Pictet-Spengler Research Articles

Manipulation of the Precursor Supply in Yeast Significantly Enhances the Accumulation of Prenylated β-Carbolines.

The tryptophan derivative 1-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (MTCA) is present in many plants and foods including fermentation products of the baker's yeast Saccharomyces cerevisiae. MTCA is formed from tryptophan and acetaldehyde via a Pictet-Spengler reaction. In this study, up to 9 mg/L of MTCA were detected as a mixture of (1S,3S) and (1R,3S) isomers in a ratio of 2.2:1 in Saccharomyces cerevisiae cultures. To the best of our knowledge, this is the first report on the presence of MTCA in laboratory baker's yeast cultures. Expression of three fungal tryptophan prenyltransferase genes, fgaPT2, 5-dmats, and 7-dmats in S.cerevisiae resulted in the formation of MTCA derivatives with prenyl moieties at different positions of the indole ring. Expression of these genes in dimethylallyl diphosphate and tryptophan overproducing strains led to generation of up to 400 mg/L of prenylated MTCAs as mixtures of (1S,3S) and (1R,3S) diastereomers in ratios similar to that of unprenylated MTCA. The structures of the described substances including their stereochemistry were unequivocally elucidated by mass spectrometry as well as one- and two-dimensional NMR spectroscopy. The results of this study provide a convenient system for the production of high amounts of designed prenylated MTCAs in S.cerevisiae. Furthermore, our work can be considered as an excellent example for the construction of more complex molecules by introducing just one key gene.

Pictet–Spengler reaction in the synthesis of condensed benzodiazepines: synthesis of 11-hetaryl derivatives of 11,12-dihydroquinazolino[3,2-c][2,3]benzodiazepin-14(6H)-ones

New derivatives of 11,12-dihydroquinazolino[3,2-c][2,3]benzodiazepin-14(6H)-one have been synthesized. 11-(2-Thienyl)- and 11-(5-R-2-furyl)-substituted compounds were prepared by the Pictet–Spengler reaction of 3-amino-2-(3,4-dimethoxybenzyl)quinazolin-4(3H)-one with heterocyclic aldehydes in aprotic media. Their chemical structures were confirmed by 1H and 13C NMR spectroscopy and mass spectrometry. We observed the opening of diazepine ring in 8,9-dimethoxy-11-(5-chloro-2-furyl)-11,12-dihydroquinazolino[3,2-c][2,3]benzodiazepin-14(6H)-one when treated with trifluoroacetic acid, and the structure of the product was determined by NMR (1H, 13C, HSQC, HMBC experiments) and mass spectrometry data. The crystal structure of 3-amino-2-[4,5-dimethoxy-2-[(5-oxofuran-2(5H)-yliden)methyl]benzyl]quinazolin-4(3H)-one was confirmed by single-crystal X-ray analysis.

Concise Syntheses of Hyrtioreticulins C and D via a C-4 Pictet-Spengler Reaction: Revised Signs of Specific Rotations.

The first syntheses of hyrtioreticulins C and D via a Pictet-Spengler reaction at the C-4 position of the indole rings are described. The synthesis proceeds in only two steps from commercially available starting materials. In this Communication, the structures of the natural products were confirmed. Furthermore, we revise the signs of the specific rotations of hyrtioreticulins C and D.

Isolation and identification of antioxidant and α-glucosidase inhibitory compounds from fruit juice of Nitraria tangutorum.

Nitraria tangutorum Bor., having edible berries, is valued for reputed health benefits in Qinghai-Tibet plateau. The phytochemical research on the fruit juice of N. tangutorum led to the isolation of twenty-six compounds including five new compounds, tangutorids A-D (1, 2, 3a, and 3b), and (3E,5E)-7-O-β-glucosyl-4-(2-methoxy-2-oxoethyl)hepta-3,5-dienoic acid (15). The structures of these compounds were elucidated through comprehensive spectroscopic analyses. Tangutorids A-F were the first examples of glucose-derived β-carbolines from natural products. The biogenetic pathways of 1-8 were proposed to involve Pictet-Spengler reactions and described starting from the co-isolated tryptophan (10) and corresponding aldehydes. All isolates were evaluated for their antioxidant and α-glucosidase inhibitory activities. Compounds 21, 22, and 24 showed antioxidant activity with SC50 values ranging from 12.2±1.9 to 30.4±2.7μg/mL, and compound 1 showed strong α-glucosidase inhibitory effect with IC50 value of 63.3±4.6μg/mL.

