclic imidazole skeleton and carbamate substituent of the catalyst are both required for the racemization process, involving the phosphoryl chloride, and subsequent stereodiscriminating step. A 10 gram scale reaction was also conducted with comparably excellent results, showing its potential for industrial application.

Criteria for intradermal skin testing and oral challenge in patients labeled as fluoroquinolone allergic

Allergy to fluoroquinolones (FQs) is the most frequently reported non–beta-lactam antibiotic allergy.1 The basic FQ structure is a bicyclic skeleton and can be classified by generation, with later generations correlating with broader gram-positive and anaerobic antimicrobial spectrum in particular.1 Interpretation of hypersensitivity reactions to FQs is likely complicated by non–IgE-mediated reactions because all FQs are small-molecule ligands for the mast cell G-protein–coupled receptor MRGPRX2 and have been shown to lead to direct mast cell activation in both in vitro models with the human MRGPRX2 receptor and murine models.

Synthetic studies on pseudolaric acid B: Enantioselective synthesis of C4,C10-di-epi-trans-fused [5-7]-bicyclic skeleton

Studies on the synthesis of antifungal and anticancer natural product, pseudolaric acid B, have led to the enantioselective synthesis of di-epi-trans-fused [5–7]-bicyclic core skeleton. The synthesis was achieved in 10 linear steps, which features the Sharpless asymmetric epoxidation, cyanide-opening reaction of epoxide, and intramolecular [5 + 2] cycloaddition reaction as the key transformations. The stereochemistry was determined by the X-ray crystallographic analysis.

Tetrahydroimidazo[1,2‐a]pyrazine Derivatives: Synthesis and Evaluation as Gαq‐Protein Ligands

The 5,6,7,8‐tetrahydroimidazo[1,2‐a]pyrazine derivative BIM‐46174 and its dimeric form BIM‐46187 (1) are heterocyclized dipeptides that belong to the very few cell‐permeable compounds known to preferentially silence Gαq proteins. To explore the chemical space of Gαq inhibitors of the BIM chemotype, a combinatorial approach was conducted towards a library of BIM molecules. This library was evaluated in a second messenger‐based fluorescence assay to analyze the activity of Gαq proteins through the determination of intracellular myo‐inositol 1‐phosphate. Structure–activity relationships were deduced and structural requirements for biological activity obtained, which were (i) a redox reactive thiol/disulfane substructure, (ii) an N‐terminal basic amino group, (iii) a cyclohexylalanine moiety, and (iv) a bicyclic skeleton. Active compounds exhibited cellular toxicity, which was investigated in detail for the prototypical inhibitor 1. This compound affects the structural cytoskeletal dynamics in a Gαq/11‐independent manner.

Discovery of DS34942424: An orally potent analgesic without mu opioid receptor agonist activity

We identified (5′S)-10′-fluoro-6′-methyl-5′,6′-dihydro-3′H-spiro[cyclopropane-1,4′-[2,6]diaza[2,5]methano[2,6]benzodiazonin]-7′(1′H)-one, 22b (DS34942424) with a unique and original bicyclic skeleton. 22b showed an orally potent analgesic in the acetic acid-induced writhing test and formalin test in ddY mice without sedation. Moreover, 22b did not exhibit mu opioid receptor agonist activity.

Total Synthesis of Epilupinine: Synthetic Strategy of Fused Bicyclic Skeleton Containing Nitrogen

The total synthesis of polycyclic natural products is often characterized by methods for constructing fused ring systems, in which there are many examples such as stepwise synthesis, cascade cyclization, rearrangement of spirocycles, and so on. In this highlight review, we focus on the total synthesis of epilupinine as the simplest natural product with a fused ring system. Due to the simple fused ring system, total synthesis of epilupinine has been attempted by various different approaches, and various methods for constructing the octahydro-2H-quinolizine (quinolizidine) skeleton have been developed.

A Vinyl Cyclopropane Ring Expansion and Iridium‐Catalyzed Hydrogen Borrowing Cascade

AbstractA vinyl cyclopropane rearrangement embedded in an iridium‐catalyzed hydrogen borrowing reaction enabled the formation of substituted stereo‐defined cyclopentanes from Ph* methyl ketone and cyclopropyl alcohols. Mechanistic studies provide evidence for the ring‐expansion reaction being the result of a cascade based on oxidation of the cyclopropyl alcohols, followed by aldol condensation with the pentamethyl phenyl‐substituted ketone to form an enone containing the vinyl cyclopropane. Subsequent single electron transfer (SET) to this system initiates a rearrangement, and the catalytic cycle is completed by reduction of the new enone. This process allows for the efficient formation of diversely substituted cyclopentanes as well as the construction of complex bicyclic carbon skeletons containing up to four contiguous stereocentres, all with high diastereoselectivity.

A Vinyl Cyclopropane Ring Expansion and Iridium-Catalyzed Hydrogen Borrowing Cascade.

