Bischler-Napieralski Reaction Research Articles

A Bischler-Napieralski and homo-Mannich sequence enables diversified syntheses of sarpagine alkaloids and analogues

Sarpagine alkaloids offer signicant opportunities in drug discovery, yet the efficient total syntheses and diverse structural modifications of these natural products remain highly challenging due to the architectural complexity. Here we show a homo-Mannich reaction of cyclopropanol with imines generated via a Bischler-Napieralski reaction enables a protecting-group-free, redox economic, four-step access to the tetracyclic sarpagine core from L-tryptophan esters. Based on this advancement, diversified syntheses of sarpagine alkaloids and analogues are achieved in a short synthetic route. The systematic anticancer evaluation indicates that natural products vellosimine and Na-methyl vellosimine possess modest anticancer activity. Intensive structural optimization of these lead molecules and exploration of the structure−activity relationship lead to the identification of analogue 15ai with an allene unit showing a tenfold improvement in anticancer activities. Further mechanism studies indicate compound 15ai exertes antiproliferation effects by inducing ferroptosis, which is an appealing non-apoptotic cell death form that may provide new solutions in future cancer therapies.

1-(2-Chlorophenyl)-6,7-dimethoxy-3-methyl-3,4-dihydroisoquinoline

This article concerns the synthesis and in silico evaluation of 1-(2-chlorophenyl)-6-7-dimethoxy-3-methyl-3,4-dihydrogioquinoline (DIQ). A variety of in silico simulations were applied to assess the potential biological activity and toxicity of the compound. Based on these analyses, the target molecule DIQ was chosen for the synthesis. DIQ was synthesized from starting 2-chloro-N-(1-(3,4-dimethoxyphenyl)propan-2-yl)benzamide applied in the Bischler–Napieralski reaction. The newly obtained 3,4-dihydroisoquinoline derivative was fully analyzed and characterized. Based on the in silico calculations, the target molecule was synthesized with respect to its contractile activity, which is a permanent interest of our studies. Thus, further investigation into the possible medicinal applications of this compound is warranted in the future.

Synthesis of the Multidrug Reversal Agent Ko143 and Its Parent Natural Product Fumitremorgin C

AbstractKo143 is a tetracyclic, synthetic analog of the fungal metabolite fumitremorgin C. Ko143 is a potent and specific inhibitor of the membrane‐bound efflux transporter ABCG2, and it reverses ABCG2‐mediated drug resistance in cancer cells. Here, we describe an improved synthesis of Ko143 that relies on the highly selective, substrate‐controlled reduction of an imine that is formed in a Bischler–Napieralski reaction with the amide derived from 6‐methoxy‐l‐tryptophan methyl ester and isovaleric acid as a key step. We have also developed a new route to 6‐methoxy‐l‐tryptophan methyl ester from Cbz‐l‐aspartic acid methyl ester, m‐anisidine and differently substituted benzaldehydes. With p‐nitrobenzaldehyde as one of the starting materials, this route gave access to 6‐methoxy‐l‐tryptophan methyl ester in five steps and 20 % overall yield; however, it is less efficient than a previously reported synthesis of 6‐methoxy‐l‐tryptophan methyl ester from 6‐methoxy indole.

Bischler–Napieralski Synthesis of Polycyclic N-Heteroaromatics Based on Tf2O-Promoted Electrophilic Activation of N-Aryl-2-Propynamides

2-Propynamides have been never used as substrates in classic and Tf2O-promoted Bischler-Napieralski reactions. In this article, a novel tandem synthesis of benzo[a]acridines is developed from N-aryl-2-propynamides and alkynes consisting of a Tf2O-promoted intermolecular Bischler-Napieralski reaction and a TfOH-promoted intramolecular Friedel-Crafts reaction.

Total synthesis of (±)-vinoxine: construction of the bridged pyrido[1,2-a]indole skeleton via Tf2O-mediated Bischler-Napieralski reaction and stereoselective radical cyclization.

The total synthesis of (±)-vinoxine was achieved featuring the assembly of a multi-substituted tetrahydropyrido[1,2-a]indole skeleton through the Tf2O-mediated Bischler-Napieralski reaction. The characteristic diazabicyclo[3.3.1]nonane skeleton was stereoselectively constructed via radical cyclization based on the one stereochemistry of the C3 position. The established methodology provides new options for the synthesis of natural products and pharmaceuticals containing the multi-substituted pyrido[1,2-a]indole skeleton.

A unified total synthesis of benzo[d][1,3]dioxole-type benzylisoquinoline alkaloids of aporphines, coptisines, and dibenzopyrrocolines.