Synthesis of tetrahydro-β-carboline-3-carbohydrazide derivatives based on Pictet-Spengler reaction and their bioactivities

According to our previous research on the antiviral activity of β-carboline and tetrahydro-β-carboline derivatives, series of novel tetrahydro-β-carboline derivatives containing acylhydrazone moiety and different substituents at 1 position were designed, synthesized via Pictet-Spengler reaction, and evaluated for their biological activities. Most of these compounds exhibited excellent antiviral activity both in vitro and in vivo . The in vivo inactivation, curative, and protection activities of part of these compounds were much higher than that of ribavirin (36.5%, 35.2%, and 37.1% at 500 μg/mL) and harmine (40.5%, 38.6% and 42.4% at 500 μg/mL). Especially, the in vivo activities of compounds VI-1 (61.4%, 57.2%, and 68.1%) and compound VI-2 (74.5%, 69.0%, and 68.1%) at 500 μg/mL, which were nearly twofold of that of ribavirin at 500 μg/mL. At the same time, the fungicidal results showed that compound IV-2 exhibited more than 60% fungicidal activities against 5 kinds of phytopathogens. Additionally, compound IV-5 exhibited more than 60% larvicidal activity against C. pipiens pallens at 0.25 mg/kg.

Kinetic and thermodynamic control in β-phenylethylamines reaction with isatin

In this work it was established that dopamine's reaction with isatin produces the respective spiroisoquinoline through a Pictet-Spengler reaction whilst phenylethylamines, having less activated aromatic rings (tyramine and phenylethylamine), produce the respective imine as a mixture of stereoisomers E and Z. This article analyses the spectroscopic and structural patterns of the stereoisomers (E/Z) obtained and proposes the experimental conditions necessary for obtaining each of them as major products.

ChemInform Abstract: NaNO2/I2‐Mediated Regioselective Synthesis of Nitrosoimidazoheterocycles from Acetophenones by a Domino Process.

A regioselective synthesis of nitrosoimidazoheterocycles from the reaction of 2-aminopyridines and acetophenones in the presence of NaNO2 and I2 is described. The reaction is suggested to proceed by a domino process involving sequential imine formation, iodination, iodide displacement by the nitro group, and finally intramolecular cyclization. Reaction of these 3-nitrosoimidazo[1,2-a]pyridines with aldehydes in the presence of Fe/AcOH furnished 5-substituted pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolines by reduction of the nitroso group followed by a Pictet–Spengler reaction in one pot. The synthesized compounds were assessed for their antibacterial and antifungal activities.

Synthesis of 1′-Aryl-1,3′-bi-β-carbolines and Their Saturated Counterparts

ABSTRACT1-Aryl-β-carboline-3-carbaldehyde building blocks have been used as the starting materials for the synthesis of novel bis-β-carboline derivatives. In the two-step synthesis the Pictet–Spengler reaction was used before the dehydrogenation of the polycyclic compound to the aromatic derivatives.

An efficient method for the synthesis of thieno[3′,2′:2,3]pyrido-[4,5-d]-thiazolo[3,2-a]pyrimidinones

An efficient method for the preparation of thieno[3′,2′:2,3]pyrido[4,5-d]thiazolo[3,2-a] pyrimidin-5-ones 5 is described. The key intermediate, 7-(3-amino-4-cyano-5-phenyl aminothieno-2-yl)-5H-thiazolo-[3,2-a]pyrimidin-5-one (3), was synthesized from 7-chloromethyl-5H-thiazolo[3,2-a]pyrimidin-5-one (1) with potassium-(2,2-dicyano-1-phenylaminoethen-1-yl)thiolate (2) by Thorpe–Ziegler isomerization. Subsequent reaction of the intermediate amine with aromatic aldehydes via Pictet–Spengler reaction provided thieno-pyridine fused thiazolo[3,2-a]pyrimidines under p-TsOH as catalyst in good yields.

