Tetrahydroisoquinoline residu

In achiral media, different NMR spectra are expected for each of the four types of enantiomeric pairs and for the two meso compounds. In general, because of the synthetic approach, the ratio of cis- to /nmv-rcsiducs is about three, which, assuming that quaternisation at one tetrahydroisoquinoline residue does not affect quaternisation at the other, leads to proportions of cis-cis, cis-trans and trans-trans isomers in the approximate ratio of 11 6 1. The preference for cis-residues has been proved by using nuclear Overhauser effect NMR measurements and by X-ray crystallography on related substances [37,38]. The H NMR chemical shifts, principally of the H8 proton, can be affected not only by whether the C1-N2 configuration in the residue is cis or trans but also by the configuration of the remote tetrahydroisoquinoline unit. 

Treatment of (11 aS)-3-isopropyl-11 a-methyl-4-phenyl-1,6,11,11 a-tetrahy-dro[l,4]oxazino[4,3-6]isoquinolin-l-one (243) with 6N HCl in a pressure tube, then the reaction of the work-up residue with propylene oxide gave (3S)-3-methyl-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (244) (99S704). 

B. 2-Acetyl-6,l-dimethoxy-l-methylene-l,2,3,4-tetrahydroisoquinoline [Isoquinoline, 2-acetyl-l,2, A,4-tetrahydro-6,7-dimethoxy-l-methylene-]. A 1-1., three-necked, round-bottomed flask equipped with a mechanical stirrer, a reflux condenser topped with a calcium chloride drying tube, and a thermometer is charged with 110 ml. of acetic anhydride, 110 ml. of pyridine, and 45.0 g. (0.22 mole) of the dihydroisoquinoline prepared in Part A. The reaction mixture is stirred and heated at 90-95° for 30 minutes, stored at room temperature overnight, and concentrated by distillation at 50° using a rotary evaporator. The residue is diluted with 20 ml. of ethyl acetate, and another evaporation under reduced pressure gives material that can be crystallized from 75 ml. of ethyl acetate to yield 38.5 41.0 g. (72-77%) of product, m.p. 106-107° (Note 11). 

Marsden BJ, Nguyen TM-D, Schiller PW. Spontaneous degradation via diketopiperazine formation of peptides containing a tetrahydroisoquinoline-3-carboxylic acid residue in the 2-position of the peptide sequence. Int J Peptide Protein Res 1993 41 313-316. 

The decapeptide Hoe 140 (6.94), its D- and/or artificial residues being d-Arg, ((4/ )-hydroxy)Pro, (2-thienyl)Ala, D-[(l,2,3,4-tetrahydroisoquinolin-3-yl)carbonyl] and i.-[(3aS, 7aS)-octahydroindol-2-yl carbonyl, is a potent and long-acting antagonist of bradykinin receptors [219][220]. This compound proved highly resistant to enzymatic degradation. It is not a substrate for kini-nase II and carboxypeptidases, and is only slowly degraded in human plasma. 

A number of nonnatural amino acids were resolved into individual enantiomers on 0-9-(2,6-diisopropylphenylcarbamoyl)quinine-based CSPby Peter and coworkers [48,90,113,114] after derivatization with Sanger s reagent, chloroformates (DNZ-Cl, FMOC-Cl, Z-Cl), Boc-anhydride, or acyl chlorides (DNB-Cl, Ac-Cl, Bz-Cl). For example, the four stereoisomers of P-methylphenylalanine, P-methyltyrosine, P-methyltryptophan, and P-methyl-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid could be conveniently resolved as various A-derivatives [113]. The applicability spectrum of cinchonan carbamate CSPs comprises also P-amino carboxylic acid derivatives, which were, for example, investigated by Peter et al. [114]. A common trend in terms of elution order of DNP-derivatized P-amino acids was obeyed in the latter study On the utilized quinine carbamate-based CSP, the elution order was S before R for 2-aminobutyric acid, while it was R before S for the 3-amino acids having branched R substituents such as wo-butyl, iec-butyl, tert-butyl, cyclohexyl, or phenyl residues. 

The geometric isomers 464 and 467 of 5(47/)-oxazolones prepared from acetophenones can be separated. Alternatively, the mixture can be isomerized under the appropriate reaction conditions to obtain the pure of (Z) or ) isomer. Each isomer can be converted to a pair of enantiomers 466 and 469 (only one enantiomer shown) (Scheme 7.152). The p-methyl phenylalanine analogues thus obtained are constrained phenylalanines and the effect of incorporation of a p-MePhe or p-MeTyr residue on the biological properties of H-Tyr-Tic-Phe-Phe-NH2 (TIPP, where Tic = l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) a delta opioid receptor antagonist, has been studied. ... 

To a stirred solution of 6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline (3.00 g, 15.4 mmol, 1.00 equiv.) in anhydrous pyridine (100 mL) under argon at room temperature was added acetic anhydride (14.5 mL, 154 mmol, 10.0 equiv.) over 15 min. The resulting mixture was stirred at room temperature for 2 h, and then at reflux for 6 h. The volatiles were removed by rotary evaporation at 80°C under high vacuum. The residue was flash chromatographed on silica gel (MeOH-CH2CI2 8 92) to afford 3.21 g (89%) of l-(6,7-dimethoxy-3,4-dihydro-lH-isoquinolin-2-yl)ethanone as a viscous brown oil. The H-NMR spectrum reflected the presence of two slowly interconverting conformers in a ratio of 1.2 1 at room temperature. 

In the case of acetophenone reactants l-aryl-l-methyl-tetrahydroisoquinolines are obtained. Conditions a mixture of 5 mmol of the b-phenylelhylamine derivative, 5 mmol of the aldehyde/ketone and 0.8 g E4a in ethanol was heated at 80 °C for 20/40 h. The solid was filtered off, the filtrate was evaporated and the residue characterised. Yields, according to NMR, are from 75-100 %. The catalyst could be easily recycled without significant loss of activity. 

