Mechanism of a Dually Catalyzed Enantioselective Oxa-Pictet-Spengler Reaction and the Development of a Stereodivergent Variant.

Enantioselective oxa-Pictet-Spengler reactions of tryptophol with aldehydes proceed under weakly acidic conditions utilizing a combination of two catalysts, an indoline HCl salt and a bisthiourea compound. Mechanistic investigations revealed the roles of both catalysts and confirmed the involvement of oxocarbenium ion intermediates, ruling out alternative scenarios. A stereochemical model was derived from density functional theory calculations, which provided the basis for the development of a highly enantioselective stereodivergent variant with racemic tryptophol derivatives.

Reactivity of ethyl nitrosoacrylate toward pyrrole, indole and pyrrolo[3,2-c]carbazole: an experimental and theoretical study.

Nitrosoalkenes react with 8-methyl-1,6-dihydropyrrolo[3,2-c]carbazole to give both 2- and 3-alkylated products via hetero-Diels-Alder reaction followed by the cycloadduct ring-opening. Quantum chemical calculations, at DFT level of theory, were carried out to investigate the regioselectivity of the cycloaddition of ethyl nitrosoacrylate with 1,6-dihydropyrrolo[3,2-c]carbazoles as well as with pyrrole and indole, allowing a more comprehensive analysis of the reactivity pattern of nitrosoalkenes with five-membered heterocycles. Furthermore, theoretical calculations confirmed that ethyl nitrosoacrylate reacts with these heterocycles via a LUMOheterodiene-HOMOdienophile controlled cycloaddition. The reactivity of one of the oxime-functionalized 1,6-dihydropyrrolo[3,2-c]carbazole was explored and a new hexahydropyrido[4',3':4,5]pyrrolo[3,2-c]carbazole system was obtained in high yield via a one-pot, two-step procedure.

Pictet-Spengler Synthesis of N-Heteroaromatics Extended Porphyrins.

BACKGROUND: Porphyrins are highly conjugated heterocyclic compounds and are found as the backbone of many natural products such as heme and chlorophyll. To improve its biological and optical properties, the functionalization of porphyrin at its ß- and meso-position has gained importance in recent years. OBJECTIVE: The purpose of this review is to describe the Pictet-Spengler method for the incorporation of nitrogenous and biologically important heterocyclic scaffolds such as pyrrolo-/indolo[1,2-a]quinoxaline, pyrrolo[1,2-a]pyrazine, and quinoline at the ß- and meso-positions of the porphyrins to increase π-conjugation and improve their biological, optical, and electrochemical properties. CONCLUSION: This review provides a comprehensive overview of the synthesis of N-heterocyclic extended porphyrins and metalloporphyrins via a modified Pictet-Spengler approach. The synthesized porphyrins were found to be highly conjugated and exhibited improved photophysical properties compared to their parent analogues. Moreover, the review article provided a brief overview of the Pictet-Spengler procedure, including product yields, reaction conditions, photophysical properties of the synthesized products, and potential applications in a variety of fields.

Synthesis of tetrahydrofuro[3,2-c]pyridines via Pictet-Spengler reaction.

A semi-one-pot method for the synthesis of 4-substituted tetrahydrofuro[3,2-c]pyridines by the Pictet-Spengler reaction was developed. The method is based on the condensation of easily accessibly 2-(5-methylfuran-2-yl)ethanamine with commercially available aromatic aldehydes followed by acid-catalyzed Pictet-Spengler cyclization. Using this approach, we synthesized a range of 4-substituted tetrahydrofuro[3,2-c]pyridines in reasonable yields. The reactivity of some of the products was investigated and selected synthetic transformations of the obtained tetrahydrofuro[3,2-c]pyridines were shown.

Synthesis of Tetrahydro-ß-carbolines by a Manganese-Catalysed Oxidative Pictet-Spengler Reaction.

