The<scp>P</scp>ictet‐<scp>S</scp>pengler Synthesis of Tetrahydroisoquinolines and Related Compounds

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

doi:10.1002/0471264180.or006.03

Cited by 38 publications

(52 citation statements)

References 64 publications

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“…10 The conditions for this ring closure are formic acid or methanesulfonic acid and have been chosen according to previous optimizations of this reaction sequence, albeit using different isocyanide inputs. 8c The formic acid ring-forming condition at room temperature is good for the more reactive dimethoxyphenyl Ugi products 24–27 .…”

Section: Resultsmentioning

confidence: 99%

Polycyclic Compounds by Ugi−Pictet−Spengler Sequence

et al. 2010

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A general approach to architecturally stimulating polycyclic structures is described by a concise, two-step procedure including a Ugi MCR (multicomponent reaction) and a subsequent Pictet–Spengler reaction starting from phenylethylamine-derived isocyanides. Ten compounds are described in full experimental detail, and yields range from medium to very good. Some of the reactions run with a high degree of stereoselectivity. The compound structures resemble steroid hormones and alkaloid classes of natural products. Exemplary products have been fully reduced to their tertiary amines. As such they could potentially become interesting biological probes.

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Section: Resultsmentioning

confidence: 99%

Polycyclic Compounds by Ugi−Pictet−Spengler Sequence

et al. 2010

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“…In Table 2, compounds with a primary amino group at the 7-position and various acyl groups (11)(12)(13)(14)(15)(16)(17)(18) had lower log D 7.0 than 1.6, and still had 1.3 to 7.0-fold more potent anti-foam cell formation activities than Pactimibe. The activities increased in a log D 7.0 -dependent manner, and tended to be higher with straight alkyl chains than branched alkyl and straight alkenyl chains.…”

Section: Resultsmentioning

confidence: 99%

“…In Chart 1, the synthetic routes of Naryl-2-octanoyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamides with no substitution at the 7-position (7,8,10) are outlined. The starting material 1, which was easily prepared from L-phenylalanine, 14) was acylated with octanoyl chloride to give 2. The methyl ester of 2 was hydrolyzed with NaOH to provide carboxylic acid (3), which was condensed with three anilines, 4-amino-2,3,6-trimethylphenyl acetate (4), 15) 2,6-diisopropylaniline, and 2,6-diisopropyl-4-nitroaniline (5) reduced by hydrogenation, and the product was converted to a HCl salt (10).…”

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confidence: 99%

Novel Tetrahydroisoquinoline Derivatives with Inhibitory Activities against Acyl-CoA: Cholesterol Acyltransferase and Lipid Peroxidation

Ohta

Takahashi

Kasai

et al. 2010

CHEMICAL & PHARMACEUTICAL BULLETIN

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To find a novel acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor with anti-lipid peroxidative activity, a series of tetrahydroisoquinoline derivatives were synthesized and evaluated. A compound with a N-(4-hydroxy-2,3,5-trimethylphenyl)carbamoyl moiety at the 3-position and an octanoyl moiety at the 2-position (7) was demonstrated to show anti-foam cell formation activity stronger than and anti-lipid peroxidative activity comparable to those of Pactimibe, while it was hardly absorbed orally. To increase its bioavailability, the acyl chain at the 2-position was shortened and various polar or basic moieties were introduced at the 7-position of 7. Among the synthesized derivatives, (S)-7-dimethylamino-N-(4-hydroxy-2,3,5-trimethylphenyl)-2-isobutyryl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide hydrochloride (21) showed about 16-fold stronger anti-foam cell formation activity, 3-fold stronger hepatic ACAT inhibitory activity, similar anti-low density lipoprotein (LDL) oxidative activity and 2-fold more potent protective activity against macrophage cell death by oxidative stress in comparison with Pactimibe. Compound 21 was efficiently absorbed after oral administration at 10 mg/kg in rats and dogs and its C max values were higher than its IC 50 values for in vitro activities. In conclusion, a tetrahydroisoquinoline structure is a useful scaffold for designing a phenolic anti-oxidative ACAT inhibitor, and compound 21 is expected to effectively prevent atherosclerosis.

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“…Both D- and L-tryptophan methyl ester were synthesized by a general synthetic procedure for amino acid esters. 17 The respective ester was subjected to Pictet–Spengler reaction with 2,4-dichlorobenzaldehyde, 3,4-dichlorobenzadehyde, and 2,6-dichlorobenzaldehyde. The reaction of the ester with 2,4-dichlorobenzaldehyde and 3,4-dichlorobenzadehyde gave both the cis and trans isomers as expected.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and Molecular Modeling of Novel Tetrahydro-β-carboline Derivatives with Phosphodiesterase 5 Inhibitory and Anticancer Properties

et al. 2010

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New derivatives based upon the tetrahydro-β-carboline-hydantoin and tetrahydro-β-carboline-piperazinedione scaffolds were synthesized. All compounds were evaluated for their ability to inhibit PDE5 in vitro, and numerous compounds with IC50 values in the low nanomolar range were identified including compounds derived from L-tryptophan. Compounds with high potency versus PDE5 were then evaluated for inhibitory activity against other PDEs to assess isozyme selectivity. Compound 5R,11aS-5-(3,4-dichlorophenyl)-2-ethyl-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indole-1,3(2H)dione 14 showed a selectivity index of >200 for cGMP hydrolysis by PDE5 versus PDE11. Meanwhile, 6R,12aR-6-(2,4-dichlorophenyl)-2-ethyl-2,3,6,7,12,12a-hexahydropyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4dione 45 demonstrated strong potency for inhibition of PDE11 with an IC50 value of 11 nM, representing the most potent PDE11 inhibitor thus far reported. Docking experiments differentiated between active and inactive analogues and revealing the conformational, steric, and lipophilic necessities for potent PDE5 inhibition. Many derivatives, including potent PDE5 inhibitors, were able to inhibit the growth of the MDA-MB-231 breast tumor cell line with low micromolar potency.

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ThePictet‐Spengler Synthesis of Tetrahydroisoquinolines and Related Compounds

Cited by 38 publications

References 64 publications

Polycyclic Compounds by Ugi−Pictet−Spengler Sequence

Polycyclic Compounds by Ugi−Pictet−Spengler Sequence

Novel Tetrahydroisoquinoline Derivatives with Inhibitory Activities against Acyl-CoA: Cholesterol Acyltransferase and Lipid Peroxidation

Synthesis and Molecular Modeling of Novel Tetrahydro-β-carboline Derivatives with Phosphodiesterase 5 Inhibitory and Anticancer Properties

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