The first total synthesis of (S)-(+)-ovigerine, (S)-(+)-N-formylovigerine, and (6aS,6a'S)-(+)-ovigeridimerine of aporphine alkaloids with a benzo[d][1,3]dioxole structure feature was established. The strategy was based upon the well-known Pd-catalyzed arylation to set the aporphine framework, and Noyori asymmetric hydrogenation followed by diastereoselective resolution to achieve excellent enantioselectivity. By slightly modifying the total synthetic route and strategically combining it with a aza-Michael addition, Bischler-Napieralski reaction and N-arylation, this methodology was also applied to the total syntheses of benzo[d][1,3]dioxole-type benzylisoquinoline alkaloids of coptisines and dibenzopyrrocolines, including two impatiens, tetrahydrocoptisine, and quaternary coptisine bromide of coptisines and two dibenzopyrrocoline analogues, with the syntheses of all of these target compounds being efficient. Among the nine synthesized compounds, the total syntheses of the three aporphines and the two impatiens, all with ee values of greater than 99%, were reported for the first time. This work also represents the first unification of synthetic routes for the total synthesis of benzo[d][1,3]dioxole-type aporphines, coptisines, and dibenzopyrrocolines.

Bischler-Napieralski Synthesis of 6-Alkynyl Phenanthridines Based on Tf2O-Promoted Electrophilic Activation of N-Aryl-2-propynamides.

An efficient method for the synthesis of 6-alkynyl phenanthridines was developed. The method offered the first example to use 2-propynamides as substrates in the Bischler-Napieralski reaction and to create alkynylnitrilium triflates as new active intermediates in organic synthesis.

Tf2O/TTBP (2,4,6-Tri-tert-butylpyrimidine): An Alternative Amide Activation System for the Direct Transformations of Both Tertiary and Secondary Amides.

Ten types of Tf2O/TTBP-mediated amide transformation reactions were investigated. The results showed that compared with pyridine derivatives 2,6-di-tert-butyl-4-methylpyridine (DTBMP) and 2-fluoropyridine (2-F-Pyr.), TTBP can serve as an alternative amide activation system for the direct transformation of both secondary and tertiary amides. For most surveyed examples, higher or comparable yields were generally obtained. In addition, Tf2O/TTBP combination was used to promote the condensation reactions of 2-(tert-butyldimethylsilyloxy)furan (TBSOF) with both tertiary and secondary amides, the one-pot reductive Bischler-Napieralski-type reaction of tertiary lactams, and Movassaghi and Hill's modern version of the Bischler-Napieralski reaction. The value of the Tf2O/TTBP-based methodology was further demonstrated by the concise and high-yielding syntheses of several natural products.

Synthesis of Carbazoles by a Diverted Bischler–Napieralski Cascade Reaction

An unforeseen twist in a seemingly trivial Bischler–Napieralski reaction led to the selective formation of an unexpected carbazole product. The reaction proved to be general, providing access to a range of diversely substituted carbazoles from readily available substrates. Judicious variation of substituents revealed a complex cascade mechanism comprising no less than 10 elementary steps, that could be diverted in multiple ways toward various other carbazole derivatives.

Synthesis and X-ray crystallographic analysis of free base and hexafluorophosphate salts of 3,4-dihydroisoquinolines from the Bischler–Napieralski reaction

Free base and hexafluorophosphate salts of 3,4-dihydroisoquinolines from the Bischler–Napieralski reaction: potential supramolecular modulation. Centrosymmetric/enantiomorphic crystals.

Synthesis of tetracyclic spiroindolines by an interrupted Bischler-Napieralski reaction: total synthesis of akuammicine.

Judicious substrate design allows interruption of the classical Bischler–Napieralski reaction, providing access to a range of diversely substituted tetracyclic spiroindolines. These complex polycyclic scaffolds are valuable building blocks for the construction of indole alkaloids, as showcased in a concise total synthesis of (±)-akuammicine.

Pd(II) and Rh(III) Complexes with Isoquinoline Derivatives Induced Mitochondria-Mediated Apoptotic and Autophagic Cell Death in HepG2 Cells

Nonplatinum metal complexes of [Pd(L1)Cl2] (C1), [Rh(L1)Cl3(DMSO)] (C2), [Pd(L2)Cl2] (C3), and [Rh(L3)Cl3(DMSO)] (C4) with isoquinoline derivatives have been prepared and characterized. C1–C4 exhib...

First Total Synthesis of the Pavine Alkaloid (±)-Neocaryachine and Its Optical Resolution

The first total synthesis of (±)-neocaryachine (1) was achieved using a radical cyclization to produce the dibenzo-9-azabicyclo[3.3.1]nonane pavine skeleton, following a Bischler-Napieralski reaction to construct an intermediate benzylisoquinoline. The resulting racemic mixture was separated by chiral column chromatography to provide pure (+)- and (-)-1.

An Aliphatic Bischler-Napieralski Reaction: Dihydropyridones by Cyclocarbonylation of 3-Allylimidazolidin-4-ones.