Herein, an efficient and green procedure for the synthesis of tetrahydro-ß-carbolines via dehydrogenative coupling of alcohols with tryptamines is reported. The reaction was carried out under mild conditions in the presence of a catalytic amount of the iPr PNP-Mn catalyst and a weak base (Na2 CO3 ). This method tolerated a variety of benzylic and aliphatic alcohol substrates with different functional groups and afforded diverse products in good to excellent isolated yields using tryptamines. Using this strategy, we successfully synthesised pharmaceutical molecules harman, harmaline, and harmine in a concise manner.

Pentafluorophenol (C6 F5 OH) Catalyzed Pictet-Spengler Reaction: A Facile and Metal-Free Approach Towards Tetrahydro-ß-Carbolines.

Herein, we have disclosed pentafluorophenol as an operative catalyst for synthesizing (spirocyclic) tetrahydro-ß-carbolines via the Pictet-Spengler reaction. This straightforward catalytic protocol works under mild conditions resulting indole alkaloids in excellent yield with remarkable functional group tolerance, including late-stage modifications. This transformation demonstrates a practical and adaptable approach to produce a highly effective gram-scale synthesis of the natural alkaloid Komavine and enables the synthesis of the commercial drug Tadalafil.

Divergent Asymmetric Total Synthesis of (-)-Voacafricines A and B.

A divergent asymmetric total synthesis of voacafricines A and B, hexacyclic monoterpene indole alkaloids, has been accomplished featuring the following key steps: a) a catalyst-controlled asymmetric Pictet-Spengler reaction of 6-methoxytryptamine with a chiral α-ketoester affording a 1,1-disubstituted tetrahydro-ß-carboline in excellent yield and diastereoselectivity; b) oxidative cleavage of a 3,5-disubstituted cyclopentene furnishing a dialdehyde intermediate, which was effectively differentiated through spontaneous cyclization with the neighboring hydroxy and secondary amine functions; c) intramolecular nucleophilic addition of a tertiary amino nitrogen atom to the in situ generated oxonium species generating stereoselectively an unprecedented 8-alkyl octahydro-2H-5,8-methanofuro[2,3-b]azepin-8-ium motif bearing five contiguous stereocenters. The synthesis confirmed the absolute configuration of these two natural products.

Evaluation of the Local Anesthetic Activity, Acute Toxicity, and Structure-Toxicity Relationship in Series of Synthesized 1-Aryltetrahydroisoquinoline Alkaloid Derivatives In Vivo and In Silico.

Isoquinoline alkaloids constitute one of the most common classes of alkaloids that have shown a pronounced role in curing various diseases. Finding ways to reduce the toxicity of these molecules and to increase their therapeutic margin is an urgent matter. Here, a one-step method for the synthesis of a series of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines was performed in 85-98% yield by the Pictet-Spengler reaction. This was accomplished using the reaction between 3,4-dimethoxyphenylethylamine and substituted benzaldehydes boiling in trifluoroacetic acid. Furthermore, 1-(3'-amino-, 4'-aminophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines were obtained in 94% and 97% yield by reduction in 1-(3'-nitro-, 4'-nitrophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines with SnCl2 × 2H2O. The structures of the substances obtained were confirmed by infrared (IR) and nuclear magnetic resonance (1H and 13C NMR) spectra. ADMET/TOPKAT in silico study concluded that the synthesized compounds exhibited acceptable pharmacodynamic and pharmacokinetic properties without carcinogenic or mutagenic potential but with variable hepatotoxicity. The acute toxicity and structure-toxicity relationship (STR) in the series of 20 derivatives of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines (3a-r, 4a, b) was studied via determination of acute toxicity and resorptive action in white mice employing intragastric step-by-step administration. The first compound, 1-phenyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3a), showed the highest toxicity with LD50 of 280 mg/kg in contrast to 1-(3'-bromo -4'-hydroxyphenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3e) which proved to be the safest of the compounds studied. Its toxicity was 13.75 times lower than that of the parent compound 3a. All compounds investigated showed high local anesthetic activity on rabbit eyes in the concentrations studied. Only 3r, 3n, and 4a caused eye irritation and redness. All investigated derivatives (except 4b) in 1% concentration were more active than lidocaine, providing longer duration of complete anesthesia. Therefore, based on the obtained results of in silico tests, local anesthesia, and acute toxicity, a conclusion can be drawn that the experimental compounds need further extensive future investigations and possible modifications so that they can act as promising drug candidates.

