The Preparation of 3,4‐Dihydroisoquinolines and Related Compounds by the<scp>B</scp>ischler‐<scp>N</scp>apieralski Reaction

Whaley, Wilson M.; Govindachari, T. R.

doi:10.1002/0471264180.or006.02

Cited by 39 publications

(55 citation statements)

References 216 publications

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“…Thus, much effort had to be directed toward establishing a high yield protocol for 3-carboxylic acid derivatives of THIQ, referred to as THIQ3CA. Traditional methods such as Pictet-Spengler, 43 Bischler-Napieralski, 44 and Pomeranz-Fritsch 45 reactions could not be readily adapted to our synthesis because of the limited availability of the required starting materials. Therefore, the THIQ3CA scaffold was constructed from three components, formaldehyde, substituted benzaldehyde, and glycine moiety donor in four steps (Scheme 2).…”

Section: Resultsmentioning

confidence: 99%

Designing Nonsaccharide, Allosteric Activators of Antithrombin for Accelerated Inhibition of Factor Xa

2011

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Antithrombin is a key regulator of coagulation and prime target of heparins, clinically used anticoagulants. Heparins induce a two-step conformational activation of antithrombin, a process that has remained challenging to target with molecules devoid of the antithrombin-binding pentasaccharide DEFGH. Computational screening of a focused library led to the design of two tetra-sulfated N-arylacyl tetrahydroisoquinoline variants as potential non-saccharide activators of antithrombin. A high yielding synthetic scheme based on Horner-Wadsworth-Emmons or Pictet-Spengler reactions was developed to facilitate the functionalization of the tetrahydoisoquinoline ring, which upon further amidation, deprotection, and sulfation gave the targeted non-saccharide activators. Spectrofluorometric measurement of affinity displayed antithrombin binding affinities in the low to high micromolar range at pH 6.0, I 0.05, 25 ºC. Measurement of second-order rate constants of antithrombin inhibition of factor Xa in the presence and absence of the designed activators showed antithrombin activation in the range of 8 – 80-fold in the pH 6.0 buffer. This work puts forward 20c, a novel tetra-sulfated N-arylacyl tetrahydroisoquinoline-based molecule, that activates AT only 3.8-fold less than that achieved with DEFGH suggesting a strong possibility of rationally designing sulfated organic molecules as clinically relevant AT activators.

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Section: Resultsmentioning

confidence: 99%

Designing Nonsaccharide, Allosteric Activators of Antithrombin for Accelerated Inhibition of Factor Xa

2011

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“…11–19 The Pictet-Spengler 11 and Bischler–Napieralski 12 reactions, which rely on cyclization of β-arylethylamine derivatives in presence of a protic or Lewis acid, 20–31 are among most common protocols for this purpose. Several other methods have also been developed including cycloaddition and enyne metathesis reactions for the synthesis of 1,2–dihydroisoquinoline–3–carboxylic acids 13 and 5,6–, 6,7–, or 7,8–functionalized THIQ3CA esters.…”

Section: Introductionmentioning

confidence: 99%

Electronically rich N-substituted tetrahydroisoquinoline 3-carboxylic acid esters: concise synthesis and conformational studies

Al‐Horani

Desai

2012

Tetrahedron

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Recent work in our laboratory has shown that the highly substituted, electronically rich 1,2,3,4–tetrahydroisoquinoline–3–carboxylic acid (THIQ3CA) scaffold is a key building block for a novel class of promising anticoagulants (Al-Horani et al. J. Med. Chem. 2011, 54, 6125–6138). The synthesis of THIQ3CA analogs, especially containing specific, electronically rich substituents, has been a challenge and essentially no efficient methods have been reported in the literature. We describe three complementary, glycine donor-based strategies for high yielding synthesis of highly substituted, electronically rich THIQ3CA esters. Three glycine donors studied herein include hydantoin 1, (±)-Boc-α-phosphonoglycine trimethyl ester 2 and (±)-Z-α-phosphonoglycine trimethyl ester 3. Although the synthesis of THIQ3CA analogs could be achieved using either of the three, an optimal, high yielding approach for the desired THIQ3CA esters was best achieved using 3 in three mild, efficient steps. Using this approach, a focused library of advanced N-arylacyl, N-arylalkyl, and bis-THIQ3CA analogs was synthesized. Variable temperature and solvent-dependent NMR chemical shift studies indicated the presence of two major conformational rotamers in 3:1 proportion for N–arylacyl–THIQ3CA analogs, which were separated by a high kinetic barrier of ~17 kcal/mol. In contrast, N–arylalkyl and bis–THIQ3CA variants displayed no rotamerism, which implicates restricted rotation around the amide bond as the origin for high-barrier conformational interconversion. This phenomenon is of major significance because structure-based drug design typically utilizes only one conformation. Overall, the work presents fundamental studies on the synthesis and conformational properties of highly substituted, electronically rich THIQ3CA analogs.

