A three-step four reactions innovative asymmetric synthesis of popular antiplatelet drug (S)-clopidogrel, marketed as Plavix, has been developed. The telescoped approach relies on the use of a sole organocatalyst, commercially available reagents and a single solvent. Fine optimization of the reaction conditions enabled isolation of the drug in 61 % overall yield and 62 % ee.

Abstract

A first catalytic preparation of the popular antiplatelet drug (S)-clopidogrel, known with the tradename of Plavix, has been developed in a one-pot and innovative approach. The synthesis can be performed using commercially available ortho-chlorobenzaldehyde, 1-naphthylsulfonyl acetonitrile, tert-butyl hydroperoxide (TBHP), 4,5,6,7-tetrahydrothieno[3,2-c]pyridine and 20 mol % of a quinidine derived organocatalyst in a single solvent. A Knoevenagel/asymmetric epoxidation/domino ring-opening esterification (DROE) sequence enabled to obtain (S)-clopidogrel in 61 % overall yield and 62 % ee. Fine optimization of the reaction conditions proved to be crucial to set up a selective and efficient process.

Perfumery has evolved from a handcraft activity, marking supreme aristocratic luxury in the Renaissance, to a global industry powering scent experiences for present-day consumers through the use of a myriad of consumer packaged goods. This contribution reviews major breakthroughs in the field, including landmark fragrance ingredients, technological advances in scent delivery, and key innovations in consumer products which created the demand for scientific and technological advancements in the scent domain. These innovations are presented chronologically, relying solely on information drawn from public written sources, spanning a time period of 150 years (1870-2020). We hope with this contribution to generate interest in the readership for this fascinating field, while celebrating 150 years of innovation for scented mass-market products..

A palladium catalyzed decarboxylative [4+2] cycloaddition of vinyl benzoxazinanones with 1,3-indanedione was developed, affording a series of biologically potential spiro-tetrahydroquinolines. Gram-scale synthesis and product elaboration demonstrated the utility of this method. The product demonstrated exhibited potency in inhibiting MDA-MB-231 cell line.

Abstract

A palladium catalyzed decarboxylative [4+2] cycloaddition of vinyl benzoxazinanones with 2-arylidene indan-1,3-dione has been established, which afford a series of bioactive spiro-tetrahydroquinolines (27 examples) in moderate to good yield (up to 87 %) with high diastereoselectivities. The synthetic utility of this reaction was demonstrated by gram-scale synthesis. Compounds synthesized by this method potently inhibited proliferation in a panel of cancer cell lines. Particularly, the most potent compounds 3 ae, 3 ah, 3 aj and 3 fa displayed selective inhibition of MDA-MB-231 breast carcinoma cells with IC₅₀ values of 1.292, 0.6118, 0.6558, 1.656 and 2.215 μM, respectively.

Imidates are important organic intermediates used in several synthetic transformations towards N-heterocycles, natural products and metal complexes with a potential catalytic effect. Herein, the recent synthetic approaches and diverse applications of imidates were categorized and summarized. A wide range of organic compounds, mainly nitriles, isocyanides, amides, imines, and alkynes are used as starting materials. This review also summarizes the latest synthetic approaches to imidates that have been developed the recent years and some of their significant applications in the field of organic synthesis.

Abstract

Recent synthetic approaches and diverse applications of imidates are presented in this review. These motifs are successfully used as intermediates in organic transformations, such as the synthesis of N-heterocycles, natural products and metal complexes with a potential catalytic effect. Consequently, many attempts have been made for the development of efficient and facile synthetic methods of imidates in the past few years, as a continuum of previous paths. A wide range of organic compounds can be used as starting materials for these syntheses, including nitriles, isocyanides, amides etc. which through simple and flexible processes are converted to the desired imidates. Herein, an exploration of the recent synthetic routes of imidates and their diverse applications in organic transformations has been categorized and summarized.

1,3,4-Trisubstituted 1,2,3-triazolium salts having either aliphatic or benzylic substituents at the N-1 and N-3 positions were synthesized in two steps involving: i) copper(I) catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC), and ii)N-alkylation of the 1,2,3-triazole intermediates. Trans-N-alkylation reactions in bulk and in the presence of excess methyl iodide were monitored by 1H NMR spectroscopy for each 1,2,3-triazolium molecular model. By assigning the different formed species and their respective evolution with time, it was possible to conclude that trans-N-alkylation exchange reactions are significantly faster for benzylic substituents than for aliphatic ones. Furthermore, the exchange reactions are noticeably faster at the N-3 position than at the N-1 position most likely due to the steric hindrance induced by the neighboring C-4 substituent. The kinetics of trans-N-alkylation reactions are thus influenced by both the chemical nature of the N-1 and N-3 substituents and the regiochemistry of the 1,2,3-triazolium group. This provides important structural design rules to improve the properties of thermosetting covalent adaptable networks involving trans-N-alkylation of 1,2,3-triazolium salts.