Influence of chain length on the activity of tripeptidomimetic antagonists for CXC chemokine receptor 4 (CXCR4)

Here we report a series of close analogues of our recently published scaffold-based tripeptidomimetic CXCR4 antagonists, containing positively charged guanidino groups in R1 and R2, and an aromatic group in R3. While contraction/elongation of the guanidine carrying side chains (R1 and R2) resulted in loss of activity, introduction of bromine in position 1 on the naphth-2-ylmethyl moiety (R3) resulted in an EC50 of 61μM (mixture of diastereoisomers) against wild-type CXCR4; thus, the antagonistic activity of these tripeptidomimetics seems to be amenable to optimization of the aromatic moiety. Moreover, for analogues carrying a naphth-2-ylmethyl substituent, we observed that a Pictet-Spengler like cyclization side reaction depended on the nature of the R1 substituent.

Catalytic Enantioselective Synthesis of Tetrahydocarbazoles and Exocyclic Pictet-Spengler-Type Reactions.

A synthetic strategy for the synthesis of chiral tetrahydrocarbazoles (THCAs) has been developed. The strategy relies on two types of 6-exo-trig cyclization of 3-substituted indole substrates. Enantioselective domino Friedel-Crafts-type reactions leading to THCAs can be catalyzed by chiral phosphoric acid derivatives (with up to >99% ee), and the first examples of exocyclic Pictet-Spengler reactions to form THCAs are reported.

Theoretical insights into the regioselectivity of a Pictet-Spengler reaction: Transition state structures leading to salsolinol and isosalsolinol

Theoretical insights into the regioselectivity of a Pictet-Spengler reaction: Transition state structures leading to salsolinol and isosalsolinol

Synthesis of novel chiral guanidine catalyst and its application in the asymmetric Pictet-Spengler reaction

A new chiral guanidine catalyst has been synthesized by the reaction of (R)-1-(1-phenylethyl)guanidine and 2,3-diphenylcycloprop-2-enone. The catalyst was evaluated for the Pictet-Spengler reaction in which tetrahydro-β-carbolines were obtained in good yields with up to 64% ee.

ChemInform Abstract: An Efficient Synthesis of Novel Pyridothieno‐Fused Thiazolo[3,2‐a]pyrimidinones via Pictet—Spengler Reaction.

AbstractTitle compounds (V) are efficiently synthesized using a Pictet—Spengler reaction of key intermediate (III), which is obtained by condensation reaction of compound (I) with 3‐cyanopyridine‐2‐thione (II) via Thorpe—Ziegler isomerization, and aromatic aldehydes (IV) under sulfamic acid catalysis in good yields.

Library of Azabenz-Annulated Core-Extended Perylene Derivatives with Diverse Substitution Patterns and Tunable Electronic and Optical Properties.

Here, we present a collection of different azabenz-annulated perylene derivatives. By developing new synthetic strategies and improving existing protocols, we have expanded the structural diversity of these dye molecules to a multifunctional class of ligating chromophores. The Pictet-Spengler (PS) reaction of 1-amino-perylenes with different aldehydes is used to modify the terminal substitution pattern. PS transformations of 1,6- and/or 1,7-diamino perylenes result in 2-fold annulated nitrogen-containing coronene-type molecules like anti-(ab)2-PBI 15, syn-(ab)2-PBI 16, and syn-(ab)2-PTE 18. In addition, azabenz-annulated perylene bisanhydrides (ab-PBA 6 and syn-(ab)2-PBA 19) were explored as universal starting materials providing access to any desired imide functionality. Furthermore, a newly developed regioselective nitration procedure for perylene monoimide diesters (PMIDE) enables the synthesis of 1-nitro-PMIDE 10 and thus of azabenz-annulated perylene derivatives with unsymmetric peri-substitution patterns (ab-PMIDE 12 and ab-PMIMA 13). According to our spectroscopic and theoretical investigations, the optical and electrochemical properties of these multifunctional chromophores can easily be modified and adjusted to many desirable applications following the synthetic strategies presented in this work.

