RESUMO
Baloxavir marboxil (1; BXM) is a potent drug used for treating influenza infections. The current synthetic route to BXM (1) is based on optical resolution; however, this method results in the loss of nearly 50% of the material. This study aimed to describe an efficient and simpler method for the synthesis of BXM. We achieved a stereoselective synthesis of BXM (1). The tricyclic triazinanone core possessing a chiral center was prepared via diastereoselective cyclization utilizing the readily available amino acid l-serine. The carboxyl moiety derived from l-serine was removed via photoredox decarboxylation under mild conditions to furnish the chiral tricyclic triazinanone core ((R)-14). The synthetic route demonstrated herein provides an efficient and atomically economical method for preparing this potent anti-influenza agent.
Assuntos
Dibenzotiepinas , Serina , Estereoisomerismo , Ciclização , Serina/química , Estrutura Molecular , Dibenzotiepinas/química , Dibenzotiepinas/síntese química , Triazinas/química , Triazinas/síntese química , Oxirredução , Descarboxilação , Morfolinas/química , Morfolinas/síntese química , Piridonas/química , Piridonas/síntese química , Processos Fotoquímicos , Antivirais/síntese química , Antivirais/químicaRESUMO
A highly efficient and versatile method for the synthesis of various sphingolipids, such as sphingomyelin, ceramide, sphingosine, sphingosine 1-phosphate, and functionalized sphingosine derivatives, was established by two types of combinations of the olefin cross metathesis reaction. One reaction was between the same olefin part and appropriate amino alcohols, which were prepared starting from N-Boc-L-serine, and the other was between appropriate olefins and the same amino alcohol. [reaction: see text].
Assuntos
Alcenos/química , Esfingolipídeos/síntese química , Esfingosina/análogos & derivados , Esfingosina/síntese química , Amino Álcoois/química , Indicadores e Reagentes , Serina/químicaRESUMO
[reaction: see text] A one-pot procedure for tetracyclic chiral aminoacetals, the useful precursors for substituted piperidine synthesis, has been established via Stille-Migita coupling, 6pi-azaelectrocyclization, and aminoacetal formation from readily prepared vinylstannanes, vinyliodides, and cis-aminoindanol derivatives. Based on the method, chiral 2,4-disubstituted 1,2,5,6-tetrahydropyridines, bearing a variety of aromatic substituents at the C-2 position, have been prepared.
RESUMO
[structure: see text] Sphingomyelin nitrogen analogue 1 was designed and synthesized as a sphingomyelinase inhibitor. The synthesis was established by continuous Hofmann rearrangement and Crutius rearrangement as key steps in constructing the 3-hydroxy-1,2-diamine structure in the backbone of 1. This analogue showed moderate inhibitory activity toward SMase isolated from B. cereus.
Assuntos
Inibidores Enzimáticos/síntese química , Esfingomielina Fosfodiesterase/antagonistas & inibidores , Esfingomielinas/síntese química , Bacillus cereus/enzimologia , Inibidores Enzimáticos/química , Esfingomielinas/químicaAssuntos
Sondas Moleculares , Esfingolipídeos/síntese química , Ceramidas/síntese química , Química Orgânica , Desenho de Fármacos , Fenômenos de Química Orgânica , Esfingomielina Fosfodiesterase/antagonistas & inibidores , Esfingomielinas/síntese química , Esfingosina/síntese química , EstereoisomerismoRESUMO
The sulfur analogue of sphingomyelin was designed and stereoselectively synthesized from S-benzyl-N-Boc-cysteine. The introduction of the phosphoryl choline moiety was successfully achieved by our own method using 2-bromoethyl dimethyl phosphite and carbon tetrabromide followed by a trimethylamine treatment. The synthesized compound proved to be a useful substrate for monitoring the enzyme activity of sphingomyelinase by detecting the liberated thiol group with a thiol-sensitive reagent.
Assuntos
Esfingomielina Fosfodiesterase/metabolismo , Esfingomielinas/síntese química , Compostos de Enxofre/síntese química , Bacillus cereus/efeitos dos fármacos , Bacillus cereus/enzimologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Esfingomielina Fosfodiesterase/antagonistas & inibidores , Esfingomielinas/metabolismo , Compostos de Enxofre/metabolismoRESUMO
The highly efficient and stereocontrolled syntheses of sphingomyelin carbon analogues 1 and 2 were achieved by effectively utilizing Hofmann rearrangement of enantiomerically pure beta-hydroxyamide 7, which was prepared by an asymmetric hydrogenation of alpha-acyl-gamma-butyrolactone 9 and ring opening with NH(3). Intermediary isocyanate 6 was selectively trapped with the vicinal hydroxy group in an intramolecular fashion to produce an oxazolidinone derivative, 5. In the synthesis of a quite polar compound such as 1, a convenient one-pot procedure of the introduction of a benzyloxycarbonyl group into the hydroxy group resulting from the oxazolidinone ring opening is another key point, because, in addition to the efficiency, this protecting group was easily removable by a simple procedure and workup at the final step. Both synthesized compounds 1 and 2 showed moderate inhibitory activity toward sphingomyelinase from B. cereus.
Assuntos
Inibidores Enzimáticos/síntese química , Esfingomielina Fosfodiesterase/antagonistas & inibidores , Esfingomielinas/síntese química , Apoptose , Bacillus cereus/enzimologia , Química Orgânica/métodos , Cromatografia Líquida de Alta Pressão , Ciclização , Relação Dose-Resposta a Droga , Indicadores e Reagentes , Estrutura Molecular , Espectroscopia de Infravermelho com Transformada de Fourier , Esfingomielina Fosfodiesterase/química , Esfingomielinas/química , Esfingomielinas/metabolismo , EstereoisomerismoRESUMO
A fluorescence-labeled sphingosine and sphingosine 1-phosphate have been successfully synthesized from the oxazolidinone methyl ester derived from glycidol via monoalkylation and the stereoselective reduction of the resulting ketone. The labeled sphingosine was converted into its phosphate by treatment with sphingosine kinase 1 (SPHK1) from mouse, and in platelets, and it was incorporated into the Chinese Hamster Ovarian (CHO) cells. In addition, MAPK was activated by NBD-Sph-1-P through Edg-1, Sph-1-P receptor.