Organocatalytic Enantioselective Pictet-Spengler Reaction of α-Ketoesters: Development and Application to the Total Synthesis of (+)-Alstratine A.

We report herein an asymmetric Pictet-Spengler reaction of α-ketoesters. In the presence of a catalytic amount of simple alanine-derived squaramide and p-nitrobenzoic acid, reaction of tryptamines with methyl 2-oxoalkanoates afforded the corresponding 1-alkyl-1-methoxycarbonyl tetrahydro-ß-carbolines (THBCs) in high yields and ee values. A primary kinetic isotope effect (KIE=4.5) using C2-deteurium-labelled tryptamine indicates that rearomatization through deprotonation of the pentahydro-ß-carbolinium ion could be the rate- and enantioselectivity-determining step. A concise enantioselective total synthesis of (+)-alstratine A, a hexacyclic cagelike monoterpene indole alkaloid, featuring this reaction as a key step, was subsequently accomplished. Remeasurement of the [a]D value of the natural product indicates that natural alstratine A is dextrorotatory rather than levorotatory as it was initially reported in the isolation paper.

Engineering a norcoclaurine synthase for one-step synthesis of (S)-1-aryl-tetrahydroisoquinolines.

Tetrahydroisoquinoline alkaloids (THIQAs) are ubiquitous compounds with important pharmaceutical and biological activity. Their key N-heterocyclic structural motifs are synthesised via Pictet-Spengler (P-S) reaction by norcoclaurine synthases (NCS) in plants. The synthesis of 1-aryl-tetrahydroisoquinoline alkaloids has attracted increasing attention due to their antitumor and antivirus activities. Herein, the L68T/M97V mutant of NCS from Thalictrum flavum with improved activity was developed by semi-rational design. This mutant not only showed higher catalytic performance (> 96% conversion) toward benzaldehyde and dopamine over the wild-type enzyme, but also catalysed the P-S reaction of the bulky substrate 4-biphenylaldehyde and dopamine with high conversion (> 99%) for the effective synthesis of 1-aryl-THIQA. In terms of stereoselectivity, all products synthesised by the L68T/M97V mutant showed high optical purity (92-99% enantiomeric excess).

Initiating DNA-Encoded Library Synthesis with a Hexathymidine DNA Oligonucleotide.

Libraries of DNA-encoded compounds (DELs) are a validated screening technology for drug discovery. Here we describe a library synthesis strategy that starts with a solid phase-bound, chemically very stable hexathymidine DNA sequence "hexT." Different heterocycle conjugates of the hexT oligonucleotide were synthesized from simple starting materials using metal or acid catalysts. The hexT conjugates were isolated, characterized, and ligated to coding DNA sequences.

Development of a Fully Continuous-Flow Approach Towards Asymmetric Total Synthesis of Tetrahydroprotoberberine Natural Alkaloids.

Continuous flow synthetic technologies had been widely applied in the total synthesis in the past few decades. Fully continuous flow synthesis is still extremely focused on multi-step synthesis of complex natural pharmaceutical molecules. Thus, the development of fully continuous flow total synthesis of natural products is in demand but challenging. Herein, we demonstrated the first fully continuous flow approach towards asymmetric total synthesis of natural tetrahydroprotoberberine alkaloids, (-)-isocanadine, (-)-tetrahydropseudocoptisine, (-)-stylopine and (-)-nandinine. This method features a concise linear sequence involving four chemical transformations and three on-line work-up processing in an integrated flow platform, without any intermediate purification. The overall yield and enantioselectivity of this four-step continuous flow chemistry were up to 50 % and 92 %ee, respectively, in a total residence time of 32.5 min, corresponding to a throughput of 145 mg/h.

Catalytic Enantioselective Pictet-Spengler Reaction of α-Ketoamides Catalyzed by a Single H-Bond Donor Organocatalyst.