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“…24,25) And the treatment of 1a with excess thionyl chloride in anhydrous EtOH at reflux for 6 h gave ethyl 1,2,3,4-tetrahydro-β-carboline-1-carboxylate (1b) as a white solid. 26) Then, ethyl β-carboline-1-carboxylate (1c) was carried out by dehydrogenation with KMnO 4 in N,Ndimethylformamide (DMF) at room temperature for 24 h. 27) 1-Amino-β-carboline (1d) was prepared by the aminolysis of (1c).…”

Section: Methodsmentioning

confidence: 99%

“…(±)-Tryptophan was chosen as the starting material for the study, which was converted into 1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (2a) according to the Pictet-Spengler reaction in good yield. 24,25) And the treatment of 2a with excess thionyl chloride in anhydrous EtOH for 6 h at reflux gave ethyl 1,2,3,4-tetrahydro-β-carboline-3-carboxylate (2b) as a white solid in 88% yield. 27) Then, ethyl β-carboline-3-carboxylate (2c) was dehydrogenated with KMnO 4 in DMF at room temperature for 24 h.…”

Section: -Aminosulfonyl-1-carbamoyl-3-(1h-benzo[d]imidazol-2-yl)-β-cmentioning

confidence: 99%

Synthesis and Structure of the β-Carboline Derivatives and Their Binding Intensity with Cyclin-Dependent Kinase 2

Wang

Jin

Lin

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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Series of 3-substituted of 6-aminosulfonyl-β-carbolines were designed and synthesized. In addition, the binding mode of these β-carboline derivatives with cyclin-dependent kinase 2 (CDK2) was studied by means of fluorescence measurements and molecular docking calculation. The results showed that replacement of 3-cyclohexylmethoxy group will increase the hydrophobic binding interaction with the deep hydrophobic pocket of CDK2 correlate to the higher binding intensity.Key words cyclin-dependent kinase 2; β-carboline; synthesis; molecular docking; fluorescence It is well known that the phases of the cell cycle are driven by cyclin-dependent kinases (CDKs). Upon complexation with its activating proteins, cyclin E or cyclin A, cyclin-dependent kinase 2 (CDK2) modulates the activity of many cellular substrates via phosphorylation on serine (Ser) and/or threonine (Thr) residues.1-4) Abnormal CDK control of the cell cycle has been strongly linked to the molecular pathology of cancer. 5)The importance of CDK2 for cell cycle progression has led to an active pursuit of small molecule inhibitors of this enzyme as a possible treatment against cancer and other hyper-proliferative disorders.6-9) All CDK inhibitors, identified so far, function by competing with ATP for binding to the catalytic site. Actually several CDK inhibitors have entered clinical evaluation for the treatment of cancer, including flavopiridol, amino-thiazole compound.10) In our program to develop CDK2 inhibitors, we recently investigate the β-carboline alkaloids containing a planar tricyclic system as a large group of naturally-occurring and synthetic alkaloids, [11][12][13][14] which has a broad spectrum of biochemical effects and pharmaceutical properties. These compounds have been shown to intercalate into DNA, to inhibit CDK, topisomerase and monoamine oxidase, and to interact with benzodiazepine receptors (BZ), 5-hydroxy serotonin receptors (5-HT), dopamine (DA) and imidazoline receptors. [15][16][17][18][19][20][21][22][23] Inspired by these results, our research group recently focused on first of all, using a structure-guided strategy based on CDK2 as appropriate means to generate potent CDK2 inhibitors; then to synthesize disubstituted β-carbolines and to complete their biological evaluation study. As a part of our systematic work, in this paper, structure modification of β-carboline based on increasing its hydrophobic nature has been adopted. Herein we reported the design and synthesis of series of 3-substituted of 6-aminosulfonyl-β-carbolines. Series of 3-substituted compounds with different hydrophobic groups (Chart 1) were synthesized and one of their structures was elucidated with X-ray crystal analysis. The new derivatives were prepared following the reaction sequences depicted in Charts 2-4. Their binding intensity with CDK2 was measured by fluorescence spectroscopy. ExperimentalSynthesis The target compounds were prepared using the reaction sequence. All the chemical structures of the synthesized compounds were confirmed by spectroscopic me...

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The Preparation of 3,4‐Dihydroisoquinolines and Related Compounds by theBischler‐Napieralski Reaction

Cited by 39 publications

References 216 publications

Designing Nonsaccharide, Allosteric Activators of Antithrombin for Accelerated Inhibition of Factor Xa

Designing Nonsaccharide, Allosteric Activators of Antithrombin for Accelerated Inhibition of Factor Xa

Electronically rich N-substituted tetrahydroisoquinoline 3-carboxylic acid esters: concise synthesis and conformational studies

Synthesis and Structure of the β-Carboline Derivatives and Their Binding Intensity with Cyclin-Dependent Kinase 2

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