A facile one-pot protocol for the synthesis of tetrazolyl-tetrahydroisoquinolines via novel domino intramolecular cyclization/Ugi-azide sequence

A facile one-pot, four-component domino reaction between 2-(2-bromoethyl)benzaldehyde, isocyanide, amine, and azide for the synthesis of tetrazolyl-tetrahydroisoquinoline derivatives has been developed. The reaction sequence involves intramolecular replacement of halide by iminium nitrogen followed by Ugi-azide reaction. The reaction is catalyst/additive free and takes place under ambient conditions with short reaction times to furnish products in good to excellent yields.     

Enantioselective synthesis of 1-vinyltetrahydroisoquinolines via Pd-catalyzed intramolecular asymmetric allylic amination reactions

1-Vinyltetrahydroisoquinolines serve as versatile intermediates for the synthesis of a variety of naturally occurring isoquinoline alkaloids. 1-Vinyl-6,8-dimethoxytetrahydroisoquinoline 4 and 1-vinyl-5,6,7-trimethoxytetrahydroisoquinoline 6 with >90% ee by means of Pd-catalyzed intramolecular asymmetric allylic amination reactions, using MPN and BOP ligands, developed in our laboratory. The fine-tuning capability of the MPN and BOP ligands has played a significant role in the optimization of enantioselectivity. Interesting substituent effect as well as solvent effect on the product selectivity and enantioselectivity was observed. Plausible mechanisms are proposed, which can accommodate various findings, including the critical importance of the activation of the trifluoroamide moiety through its coordination to the Lewis acidic Pd²⁺ metal center.     

Chiral capillary electrophoresis-mass spectrometry of tetrahydroisoquinoline-derived neurotoxins: observation of complex stereoisomerism

Previous studies have shown that certain 1,2,3,4-tetrahydroisoquinoline derivatives (TIQs) are neurotoxins inducing Parkinsonism. Further, individual enantiomers of these toxins such as (R/S)-N-methylsalsolinol ((R/S)-NMSal) possess distinct neurotoxicological properties. In this work, a chiral capillary electrophoresis (CE) method with electrospray ionization-tandem mass spectrometric (ESI-MS/MS) detection was developed for the quantification of TIQ enantiomers. Enantioseparation was achieved with sulfated β-cyclodextrin (sulfated β-CD) as chiral selector. To avoid any potential contamination of MS ionization source by the non-volatile chiral selector, partial filling technique was deployed in the CE separation. TIQ derivatives, including (R/S)-6,7-dihydroxy-1-methy-TIQ (salsolinol, Sal), (R/S)-1-benzyl-TIQ (BTIQ), and (R/S)-NMSal, were base-line resolved with resolution values (R) ranging from 3 (for Sal) to 4.5 (for BTIQ), which were much better than those reported previously by HPLC methods. ESI-MS/MS detection of the resolved TIQ enantiomers was specific and sensitive (LOD=1.2 μM for Sal enantiomers). The proposed chiral CE-MS/MS method was used to study in vitro formation of (R/S)-NMSal. It was found that NMSal was formed from the incubation of epinine (a dopamine metabolite) with acetaldehyde (a metabolite of alcohol). More interestingly, four isomers of NMSal were separated and detected in the incubation solution. They were identified as (R)-e.e-NMSal, (R)-e.a-NMSal, (S)-e.e-NMSal, and (S)-e.a-NMSal. This was the first lab evidence that this Parkinsonian neurotoxin exists in multiple isomeric forms.     

Synthesis of tetrahydroisoquinoline-based pseudopeptides and their characterization as suitable reverse turn mimetics

New peptidomimetics containing the Tic moiety were synthesized in enantiomerically pure form and their conformational features were studied by NMR, IR, and molecular modeling techniques. The presence of a reverse turn conformation was observed in all the structures, suggesting the key role of the scaffold as reverse turn inducer. In particular, all the analyses led to the conclusion that a β-turn conformation is mostly stabilized in tetrapeptide mimetic 4b and in hexapeptide mimetics 5a,b. In the case of 5a,b, the C1 stereochemistry plays a central role in determining stable conformations, supporting the formation of a β-hairpin arrangement with a 14-membered intramolecular hydrogen bond ring only in 5b.     

