2- -1,2,3,4-tetrahydroisoquinoline-3-carboxylate

Phosphinous amides, based on proline and tetrahydroisoquinoline carboxylic acid, bearing a second donor center (50, Ar=Ph R =H, CH3,Tr, Ph R =H, CH3,Tr, Ph and 51, R =H,Tr R =H,Tr) (Scheme 40) have been developed for use in allylic alkylation and amination of substituted propenyl acetates, yielding the corresponding products in 87-98% (5-94% ee) and 29-97% (14-93% ee) respectively [55, 167]. With bidentate ligands of type 38 where R=(S)-PhMeCH, and with the bis(aminophosphanes) 52 (R=Ph) similar allylic alkylations have been also tested [168,169]. 

Intramolecular arylation of the amino acid ester 77 afforded the tetrahydroisoin-dole carboxylate 78, and the tetrahydroisoquinoline carboxylate 80 was obtained from the amino acid ester 79. In the cyclizations, ligand IV-12 was used [45]. 

Shortly after, the development of the intramolecular variant of this reaction was reported by Gaertzen and Buchwald [106]. A simple and flexible route to obtain dihydroisoindole and tetrahydroisoquinoline carboxylic acid derivatives was developed using the palladium-catalyzed intramolecular a-arylation of readily available a-amino acid esters (Scheme 8.58). The construction of quaternary carbon centers that tolerate a number of different substituents around the enolate center, including phenyl or bulky isopropyl groups, was reported. A number of different Af-substituents including alkyl, aryl, or carboxyl groups could be employed [106]. 

Scheme 8.58 Synthesis of dihydroisoindole and tetrahydroisoquinoline carboxylic acid esters [106].

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). 

Kazmierski, W. Hruby, V.J. (1988) A New Approach to Receptor Ligand Design -Synthesis and Conformation of a New Class of Potent and Highly Selective Mu-Opioid Antagonists Utilizing Tetrahydroisoquinoline Carboxylic-Acid Tetrahedron, Vol. 44, No. 3, pp. 697-710. 

Isoquinoline can be reduced quantitatively over platinum in acidic media to a mixture of i j -decahydroisoquinoline [2744-08-3] and /n j -decahydroisoquinoline [2744-09-4] (32). Hydrogenation with platinum oxide in strong acid, but under mild conditions, selectively reduces the benzene ring and leads to a 90% yield of 5,6,7,8-tetrahydroisoquinoline [36556-06-6] (32,33). Sodium hydride, in dipolar aprotic solvents like hexamethylphosphoric triamide, reduces isoquinoline in quantitative yield to the sodium adduct [81045-34-3] (25) (152). The adduct reacts with acid chlorides or anhydrides to give N-acyl derivatives which are converted to 4-substituted 1,2-dihydroisoquinolines. Sodium borohydride and carboxylic acids combine to provide a one-step reduction—alkylation (35). Sodium cyanoborohydride reduces isoquinoline under similar conditions without N-alkylation to give... 

Implication of the same type of intermediate (342 X = H) allows the rationaUzation of the acid-catalyzed decarboxylation of 1,2,3,4-tetrahydro-j8-carboline-l-carboxylic acids. As is stated in Section III,A,1, a, the tetrahydroisoquinoline-1-carboxylic acids and a-amino acids of analogous structure are converted into the corresponding... 

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). 

Cyclocondensation of 2-(2-chloroacetyl)-l, 2,3,4-tetrahydroisoquinoline-3-carboxylate 418 (R =N02, R = Me) with liquid NH3 in MeOH in a stainless steel pressure vessel at room temperature overnight gave 8-nitro-2,3,4,6,1 1,1 la-hexahydro-l//-pyrazino[l,2-i]isoquinoline-l,4-dione (419, R=H, R =N02) (97MIP4). (1 la/i)-2-Cycloalkyl-8-hydroxy-2,3,4,6,ll, 1 la-hexahydro-l//-pyrazino[l,2-i]isoquinoline-l,4-diones 419 (R = cycloalkyl, R = OH) were prepared in the reactions of (3/i)-2-chloroace-tyl-l,2,3,4-tetrahydroisoquinoline-3-carboxylate (418, R = OH, R = Et) with cycloalkylamines (98MIP7). 

The reaction of electron deficient iV-benzenesulfonyl- 3-phenethylainines 84 with ethyl chloro(methylthio)acetate gives tetrahydroisoquinoline-1-carboxylates 85 in high yields <96H(42)141>. 

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. 

Ugi five-center three-component reaction of pipecolinic acid and glycol aldehyde dimer with isocyanides gave a 1 1.7-2.1 diastereomeric mixture of l-oxoperhydropyrido[2,Tc][l,4]oxazine-9-carboxamides 397 (Scheme 35) <20010L4149>. Using CF3CH2OH as solvent is critical for the reaction. When 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid was employed, 1,3,4,6,11,11 a-hexahydro-[ l,4]oxazino[4,3+]isoquinoline-4-carboxarnide was formed. 

Diels-AIder reactions were utilized to prepare isoquinoline derivatives. Various tetrahydroisoquinoline-3-carboxylic acid derivatives were prepared by an enyne metathesis followed by a Diels-AIder reaction. For example the enyne 71 was treated with Grubb s catalyst to afford diene 72 in 65% yield. Subsequent Diels-AIder reaction and oxidation gave tetrahydroisoquinoline 73 in 93% yield <0OCC5O3>. Dihydrosoquinoline 75 was prepared... 

Peroxidase and laccase enzymes were used to catalyze the decarboxylation of various tetrahydroisoquinoline-1-carboxylic acids to give high yields of the corresponding 3,4-dihydroisoquinolines (204). Compounds such as 125 (Scheme 29) are derived from Pictet-Spengler ring closure via a-keto acid and aryl amine condensation and are of biogenetic importance. The possible relevance of iso-... 

Scheme 29. Oxidative decarboxylation of tetrahydroisoquinoline-1-carboxylic acids by fungal laccase and horseradish peroxidase.

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. 

Matter, H., Schudok, M., Schwab, W., Thorwart, W., Barrier, D., Billen, G., Haase, B., Neises, B., Weithmann, K., WOLLMANN, T. Tetrahydroisoquinoline-3-carboxylate based matrix-metalloproteinase inhibitors design, synthesis and structure-activity relationship. Bioorg. Med. Chem. 2002, 10(11), 3529-3544. 

Tetrahydroisoquinoline-3-carboxylate based matrix metalloproteinase inhibitors design, synthesis and structure-activity relationship. Bioorg. Med. Chem. 2002, 10, 3529-3544. 

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