Synthetic approaches to carnegine, a simple tetrahydroisoquinoline alkaloid

The different approaches towards the total synthesis of carnegine, a simple tetrahydroisoquinoline alkaloid isolated from several Cactaceae and Chenopodiaceae as well as other plants, are presented. Emphasis is placed on the various enantioselective strategies leading to the natural product in chiral form.     

Synthesis of a novel tetrahydroisoquinoline pentacyclic framework

N-Acyliminium cyclization of 6-substituted (3R^∗,6R^∗,11aS^∗)-3-arylmethyl-pyrazino[1,2-b]isoquinoline-1,4-diones gave with very good yields a novel tetrahydroisoquinoline pentacyclic core framework (29), while this reaction failed in all-cis-isomers to give instead conjugated enamines by deprotonation. Electronic and steric factors that govern the approach to both diastereomers from 6-substituted pyrazino[1,2-b]isoquinoline-1,4-diones have been studied.     

Solid-phase synthesis of 1-substituted tetrahydroisoquinoline derivatives employing BOC-protected tetrahydroisoquinoline carboxylic acids

Compounds containing the tetrahydroisoquinoline ring system were prepared using solid-supported ester derivatives on a nucleophile-sensitive resin, starting from the corresponding BOC-protected amino acids. The key heterocyclic intermediates were obtained from the Pictet-Spengler reaction between ethyl glyoxylate or methyl 4-formylbenzoate and dopamine or 3-hydroxyphenethylamine. After the resulting amino esters were converted to the BOC derivatives, the phenolic hydroxyl groups were alkylated with a series of alkyl halides to afford the corresponding ethers. Ester hydrolysis afforded the BOC-protected tetrahydroisoquinoline carboxylic acid scaffolds, which were then attached to (4-hydroxyphenyl)sulfide resin (Marshall linker) as the corresponding ester. The BOC group was removed under acidic conditions, and the resulting support-bound amine hydrochlorides were converted to the corresponding amides using a set of carboxylic acids. The support-bound amides were liberated with amines to produce the desired tetrahydroisoquinoline carboxamides. Optimization of the resin loading conditions is described in addition to the identification of impurities observed during the development of the optimum conditions for solid-phase synthesis.     

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.     

Utilization of a benzyl protective group in the synthesis of tetrahydroisoquinoline derivatives

The corresponding N-benzyl-1,2,3,4-tetrahydroisoquinolines, the debenzylation of which is realized by hydrogenation in the presence of Pd black, were synthesized by the reaction of 1-(3-hydroxyphenyl)-2-benzylaminoethanol with aldehydes.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1084–1087, August, 1981.     

Isolation of salsolinol, a tetrahydroisoquinoline alkaloid, from the marine sponge Xestospongia cf. vansoesti as a proteasome inhibitor

Salsolinol (1), a tetrahydroisoquinoline alkaloid, was isolated from the marine sponge Xestospongia cf. vansoesti collected in Indonesia as a proteasome inhibitor, along with three salsolinol derivatives, norsalsolinol (2), cis-4-hydroxysalsolinol (3), and trans-4-hydroxysalsolinol (4). Compounds 1 and 2 inhibited the chymotrypsin-like activity of the proteasome with IC(50) values of 50 and 32 μg/ml, respectively, but 3 and 4 showed no inhibitory effect even at 100 μg/ml.     

Electrode processes in the oxidation of tetrahydroisoquinoline derivatives

The electrochemical oxidation of the alkaloid laudanosine (Ia) to O-methylflavinantine (II) has been studied in acetonitrile solvent. Using cyclic voltammetry, rotating disc voltammetry and preparative electrolyses on several alkaloids, simple aliphatic amines and aromatic compounds, some aspects of the mechanism of this coupling reaction are elucidated. The first anodic wave for laudanosine at platinum has E_p=0.55 V vs. Ag/Ag⁺. The electrode rapidly becomes partially passivated at potentials above 0.5 V. This is due to a film which “dissolves” below 0.5 V, at a rate independent of the potential. It is shown that the reaction (Ia)→(II) proceeds at 0.5 V by initial oxidation of the amine moiety. If acids such as sodium bicarbonate are added to the anolyte the amine is protonated causing the first wave to disappear. Oxidation at 1.1 V under these acidic conditions produces the same product, but more rapidly and in significantly higher yield because electrode filming and side reactions resulting from the amine oxidation are abrogated.     

Oceanalin A, a hybrid alpha,omega-bifunctionalized sphingoid tetrahydroisoquinoline beta-glycoside from the marine sponge Oceanapia sp

[reaction: see text] The novel antifungal compound oceanalin A, an unprecedented "hybrid sphingolipid", was isolated from the marine sponge Oceanapia sp. The structure was elucidated using NMR and MS spectral analysis and chemical degradation. Oceanalin A exhibits in vitro antifungal activity against Candida glabrata with an MIC of 30 mug/mL.     