A vinyl cyclopropane rearrangement embedded in an iridium‐catalyzed hydrogen borrowing reaction enabled the formation of substituted stereo‐defined cyclopentanes from Ph* methyl ketone and cyclopropyl alcohols. Mechanistic studies provide evidence for the ring‐expansion reaction being the result of a cascade based on oxidation of the cyclopropyl alcohols, followed by aldol condensation with the pentamethyl phenyl‐substituted ketone to form an enone containing the vinyl cyclopropane. Subsequent single electron transfer (SET) to this system initiates a rearrangement, and the catalytic cycle is completed by reduction of the new enone. This process allows for the efficient formation of diversely substituted cyclopentanes as well as the construction of complex bicyclic carbon skeletons containing up to four contiguous stereocentres, all with high diastereoselectivity.

Progress toward the assembly of the bicyclic theonellamide skeleton

An orthogonally protected τ-histidinoalanine residue was synthesized via regioselective alkylation of optically pure Boc-l-His-OTCE (TCE = trichloroethyl) with a sulfamidate electrophile derived from Fmoc-d-Ser-OBn. The goal was the synthesis of a non-natural theonellamide, invoking readily accessible variants of the other 10 amino acids. Peptide fragments corresponding to the east and west rings of “theonellamide X″ were synthesized in solution. Each ring was formed independently, providing insights into protecting group limitations, side reactions, and the optimal order of events to approach the formation of the bicyclic system. Ultimately, an undecapeptide was prepared, with the eastern ring formed. The twelfth amino acid, an l-α-aminoadipic acid building block, was prepared and preliminary investigations into its attachment to the undecapeptide are reported.

Controllable Si−C Bond Activation Enables Stereocontrol in the Palladium‐Catalyzed [4+2] Annulation of Cyclopropenes with Benzosilacyclobutanes

AbstractA novel and unusual palladium‐catalyzed [4+2] annulation of cyclopropenes with benzosilacyclobutanes is reported. This reaction occurred through chemoselective Si−C(sp2) bond activation in synergy with ring expansion/insertion of cyclopropenes to form new C(sp2)−C(sp3) and Si−C(sp3) bonds. An array of previously elusive bicyclic skeleton with high strain, silabicyclo[4.1.0]heptanes, were formed in good yields with excellent diastereoselectivity under mild conditions. An asymmetric version of the reaction with a chiral phosphoramidite ligand furnished a variety of chiral bicyclic silaheterocycle derivatives with good enantioselectivity (up to 95.5:4.5 er). Owing to the mild reaction conditions, the good stereoselectivity profile, and the ready availability of the functionalized precursors, this process constitutes a useful and straightforward strategy for the synthesis of densely functionalized silacycles.

Controllable Si-C Bond Activation Enables Stereocontrol in the Palladium-Catalyzed [4+2] Annulation of Cyclopropenes with Benzosilacyclobutanes.

A novel and unusual palladium-catalyzed [4+2] annulation of cyclopropenes with benzosilacyclobutanes is reported. This reaction occurred through chemoselective Si-C(sp2 ) bond activation in synergy with ring expansion/insertion of cyclopropenes to form new C(sp2 )-C(sp3 ) and Si-C(sp3 ) bonds. An array of previously elusive bicyclic skeleton with high strain, silabicyclo[4.1.0]heptanes, were formed in good yields with excellent diastereoselectivity under mild conditions. An asymmetric version of the reaction with a chiral phosphoramidite ligand furnished a variety of chiral bicyclic silaheterocycle derivatives with good enantioselectivity (up to 95.5:4.5 er). Owing to the mild reaction conditions, the good stereoselectivity profile, and the ready availability of the functionalized precursors, this process constitutes a useful and straightforward strategy for the synthesis of densely functionalized silacycles.

Palladium-Catalyzed Cascade Cyclization/Alkynylation Reactions.

Palladium-catalyzed cascade cyclization reactions have witnessed significant improvements in recent years. Among them, palladium-catalyzed cascade cyclization/alkynylation are especially attractive, which can assemble structurally diverse monocyclic, bicyclic, fused polycyclic, and spirocyclic skeletons with excellent chemoselectivities. In this Minireview, palladium-catalyzed cascade cyclization/alkynylation have been summarized and discussed in detail with focus on oxypalladation and aminopalladation-initiated cascade cyclization, intramolecular Heck-type cascade cyclization, carbocyclizations, cascade cyclizations, and other types of cascade cyclization reactions. Some significant and representative synthetic methodologies and their synthetic applications and reaction mechanisms have also been described.