A comprehensive study of the preparation and reactivity of N-tert-butanesulfinyl glycosylamines with simple Grignard and organo lithium reagents is reported. As they readily react as latent imine equivalents with a variety of carbon nucleophiles in batch and continuous flow chemistry, these carbohydrate derivatives constitute very useful precursors for the diastereoselective synthesis of bioactive compounds such as iminosugar-C-glycosides.

Abstract

A comprehensive study of the preparation and reactivity of N-tert-butanesulfinyl glycosylamines with simple Grignard and organo lithium reagents in batch vs. continuous flow chemistry is reported. As they readily react as latent imine equivalents with a variety of carbon nucleophiles, these carbohydrate derivatives constitute very useful precursors for the diastereoselective synthesis of bioactive compounds such as iminosugar-C-glycosides. A hybrid protocol, involving the addition of benzylmagnesium chloride to a (S _R )-arabinofuranosylamine substrate in flow, at room temperature, combined with a cyclization protocol in batch is also described for the first time. Of note, this semi-continuous flow process shortens the synthesis of imino-C-glycoside scaffolds to a single workday.

Herein, the development of a Cu(OTf)₂ catalysed chemoselective amination of alcohols using heterocyclic thiones is described. Notably, the method is additive, ligand or inert atmosphere free and shows good tolerance towards variety of alcohols and thiotetrazole derivatives affording good to excellent yields of the product.

Abstract

Herein,a protocol for the chemoselective formation of C−N bond using Cu(OTf)₂ as catalyst has been described using heterocyclic thiones. The reaction occurs preferentially at the nitrogen centre over the sulphur atom leading to C−N bond formation. Water being the only by-product, the reaction is environmentally friendly. The reaction proceeds without any additive, ligand or inert atmosphere and shows good tolerance towards variety of alcohols and thiotetrazole derivatives. Our developed protocol could be scaled up to gram scale efficiently, which highlights the efficacy of this method and might offer potential application in synthetic industry.

This review is devoted to the heterocyclization of C,N-diarylformamidines and covers publications from 1999 to 2022. The comprehensive information collected enables other researchers to quickly understand the possibility of constructing various complex heterocycles from simple, readily available reagents.

Abstract

Obtaining highly functionalized heterocyclic structures is an important topic of modern organic synthesis, as it reveals the possibility of constructing more complex systems and therefore, expanding the range of various drugs. Aiming at synthesizing complex molecules from simple and readily available reagents, the modification of C,N-diarylformamidines, well known in medicinal chemistry, is of great interest. This article reviews comprehensively the field of C,N-diarylformamidine chemistry and covers publications on this topic from 1999 to 2022.

A novel PPh₃-mediated nucleophilic sulfonation of sulfonyl chlorides with arynes has been demonstrated. This protocol exhibits broad functional group tolerance and provides a direct approach to a variety of aryl and alkyl sulfones.

Abstract

Sulfonyl chlorides are a class of cheap and readily available basic chemicals, which have routinely served as electrophilic reagents in their chemical transformations. Herein, we disclose a novel PPh₃-mediated nucleophilic sulfonation method of sulfonyl chlorides with arynes. Different from the classical P(III)-mediated reductive deoxygenation reaction of sulfonyl chlorides, the valence state of the sulfur atom has not been changed. This protocol exhibits broad functional group tolerance and provides a direct approach to a variety of aryl and alkyl sulfones.

The binding recognition of two structurally constrained sialyl derivatives by Siglec-7was investigated. The flexibility of Siglec-7 loops allowed the preferred accommodation of the more rigid compound containing a biphenyl moiety. Our results set the basis for the design and development of novel compounds as potential modulators for Siglec-7.

Abstract

We investigated two recently synthesized and characterized sialyl derivatives, bearing the Neu5Ac-α-(2-6)-Gal epitope, as promising binders for Siglec-7, an inhibitory Siglec mainly found on natural killer cells. A variety of sialoglycan structures can be recognized by Siglec-7 with implications in the modulation of immune responses. Notably, overexpression of sialylated glycans recognized by Siglec-7 can be associated with the progression of several tumors, including melanoma and renal cell carcinoma. NOE-based NMR techniques, including Saturation Transfer Difference and transferred-NOESY NMR, together with molecular docking and dynamic simulations were combined to shed light on the molecular basis of Siglec-7 recognition of two conformationally constrained Sialyl-Tn antigen analogs. We, therefore, identify the ligands epitope mapping and their conformational features and propose 3D models accurately describing the protein-ligand complexes. We found that the binding site of Siglec-7 can accommodate both synthetic analogs, with the sialic acid mainly involved in the interaction. Moreover, the flexibility of Siglec-7 loops allows a preferred accommodation of the more rigid compound bearing a biphenyl moiety at position 9 of the sialic acid that contributed to the interaction to a large extent. Our findings provided insights for developing potential novel high affinity ligands for Siglec-7 to hinder tumor evasion.