Phosphate mediated biomimetic synthesis of tetrahydroisoquinoline alkaloids

A one-pot synthesis of tetrahydroisoquinoline alkaloids in a phosphate buffer has been achieved, and a reaction mechanism proposed. The utilisation of mild reaction conditions readily afforded a range of isoquinolines, including norcoclaurine.     

Circular dichroism and configuration of (−)-1-methyl-1,2,3,4,tetrahydroisoquinoline

In the CD (circular dichroism) spectra of (–)-1-methyl-1,2,3,4, tetrahydroisoquinoline, three CE (Cotton effects) are observed in the 300–200 nm region that are due to the absorption bands of the aromatic chromophore. The synthesis of this substance from (S)(–)--phenylethylamine and the CD spectra confirm its (S)-configuration.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1238–1240, September, 1987.     

New strategy for the synthesis of tetrahydroisoquinoline alkaloids

[reaction: see text] A general strategy for the formation of 1,3-cis-substituted tetrahydroisoquinolines is described from ortho-iodo imines involving Larock isoquinoline synthesis, addition of organolithium compounds to unactivated isoquinolines, and ionic hydrogenation. In addition, a new synthesis of lactams via an unprecedented azide cyclization in the presence of a sulfonium ion is described.     

Studies on Cu-catalyzed asymmetric alkynylation of tetrahydroisoquinoline derivatives

Enantioselective C–C bond formations between the sp³ C–H bond of prochiral CH₂ and terminal alkynes via the cross-dehydrogenative coupling (CDC) reaction were studied. Efficient asymmetric syntheses of alkynyl tetrahydroisoquinoline derivatives were achieved by using a catalytic amount of CuOTf together with PyBox chiral ligand. When dihydroisoquinolinium salts were used as electrophiles, the combination of CuBr/QUINAP provided the best results for asymmetric syntheses of alkynyl tetrahydroisoquinoline derivatives. The factors influencing the enantioselectivity were studied.     

Synthesis of C-1 indol-3-yl substituted tetrahydroisoquinoline derivatives via a Pictet-Spengler approach

A protocol for the diastereoselective synthesis of C-1 indol-3-yl substituted tetrahydroisoquinoline derivatives via Pictet-Spengler condensation with L-DOPA or l-DOPA derivatives and 1H-indole-3-carbaldehydes is presented. The protocol is used for the successful synthesis of several tetrahydroisoquinolines as well as diketopiperazine fused analogues.     

A novel straightforward synthesis of enantiopure tetrahydroisoquinoline alkaloids.

A novel, direct,and high-yielding stereoselective method for enantiopure 1-substituted tetrahydroisoquinolines (THIQ) is described. The successful approach, which creates the stereocenter during the formation of the THIQ nucleus is based on (i) formation of chiral 2,3-substituted perhydro-1,3-benzoxazines derived from (-)-8-aminomenthol, (ii) diastereoselective intramolecular ring opening of the N,O-acetal moiety by an arylmetal generated from the substituent at the nitrogen atom in the perhydrobenzoxazine ring, and (iii) removal of the chiral auxiliary appendage. The starting perhydrobenzoxazines are easily prepared from (-)-8-aminomenthol and two different aldehydes, and the intramolecular opening is stereospecific, leading to a single stereoisomer. The method allows the preparation of a wide variety of enantiopure 1-substituted THIQ, with different substituents at C-1, by changing the nature of the starting aldehydes.     

Enhanced Enzymatic Synthesis of a Cephalosporin,Cefadroclor, in the Presence of Organic Co-solvents

In this study, we investigated the enzymatic synthesis of a semi-synthetic cephalosporin, cefadroclor, from 7-aminodesacetoxymethyl-3-chlorocephalosporanic acid (7-ACCA) and p-OH-phenylglycine methyl ester (D-HPGM) using immobilized penicillin G acylase (IPA) in organic co-solvents. Ethylene glycol (EG) was employed as a component of the reaction mixture to improve the yield of cefadroclor. EG was found to increase the yield of cefadroclor by 15–45%. An investigation of altered reaction parameters including type and concentration of organic solvents, pH of reaction media, reaction temperature, molar ratio of substrates, enzyme loading, and IPA recycling was carried out in the buffer mixture. The best result was a 76.5% conversion of 7-ACCA, which was obtained from the reaction containing 20% EG (v/v), D-HPGM to 7-ACCA molar ratio of 4:1 and pH 6.2, catalyzed by 16 IU mL^?1 IPA at 20 °C for 10 h. Under the optimum conditions, no significant loss of IPA activity was found after seven repeated reaction cycles. In addition, cefadroclor exhibited strong inhibitory activity against yeast, Bacillus subtilis NX-2, and Escherichia coli and weaker activity against Staphylococcus aureus and Pseudomonas aeruginosa. Cefadroclor is a potential antibiotic with activity against common pathogenic microorganisms.