Enantioselective Synthesis of (+)-Peganumine A

A gram-scale enantioselective total synthesis of (+)-peganumine A was accomplished in 7 steps from commercially available 6-methoxytryptamine. Key steps included (a) a Liebeskind-Srogl cross-coupling; (b) a one-pot construction of the tetracyclic skeleton from an ω-isocyano-γ-oxo-aldehyde via a sequence of an unprecedented C-C bond forming lactamization and a transannular condensation; (c) a one-pot organocatalytic process merging two achiral building blocks into an octacyclic structure via a sequence of enantioselective Pictet-Spengler reaction followed by a transannular cyclization. This last reaction created two spirocycles and a 2,7-diazabicyclo[2.2.1]heptan-3-one unit with excellent control of both the absolute and relative stereochemistry of the two newly created quaternary stereocenters.

From Cyclic CF3-ketimines to a Family of Trifluoromethylated Nazlinine and Trypargine Analogues.

An efficient (one- and two-step) synthesis of trifluoromethylated derivatives of the natural alkaloids nazlinine, trypargine, and homotrypargine was elaborated. Trifluoromethyl-substituted 5-7-membered cyclic imines were used as a masked carbonyl component in the Pictet-Spengler reaction with various tryptamines. As a result, this approach opens access to a family of alkaloid-like compounds bearing a CF3 group at position 1 of tetrahydro-β-carboline.

Consecutive Pictet–Spengler Condensations toward Bioactive 8‐Benzylprotoberberines: Highly Selective Total Syntheses of (+)‐Javaberine A, (+)‐Javaberine B, and (–)‐Latifolian A

Enantiopure 8‐benzylprotoberberines were synthesized by two consecutive Pictet–Spengler (PS) condensations with protected 3,4‐dihydroxyphenylacetaldehydes. The first PS to (+)‐(R)‐norprotosinomenine was optimized to 90 % ee with 5 mol‐% of (R)‐TRIP as chiral Brønsted acid (> 99 % ee after trituration). The second PS did not require any catalyst, and its regioselectivity was strongly dependent on the solvent: 99:1 para selectivity was obtained in trifluoroethanol leading to (+)‐javaberine A; 81:19 ortho selectivity was reached in apolar aprotic solvents for the synthesis of (+)‐javaberine B. Complete, natural diastereoselectivity was observed in the second PS. Through selective catechol oxidation the spirocyclic alkaloid (–)‐latifolian A was prepared from protected (+)‐javaberine A.

Synthesis of novel 1,2,3-triazole tethered 1,3-disubstituted β-carboline derivatives and their cytotoxic and antibacterial activities

In this paper new β-carboline derivatives possessing the 1,2,3-triazole ring at C-1 substituent were synthesized from L-tryptophan by Pictet–Spengler reaction followed by a Huisgen 1,3-dipolar addition. In vitro cytotoxicity and antibacterial activity of synthetic compounds were investigated. Methyl 1-(3-((1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)-β-carboline-3-carboxylate (7f) showed the highest cytotoxic activity with IC50 values of 46 and 32 μM against Hela and HepG2 cell lines, respectively. Compounds 7d and 7i (possessing 4-bromophenyl substituent) and 5c showed excellent inhibition activity for Enterococcus faecium with MIC of 8 μg/mL. The results demonstrated that the presence of 1,2,3-triazole rings in β-carboline derivatives improve their biological activities.

NaNO2/I2‐Mediated Regioselective Synthesis of Nitrosoimidazoheterocycles from Acetophenones by a Domino Process

A regioselective synthesis of nitrosoimidazoheterocycles from the reaction of 2‐aminopyridines and acetophenones in the presence of NaNO2 and I2 is described. The reaction is suggested to proceed by a domino process involving sequential imine formation, iodination, iodide displacement by the nitro group, and finally intramolecular cyclization. Reaction of these 3‐nitrosoimidazo[1,2‐a]pyridines with aldehydes in the presence of Fe/AcOH furnished 5‐substituted pyrido[2′,1′:2,3]imidazo[4,5‐c]isoquinolines by reduction of the nitroso group followed by a Pictet–Spengler reaction in one pot. The synthesized compounds were assessed for their antibacterial and antifungal activities.