The N-chloroformylimidazolidinone derivative of enantiopure l-alanine was deprotonated to form an enolate and functionalized with a series of allylic halides. Treatment of the resulting carbamoyl chlorides with potassium iodide led to cyclization of the allylic substituent onto the carbonyl group in an intramolecular aliphatic Friedel-Crafts-type acylation that corresponds to an aliphatic Bischler-Napieralski reaction. The product 3,4-dihydropyridinones were amenable to further functionalization, and finally hydrolysis, to deliver a series of enantio-enriched pipecolic acid derivatives.

Biomimetic Total Synthesis of Dysoxylum Alkaloids.

A five-step total synthesis of Dysoxylum alkaloids has been achieved using a biomimetic approach from zanthoxylamide protoalkaloids. The synthesis featured a direct amidation and a Bischler-Napieralski reaction to form the dihydroisoquinoline ring, which was then subjected to a Noyori asymmetric transfer hydrogenation to establish the stereogenic center at C-1. Our synthetic sequence provides an important perspective on the biosynthetic origin of Dysoxylum alkaloids, since 6 natural alkaloids and 12 synthetic analogues were obtained with high enantioselectivity and in overall yields up to 68%. In addition, we describe the acute toxicity toward zebrafish embryos of Dysoxylum alkaloids, comparing their toxicity with that of their corresponding zanthoxylamide protoalkaloids and establishing an enantioselectivity-toxicity relationship.

Synthesis, Characterization, and Properties of Diazapyrenes via Bischler-Napieralski Reaction.

Via Bischler-Napieralski cyclization of amide precursors as the key step, a series of diazapyrene derivatives were designed and successfully synthesized. Their crystal structures, optoelectronic properties, and acid-responsive feature were investigated, which demonstrated that the doping of nitrogen atoms to the pyrene framework remarkably modulates their physical and chemical properties.

Unexpected PF6 Anion Metathesis during the Bischler–Napieralski Reaction: Synthesis of 3,4-Dihydroisoquinoline Hexafluorophosphates and Their Tetrahydroisoquinoline Related Alkaloids

A series of N-phenethylcinnamamides were subjected to the Bischler–Napieralski reaction to furnish diverse 1-styryl-3,4-dihydroisoquinolines. We noticed that the desired products were unstable when the reaction was performed under conventional solvent conditions. However, when [bmim]PF6 was used as the reaction media, the nature of the Bischler–Napieralski reaction promoted an unusual in situ ionic interchange between this ionic liquid and the dihydroisoquinoline core that led to the stabilization of the desired 1-styryl-3,4-dihydroisoquinolines, allowing their isolation as hexafluorophosphate salts. Finally, the one-pot reduction/reductive methylation process afforded the N-methyl derivatives, establishing that our findings can be an efficient and useful strategy for the concise synthesis of tetrahydroisoquinoline alkaloids.

Synthesis of upper rim-double-bridged calix[4]arenes bearing seven membered rings and related compounds.

Meta/meta- and meta/para-disubstituted organomercury calix[4]arenes in the cone conformation were transformed into corresponding amino derivatives. Acylation and subsequent intramolecular cyclization using the Bischler–Napieralski reaction provided, in the case of the meta/meta-series, double bridged calixarenes possessing seven membered rings on the upper rim. A similar synthetic strategy applied to meta/para-isomers allowed for the isolation of monobridged compounds bearing an additional trifluoroacetamido group located distally to seven-membered rings. Both series represent inherently chiral systems, which were successfully resolved using preparative chiral HPLC. The pure enantiomers exhibited a recognition ability towards selected chiral guest molecules as documented by the 1H NMR titration experiments. The absolute configuration of the phenyl-substituted enantiomer (meta/meta-) was confirmed by single crystal structure determination (X-ray).

Synthesis of enantiomerically pure inherently chiral calix[4]arenes using the meta-substitution strategy

A meta-substituted aminocalix[4]arene 4 immobilized in the cone conformation was prepared via mercuration of the starting tetra-propoxy derivative, followed by nitrosation and reduction reactions. Acylation of the amino group by chiral amino acid residues ((S)-N-trifluoroacetyl-Ala or (S)-N-trifluoroacetyl-Phe) allowed for the preparation of diastereomeric amides that were separated by preparative TLC on silica gel. Subsequent cyclization under Bischler-Napieralski reaction conditions yielded calixarenes 7b and 7c bearing an oxazole moiety in the meta position instead of the expected upper rim-bridged compounds. The reaction sequence represents a straightforward approach towards enantiomerically pure inherently chiral calix[4]arene derivatives (without HPLC separation steps). The absolute configuration of the enantiomers were confirmed by single crystal structure determination (X-ray).

Domino Bischler–Napieralski – Michael Reaction and Oxidation – New Route to Coumarin‐Pyrrole‐Isoquinoline Fused Pentacycles

Lamellarin scaffold is synthesized by a metal free convergent route involving domino Bischler–Napieralski reaction – Michael reaction – oxidation sequence. Six lamellarin analogues were synthesised having substituent on aryl as well as coumarin ring A.