The asymmetric Pictet-Spengler reaction (PSR) with aldehydes is well known. However, PSR involving ketones as electrophilic partners is far-less developed. We report herein the first examples of catalytic enantioselective PSR of tryptamines with α-ketoamides. A new class of easily accessible prolyl-urea organocatalysts bearing a single H-bond donor function catalyzes the title reaction to afford 1,1-disubstituted tetrahydro-ß-carbolines in excellent yields and enantioselectivities. The kinetic isotope effect using C2-deuterium-labelled tryptamine indicates that the rearomatization of the pentahydro-ß-carbolinium ion intermediate might be the rate- and the enantioselectivity-determining step.

Diversity-oriented synthesis of marine sponge derived hyrtioreticulins and their anti-inflammatory activities.

Diversity-oriented synthesis is aimed to increase the chemical diversity of target natural products for extensive biological activity evaluation. Indole ring is an important functional group in a large number of drugs and other biologically active agents, and indole-containing natural products have been frequently isolated from marine sources in recent years. In this paper, a series of indole-containing marine natural hyrtioreticulin derivatives, including 19 new ones, were designed, synthesized through a key Pictet-Spengler reaction, and evaluated for their inflammation related activity. Compound 13b displayed the most promising activity by inhibiting TNF-α cytokine release with an inhibitory rate of 92% at a concentration of 20 µmol·L-1. A preliminary structure-activity relationship analysis was also discussed. This research may throw light on the discovery of marine indole alkaloid derived anti-inflammatory drug leads.

Diversity-oriented synthesis of marine sponge derived hyrtioreticulins and their anti-inflammatory activities / 中国天然药物

Diversity-oriented synthesis is aimed to increase the chemical diversity of target natural products for extensive biological activity evaluation. Indole ring is an important functional group in a large number of drugs and other biologically active agents, and indole-containing natural products have been frequently isolated from marine sources in recent years. In this paper, a series of indole-containing marine natural hyrtioreticulin derivatives, including 19 new ones, were designed, synthesized through a key Pictet-Spengler reaction, and evaluated for their inflammation related activity. Compound 13b displayed the most promising activity by inhibiting TNF-α cytokine release with an inhibitory rate of 92% at a concentration of 20 μmol·L-1. A preliminary structure-activity relationship analysis was also discussed. This research may throw light on the discovery of marine indole alkaloid derived anti-inflammatory drug leads.

The ethoxycarbonyl group as both activating and protective group in N-acyl-Pictet-Spengler reactions using methoxystyrenes. A short approach to racemic 1-benzyltetrahydroisoquinoline alkaloids.

We present a systematic investigation on an improved variant of the N-acyl-Pictet-Spengler condensation for the synthesis of 1-benzyltetrahydroisoquinolines, based on our recently published synthesis of N-methylcoclaurine, exemplified by the total syntheses of 10 alkaloids in racemic form. Major advantages are a) using ω-methoxystyrenes as convenient alternatives to arylacetaldehydes, and b) using the ethoxycarbonyl residue for both activating the arylethylamine precursors for the cyclization reaction, and, as a significant extension, also as protective group for phenolic residues. After ring closure, the ethoxycarbonyl-protected phenols are deprotected simultaneously with the further processing of the carbamate group, either following route A (lithium alanate reduction) to give N-methylated phenolic products, or following route B (treatment with excess methyllithium) to give the corresponding alkaloids with free N-H function. This dual use of the ethoxycarbonyl group shortens the synthetic routes to hydroxylated 1-benzyltetrahydroisoquinolines significantly. Not surprisingly, these ten alkaloids did not show noteworthy effects on TPC2 cation channels and the tumor cell line VCR-R CEM, and did not exhibit P-glycoprotein blocking activity. But due to their free phenolic groups they can serve as valuable intermediates for novel derivatives addressing all of these targets, based on previous evidence for structure-activity relationships in this chemotype.

Synthesis of Indofulvin Pseudo-Natural Products Yields a New Autophagy Inhibitor Chemotype.

