Mild Debenzylation of Aryl
Benzyl Ether with BCl<sub>3</sub> in the Presence of Pentamethylbenzene
as a Non-Lewis-Basic Cation Scavenger

Okano, Kentaro; Okuyama, Kei Ichiro; Fukuyama, Tohru; Tokuyama, Hidetoshi

doi:10.1055/s-2008-1077980

Cited by 34 publications

(16 citation statements)

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Section: Resultsmentioning

confidence: 99%

“…In other words, the deprotection at the 3-position and the protection of the 6-position were conducted simultaneously in the presence of meta -cresol in TFA to give the corresponding compound 29 (step p). Interestingly, an excess amount of meta -cresol also played a role in capturing the tert -butyl cation derived from the deprotection, and unexpected side-reactions could be prevented. , …”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, an excess amount of meta-cresol also played a role in capturing the tert-butyl cation derived from the deprotection, and unexpected side-reactions could be prevented. 36,37 Since the target compound 29 had better stability, the appropriate workup conditions for the removal of TFA were examined again. Aqueous sodium acetate (NaOAc) could neutralize TFA, and target compound 29 was crystallized directly from the reaction medium without an extraction procedure.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Development of a Manufacturing Process toward the Convergent Synthesis of the COVID-19 Antiviral Ensitrelvir

et al. 2023

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We describe the development of the practical manufacturing of Ensitrelvir, which was discovered as a SARS-CoV-2 antiviral candidate. Scalable synthetic methods of indazole, 1,2,4-triazole and 1,3,5-triazinone structures were established, and convergent couplings of these fragments enabled the development of a concise and efficient scale-up process to Ensitrelvir. In this process, introducing a meta -cresolyl moiety successfully enhanced the stability of intermediates. Compared to the initial route at the early research and development stage, the overall yield of the longest linear sequence (6 steps) was improved by approximately 7-fold. Furthermore, 9 out of the 12 isolated intermediates were crystallized directly from each reaction mixture without any extractive workup (direct isolation). This led to an efficient and environmentally friendly manufacturing process that minimizes waste of organic solvents, reagents, and processing time. This practical process for manufacturing Ensitrelvir should contribute to protection against COVID-19.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

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Development of a Manufacturing Process toward the Convergent Synthesis of the COVID-19 Antiviral Ensitrelvir

et al. 2023

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“…A BCl 3 -mediated O -debenzylation of the pyridine derivative 3a afforded the O -unprotected analog 5a in moderate yield ( Table 2 , i ). This reaction was repeated in the presence of the cation scavenger pentamethylbenzene [ 54 ] ( ii ) to afford compound 5a in excellent yield.…”

Section: Resultsmentioning

confidence: 99%

Half-Sandwich Type Platinum-Group Metal Complexes of C-Glucosaminyl Azines: Synthesis and Antineoplastic and Antimicrobial Activities

et al. 2023

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While platinum-based compounds such as cisplatin form the backbone of chemotherapy, the use of these compounds is limited by resistance and toxicity, driving the development of novel complexes with cytostatic properties. In this study, we synthesized a set of half-sandwich complexes of platinum-group metal ions (Ru(II), Os(II), Ir(III) and Rh(III)) with an N,N-bidentate ligand comprising a C-glucosaminyl group and a heterocycle, such as pyridine, pyridazine, pyrimidine, pyrazine or quinoline. The sugar-containing ligands themselves are unknown compounds and were obtained by nucleophilic additions of lithiated heterocycles to O-perbenzylated 2-nitro-glucal. Reduction of the adducts and, where necessary, subsequent protecting group manipulations furnished the above C-glucosaminyl heterocycles in their O-perbenzylated, O-perbenzoylated and O-unprotected forms. The derived complexes were tested on A2780 ovarian cancer cells. Pyridine, pyrazine and pyridazine-containing complexes proved to be cytostatic and cytotoxic on A2780 cells, while pyrimidine and quinoline derivatives were inactive. The best complexes contained pyridine as the heterocycle. The metal ion with polyhapto arene/arenyl moiety also impacted on the biological activity of the complexes. Ruthenium complexes with p-cymene and iridium complexes with Cp* had the best performance in ovarian cancer cells, followed by osmium complexes with p-cymene and rhodium complexes with Cp*. Finally, the chemical nature of the protective groups on the hydroxyl groups of the carbohydrate moiety were also key determinants of bioactivity; in particular, O-benzyl groups were superior to O-benzoyl groups. The IC50 values of the complexes were in the low micromolar range, and, importantly, the complexes were less active against primary, untransformed human dermal fibroblasts; however, the anticipated therapeutic window is narrow. The bioactive complexes exerted cytostasis on a set of carcinomas such as cell models of glioblastoma, as well as breast and pancreatic cancers. Furthermore, the same complexes exhibited bacteriostatic properties against multiresistant Gram-positive Staphylococcus aureus and Enterococcus clinical isolates in the low micromolar range.