Recent Studies of (+)-3-Carene Transformations with the Retention of the Native Framework

(PDF) Graphical Abstract: This review presents last decade and some past especially relevant studies in the field of (+)-3-carene synthetic transformations. This paper discusses exclusively the transformations of (+)-3-carene, proceeding with the retention of the native bicyclic carbon skeleton. The data concerning the features of epoxidation and oxidation reactions of (+)-3-carene, the synthesis of sulphur- and selenium-containing derivatives and their use in asymmetric synthesis are given. It also describes methods for producing amino derivatives of (+)-3-carene, substituted heterocycles based on it, reactions for the preparation of aziridines, azido-alcohols and azidoamines, as well as chiral phosphites as bidentate ligands.

Discovery of a novel bicyclic compound, DS54360155, as an orally potent analgesic without mu-opioid receptor agonist activity.

We synthesized derivatives of a natural alkaloid, conolidine, and evaluated these derivatives in the acetic acid-induced writhing test and formalin test in ddY mice after oral administration. As a result, we identified (5S)-6-methyl-1,3,4,5,6,8-hexahydro-7H-2,5-methano[1,5]diazonino[7,8-b]indol-7-one sulfate salt, 15a (DS54360155), with a unique and original bicyclic skeleton, as an analgesic more potent than conolidine. Moreover, 15a did not exhibit mu-opioid receptor agonist activity.

Copper‐Catalyzed Asymmetric Borylative Cyclization of Cyclohexadienone‐Containing 1,6‐Dienes

AbstractDue to the low reactivity of 1,6‐dienes and the challenge of selectively differentiating such two olefins, the development of metal‐catalyzed asymmetric cyclization of 1,6‐dienes remains largely underdeveloped. Herein, we describe the first copper(I)‐catalyzed asymmetric borylative cyclization of cyclohexadienone‐tethered terminal alkenes (1,6‐dienes) via a tandem process: the regioselective borocupration of the electron‐rich terminal alkene and subsequent conjugate addition of stereospecific secondary alkyl‐copper(I) to the electron‐deficient cyclohexadienone, affording enantioenriched bicyclic skeletons bearing three contiguous stereocenters in all cis‐form. Meanwhile, this mild catalytic protocol is generally compatible with a wide range of functional groups, which allows further facile conversion of the cyclization products.magnified image

Preparation of Bicyclic Ketal Skeletons with Aldehyde and α-Ketone Acid through Cascade Friedel–Crafts Reaction and Stereoselective Acetalization in One Pot

Bicyclic ketal skeletons are important structure fragments that are frequently contained in natural products. A novel tandem Friedel–Crafts reaction and subsequent stereoselective acetalization were developed with readily available aldehyde and ketone acid. The reaction proceeded smoothly in the presence of catalytic Brønsted acid and afforded the corresponding product with moderate yield and high stereoselectivity.

Synthetic studies towards daphniyunnine B: Construction of AC bicyclic skeleton with two vicinal all carbon quaternary stereocenters

The AC bicyclic skeleton of daphniyunnine B with the required 3 stereocenters (C4, C5 and C8) was accomplished in a concise route which featured two Claisen-type rearrangement reactions to construct the required vicinal all carbon quaternary stereocenters (C5 and C8) and an intramolecular iodo-cyclization reaction to assemble the cis-confused bicyclic lactam.

Discovery of conolidine derivative DS39201083 as a potent novel analgesic without mu opioid agonist activity.

We discovered a novel compound, 5-methyl-1,4,5,7-tetrahydro-2,5-ethanoazocino[4,3-b]indol-6(3H)-one sulfuric acid salt (DS39201083), which was formed by derivatization of a natural product, conolidine. DS39201083 had a unique bicyclic skeleton and was a more potent analgesic than conolidine, as revealed in the acetic acid-induced writhing test and formalin test in ddY mice. The compound showed no agonist activity at the mu opioid receptor.

Crystal structures of three cyclohexane-based \u03b3-spirolactams: determination of configurations and conformations

The title compounds, 2-azaspiro[4.5]deca-1-one, C9H15NO, (1a), cis-8-methyl-2-azaspiro[4.5]deca-1-one, C10H17NO, (1b), and trans-8-methyl-2-azaspiro[4.5]deca-1-one, C10H17NO, (1c), were synthesized from benzoic acids 2 in only 3 steps in high yields. Crystallization from n-hexane afforded single crystals, suitable for X-ray diffraction. Thus, the configurations, conformations, and interesting crystal packing effects have been determined unequivocally. The bicyclic skeleton consists of a lactam ring, attached by a spiro junction to a cyclohexane ring. The lactam ring adopts an envelope conformation and the cyclohexane ring has a chair conformation. The main difference between compound 1b and compound 1c is the position of the carbonyl group on the 2-pyrrolidine ring with respect to the methyl group on the 8-position of the cyclohexane ring, which is cis (1b) or trans (1c). A remarkable feature of all three compounds is the existence of a mirror plane within the molecule. Given that all compounds crystallize in centrosymmetric space groups, the packing always contains interesting enantiomer-like pairs. Finally, the structures are stabilized by intermolecular N–H···O hydrogen bonds.