Chemical and biological limitations in bioactive compound design based on natural product (NP) structure can be overcome by the combination of NP-derived fragments in unprecedented arrangements to afford "pseudo-natural products" (pseudo-NPs). A new pseudo-NP design principle is described, i.e., the combination of NP-fragments by transformations that are not part of current biosynthesis pathways. A collection of indofulvin pseudo-NPs is obtained from 2-hydroxyethyl-indoles and ketones derived from the fragment-sized NP griseofulvin by means of an iso-oxa-Pictet-Spengler reaction. Cheminformatic analysis indicates that the indofulvins reside in an area of chemical space sparsely covered by NPs, drugs, and drug-like compounds and they may combine favorable properties of these compound classes. Biological evaluation of the compound collection in different cell-based assays and the unbiased high content cell painting assay reveal that the indofulvins define a new autophagy inhibitor chemotype that targets mitochondrial respiration.

Strictosidine synthase, an indispensable enzyme involved in the biosynthesis of terpenoid indole and ß-carboline alkaloids.

Terpenoid indole (TIAs) and ß-carboline alkaloids (BCAs), such as suppressant reserpine, vasodilatory yohimbine, and antimalarial quinine, are natural compounds derived from strictosidine. These compounds can exert powerful pharmacological effects but be obtained from limited source in nature. the whole biosynthetic pathway of TIAs and BCAs, The Pictet-Spengler reaction catalyzed by strictosidine synthase (STR; EC: 4.3.3.2) is the rate-limiting step. Therefore, it is necessary to investigate their biosynthesis pathways, especially the role of STR, and related findings will support the biosynthetic generation of natural and unnatural compounds. This review summarizes the latest studies concerning the function of STR in TIA and BCA biosynthesis, and illustrates the compounds derived from strictosidine. The substrate specificity of STR based on its structure is also summarized. Proteins that contain six-bladed four-stranded ß-propeller folds in many organisms, other than plants, are listed. The presence of these folds may lead to similar functions among organisms. The expression of STR gene can greatly influence the production of many compounds. STR is mainly applied to product various valuable drugs in plant cell suspension culture and biosynthesis in other carriers.

Beyond Pseudo-natural Products: Sequential Ugi/Pictet-Spengler Reactions Leading to Steroidal Pyrazinoisoquinolines That Trigger Caspase-Independent Death in HepG2 Cells.

In this work, we describe how stereochemically complex polycyclic compounds can be generated by applying a synthetic sequence comprising an intramolecular Ugi reaction followed by a Pictet-Spengler cyclization on steroid-derived scaffolds. The resulting compounds, which combine a fragment derived from a natural product and a scaffold not found in nature. are both structurally distinct and globally similar to natural products at the same time, and interrogate an alternative region of the chemical space. One of the new compounds showed significant antiproliferative activity on HepG2 cells through a caspase-independent cell-death mechanism, an appealing feature when new antitumor compounds are searched.

Strictosidine synthase, an indispensable enzyme involved in the biosynthesis of terpenoid indole and β-carboline alkaloids / 中国天然药物

Terpenoid indole (TIAs) and β-carboline alkaloids (BCAs), such as suppressant reserpine, vasodilatory yohimbine, and antimalarial quinine, are natural compounds derived from strictosidine. These compounds can exert powerful pharmacological effects but be obtained from limited source in nature. the whole biosynthetic pathway of TIAs and BCAs, The Pictet-Spengler reaction catalyzed by strictosidine synthase (STR; EC: 4.3.3.2) is the rate-limiting step. Therefore, it is necessary to investigate their biosynthesis pathways, especially the role of STR, and related findings will support the biosynthetic generation of natural and unnatural compounds. This review summarizes the latest studies concerning the function of STR in TIA and BCA biosynthesis, and illustrates the compounds derived from strictosidine. The substrate specificity of STR based on its structure is also summarized. Proteins that contain six-bladed four-stranded β-propeller folds in many organisms, other than plants, are listed. The presence of these folds may lead to similar functions among organisms. The expression of STR gene can greatly influence the production of many compounds. STR is mainly applied to product various valuable drugs in plant cell suspension culture and biosynthesis in other carriers.