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“…First, Friedel-Crafts alkylation using bromide 125 and AgOTf as an activating agent attached the methyl p-anisylacetate unit 51) (Chart 23). The pyrrolo[2,3-c] carbazole derivative 128 was then constructed in three steps comprising palladium-catalyzed pinacolborylation, Suzuki-Miyaura coupling 52,53) with 126 to incorporate the azidephenyl group, and subsequent intramolecular C-H insertion of a nitrene species generated from azide 127 under heating. The total synthesis of dictyodendrin A (107) was completed by using a modification of Fürstner's protocol.…”

Section: Application To the Total Synthesis Of Dictyodendrinsmentioning

confidence: 99%

Construction of <i>N</i>-Heterocycles Fused with a Highly Substituted Benzene Ring by a Benzyne-Mediated Cyclization/Functionalization Cascade Reaction and Its Application to the Total Synthesis of Marine Natural Products

Tokuyama

2021

Chem. Pharm. Bull.

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This account summarizes the development of a benzyne-mediated cyclization/functionalization protocol for the versatile construction of highly substituted benzene derivatives fused with an N-heterocyclic ring such as indolines, indoles, and related nitrogen-containing heterocycles. The protocol comprises sequential reactions initiated by generating a benzyne species and subsequent cyclization via addition of magnesium amide to the benzyne, followed by trapping of the resultant magnesium compound in situ with various electrophiles. The substituent scope was expanded by conducting a transmetalation on a copper species to introduce alkyl, aryl, and alkenyl substituents. The utility of the sequential reaction was demonstrated in the synthesis of a carbazole natural product (heptaphylline), pyrrolo[4,3,2-de]quinoline alkaloids (batzellines), and pyrrolo[2,3-c]carbazole alkaloids (dictyodendrines).

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Mild Debenzylation of Aryl Benzyl Ether with BCl₃ in the Presence of Pentamethylbenzene as a Non-Lewis-Basic Cation Scavenger

Cited by 34 publications

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Development of a Manufacturing Process toward the Convergent Synthesis of the COVID-19 Antiviral Ensitrelvir

Development of a Manufacturing Process toward the Convergent Synthesis of the COVID-19 Antiviral Ensitrelvir

Half-Sandwich Type Platinum-Group Metal Complexes of C-Glucosaminyl Azines: Synthesis and Antineoplastic and Antimicrobial Activities

Construction of <i>N</i>-Heterocycles Fused with a Highly Substituted Benzene Ring by a Benzyne-Mediated Cyclization/Functionalization Cascade Reaction and Its Application to the Total Synthesis of Marine Natural Products

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Mild Debenzylation of Aryl Benzyl Ether with BCl3 in the Presence of Pentamethylbenzene as a Non-Lewis-Basic Cation Scavenger

Cited by 34 publications

References 0 publications

Development of a Manufacturing Process toward the Convergent Synthesis of the COVID-19 Antiviral Ensitrelvir

Development of a Manufacturing Process toward the Convergent Synthesis of the COVID-19 Antiviral Ensitrelvir

Half-Sandwich Type Platinum-Group Metal Complexes of C-Glucosaminyl Azines: Synthesis and Antineoplastic and Antimicrobial Activities

Construction of <i>N</i>-Heterocycles Fused with a Highly Substituted Benzene Ring by a Benzyne-Mediated Cyclization/Functionalization Cascade Reaction and Its Application to the Total Synthesis of Marine Natural Products

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Mild Debenzylation of Aryl Benzyl Ether with BCl₃ in the Presence of Pentamethylbenzene as a Non-Lewis-Basic Cation Scavenger