Synthesis of tetrahydroisoquinolines through TiCl4-mediated cyclization and Et3SiH reduction

A versatile and efficient telescoped reaction sequence for the synthesis of tetrahydroisoquinolines(THIQs)is reported that uses TiCl4 to promote cyclization of a benzylaminoacetal derivative and Et3SiH for reduction of the intermediate 4-hydroxy-THIQ.This method is complimentary to the classical Pomeranz-Fritsch and related reactions since it tolerates electron-withdrawing substituents and allows access to 8-substituted THIQs.     

Lewis acid-catalyzed Friedel-Crafts/Michael cascade reaction of N,N-dialkyl-3-vinylanilines with N-tosylaziridines for the stereoselective synthesis of highly functionalized tetrahydroisoquinolines

A Lewis acid-catalyzed Friedel-Crafts/Michael cascade reaction between N-dialkyl-3-vinylanilines and N-tosylaziridines has been developed for the stereoselective synthesis of tetrahydroisoquinolines (THIQs). The reaction using Gd(OTf)₃ as the Lewis acid catalyst was tolerant to the various N-dialkyl-3-vinylaniline and N-tosylaziridine substrates and provided access to 28 new, highly functionalized THIQs in typically high yields with moderate- to- excellent diastereoselectivities.     

Asymmetric synthesis of 1-vinyltetrahydroisoquinoline through Pd-catalyzed intramolecular allylic amination

Asymmetric synthesis of 6,7-dimethoxy-1-vinyltetrahydroisoquinolines through Pd-catalyzed intramolecular allylic amination of 3-(amidoethylphenyl)prop-2-enyl carbonates was studied, using a library of fine-tunable monodentate phosphoramidite ligands. Under optimized conditions, excellent enantiopurity (up to 96% ee) and 100% product selectivity were achieved. 1-Vinyltetrahydroquinoline thus obtained is a highly versatile intermediate for the synthesis of various biologically active alkaloids of medicinal interest.     

Microbial synthesis of natural,semisynthetic, and new-to-nature tetrahydroisoquinoline alkaloids

The tetrahydroisoquinoline (THIQ) moiety forms the backbone of several natural, synthetic, and semisynthetic drugs approved for the treatment of cancer, pain, gout, and various neurodegenerative diseases. Plants synthesize up to 3000 THIQ structures constituting the benzylisoquinoline, phenethylisoquinoline, Amaryllidaceae, and ipecac alkaloid classes. This review outlines the ongoing surge in activity surrounding the production of natural, semisynthetic, and new-to-nature THIQ metabolites in engineered microbial systems. These efforts have accelerated THIQ pathway discovery and engineering, unlocked new domains of chemical space, and spurred the development of highly productive microbial strains synthesizing unprecedented yields of THIQ precursors. Consolidating these advancements into a single bioprocess holds potential to outcompete crop-based manufacturing and total synthesis for the production of high-value THIQ pharmaceuticals at scale.     

Tandem enlargement of the tetrahydropyridine ring in 1-aryl-tetrahydroisoquinolines using activated alkynes—a new and effective synthesis of benzoazocines

Tetrahydroisoquinolines 3a-e underwent piperidine ring enlargement under the action of activated alkynes, giving benzoazocines 4, 5 and 7-11 in high yields.     

Synthesis and biological evaluation of tetrahydroisoquinoline derivatives as potential multidrug resistance reversal agents in cancer

Tetrahydroisoquinoline derivatives were synthesized and their multidrug resistance reversal activities were evaluated in vitro. The results showed that some of the synthetic compounds had higher multidrug resistance （MDR） reversal activities than verapamil.