In a similar fashion, 2-aroyl-l-methylene-l,2,3,4-tetrahydroisoquinoline enamides yield on irradiation the corresponding 8-oxoberberines.18 Cyclization of analogous enamides containing or/Ao-substituents in the aryl residue is followed by elimination of the substituent leading to formation of the unsaturated oxyprotoberberines.19 Thus, for example, the enamide (23) is converted on irradiation in benzene into the oxyprotoberberine (24), presumably via the intermediate (25). An alternative pathway involving methoxyl migration has been observed by other workers.20 Related cyclizations have been employed in the syntheses of ( )-angustoline21 and of lycorine-type alkaloids.22... 

A fiirther six additional ecteinascidins have subsequently been reported. Two, ecteinascidin 722 (97) and ecteinascidin 736 (98), contain two tetrahydroisoquinoline units (A and B) but the C unit is a tetrahydro-P-carboline residue [66]. The remaining four ecteinascidins, Et 597 (99), Et 583 (100), Et 594 (101) and Et 596 (102) are also biologically active and have been described as putative biosynthetic precursors of the other ecteinascidins [68]. These ecteinascidins also have tetrahydroisoquinoline units A and B, but L-cysteine or its a-oxo analogue is the C unit. Identification of the absolute stereochemis of that unit has led to confirmation that the absolute stereochemistries of the ecteinascidins are the same as for the safracins and saframycins [68]. 

Oxidation of codamine ethyl ether (LXVI) cleaved the benzylisoquinoline system to 4-methoxy-5-ethoxyphthalic acid (LXVH) and veratric acid (VT). While the formation of these two acids precluded the location of the phenolic hydroxyl in the benzyl residue, LXVTI could have arisen from either a 6- or 7-ethoxy-substituted isoquinoline system. This question was settled by repeating the potassium permanganate oxidation of 0.0085 g. of codamine ethyl ether (LXVI) under gentle conditions. This time, 1-ke-to-2-methyl-6-methoxy-7-ethoxy-l, 2,3,4-tetrahydroisoquinoline (LXVIII) was isolated its structure was confirmed by synthesis, and therefore codamine is XXII. 

In an attempt to determine the position of the phenolic hydroxyl in daphnandrine, Bick, Ewen, and Todd (112) ethylated i T-methyldaphnan-drine dimethiodide with ethyl iodide and ethanolic sodium ethoxide and then subjected the resulting V-methyl-O-ethyldaphnandrine to the Hofmann degradation. A methine base was obtained which on ozonolysis yielded 2-methoxy-4, 5-diformyldiphenyl ether (XXXIV) as before. This showed that the phenolic group in daphnandrine must be attached to one of the tetrahydroisoquinoline nuclei and cannot occupy a position in the benzyl residue as it does in oxyacanthine and repandine (XXVI). 

The chromatographically and chemically demanding pyridoxyl group which anyhow did not display the required tautomerizing activity could consequently be replaced by the cheaper benzyl residue (see Scheme 21) (33,38). Thus, reaction of diketones like 75 with benzylamine and subsequent reduction of the intermediate isoquinolinium salt 86 provided a very efficient one-pot synthesis of the required tetrahydroisoquinolines 92 and 93, which were moreover already ben-zylated for further syntheses. 

To a solution of 1 (1 mmol) in dichloroethane (2 mL) were added EtOH (293 pL, 5.02 mmol) and a suspension of AuClCPPhs) (1 mmol) and AgNTf2 (1 mmol) in dichloroethane (1 mL), and the reaction mixture was stirred at room temperature for stipulated time (0.5-7 h). On completion of the reaction, saturated aqueous NaHCOs was added and the product was extracted with CHCI3 (3x10 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by sihca gel column chromatography (hexane-EtOAc) to afford 1,2-dihydroisoquinoline 2 with 28-87% of yield. In a similar fashion, l-alkylydeneyl-l,2,3,4-tetrahydroisoquinoline 4 were prepared starting from substrate 3 with requisite amount of catalyst as mentioned in the reaction scheme. All the products were characterized with detailed spectral studies and elemental analyses. 

Methylthiazolidine-4-carboxylic acid, a condensation product of cysteine and acetaldehyde, occurs even in human blood as a consequence of ethanol consumption. Serine and threonine analogously produce C-2 substituted (2J S,4S)-oxazolidine-4-carboxylic acids (2-124). Heterocyclic products, C-2 substituted (2J S,4S)-pyrimidine-4-carboxylic acids, are also produced in the reaction of aldehydes with asparagine (2-125). Phenylalanine yields C-1 substituted (lJ S,3S)-tetrahydroisoquinoline-3-carboxylic acids (2-126) and analogous products arise from tyrosine. Tryptophan reacts with aldehydes under the formation of 9H-pyrido[3,4-b]indole (also known as -carboline or norharmane) derivatives, (lJ S,3S)-l,2,3,4-tetrahydro-fi-carboline-3-carboxylic acids (2-127, R = H or alkyl or residues of other aldehydes and sugars), the reaction of tryptamine yields the corresponding (lRS)-l,2,3,4-tetrahydro-P-carbolines. 

Surely, the introduction of a covalent bond between the aromatic ring of an a-amino acid residue and the peptide backbone has proven to be a useful further conformation restriction. For example, 1,2,3,4-tetrahydroisoquinoline carboxylic acid (Tic) is a cyclic constrained analog of phenylalanine (Figure 5), in which a methylene bridge is placed between the a-nitrogen, and 2 -carbon of the aromatic ring (Kazmierski Hruby, 1988). 

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