Biologically tetrahydroisoquinolines

Mannich and Mannich-like reactions are widely used for the chemical synthesis of heterocycles, and in alkaloid biosynthesis in plants. One such reaction important in nature is a biological equivalent of the Pictet-Spengler tetrahydroisoquinoline synthesis (see Section 11.10.4), and offers a slight twist, in that the enol nucleophile is actually a phenol. 

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. ... 

Substituted tetrahydroisoquinolines may be determined by oxidation in situ in biological fluids after the separation and oxidation by UV irradiation to the isoquinolinium derivatives [140]. The fluorescence of the derivatives is ca. five-fold greater than obtained only by oxidation in solution, and permits detection of 1-2 ng/ml of sample. 

In order to evaluate the consequences of the replacement induced by substituting a SiMe2 group for a methylene group on their biological activity, two series of tetrahydrosilaisoquinolines and tetrahydroisoquinolines derivatives have been synthesized and compared.508-511... 

The enormous number of naturally occurring isoquinoline alkaloids, and their importance biologically, has stimulated a great deal of effort in their synthesis. The asymmetric alkylation of the 1-position of the tetrahydroisoquinoline nucleus affords an extremely valuable method for the construction of... 

All the examples mentioned above belong to 1-oxoisoquinoline ring system. 3-Oxo-isoquinolones 76 are also found in nature. They possess various biological activities On reduction they furnish tetrahydroisoquinolines. 

Isoquinoline derivatives are an important family of natural products. They have diverse biological activities and are used, for example, as bronchodi-lators, skeletal muscle relaxants, and antiseptics. The solid-phase synthesis of a 43,000-compound tetrahydroisoquinoline 2 combinatorial library has been reported by Griffith et al. [32]. The library was synthesized by a three-step procedure. An imine was formed by reacting a substituted benzaldehyde with a methylbenzhydrylamine (MB HA) resin-bound amino acid. Imine formation was driven to completion using trimethylorthoformate as a dehydrating reagent. Treatment of the imine with homophthalic anhydride provided the desired tetrahydroisoquinoline (Fig. 3a). 

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]. 

The especially widespread occurrence of the less oxidized corresponding di-and tetrahydroisoquinolines in both families (see Sections II and III) requires more detailed considerations on the biological source of the nitrogen, also in view of the uncommon use of the toxin ammonia outside the primary metabolism (57). Moreover, formation of fully conjugated isoquinolines according to Scheme 3 would necessitate a subsequent hydrogenation of the resulting stable aromates 33 and 35, a biochemically unusual reaction type (5), which also, chemically, requires relatively hard reaction conditions (e.g., Zn-HCl, see Section V,C,3). 

Anodic monofluorination of the biologically interesting oxindole 61 has been described. This process was greatly affected by use of supporting fluoride salts. Et4NF4HF was the most effective sdt for this purpose (Table 19) when used with a carbon or platinum anode. The 3-0X0-1,2,3,4-tetrahydroisoquinoline derivative 63 was success-... 

Cribrostatin 4 (41), a member of the tetrahydroisoquinoline family of natural products, was isolated in 2000 from the blue sponge Crihrochalina [18] and has been shown to display cytotoxic and antimicrobial activities at low micromolar concentrations [19]. Both the complex molecular architecture and biological profile of (—)-cribrostatin 4 have attracted the interest of the synthetic community, with a number of synthetic approaches towards the alkaloid reported to date [20]. 

The Pictet-Spengler (PS) reaction is an important method to construct biologically important tetrahydroisoquinoline and tetrahydro- 3-carboline skeletons. Since it represents the intramolecular Friedel-Crafts cyclization of arenes and imines, we cover the asymmetric organocatalytic PS reaction in this chapter [61]. 

Examples of improved chemoselectivity by immobilized diyne on a solid-support [19-21] or of improved reactivity of less reactive alkynes by use of microwave [21-24] were recently described. A wide variety of diynes and monoynes containing functional groups were applied to this reaction in the past decade. Arylboronates [25, 26] and diiodo benzenes [27, 28] [Eq. (12)] were thus obtained and involved in further transformatiOTis. Several types of compounds able to present biological activities could also be synthesized such as benzo-fused lactams and lactones [23, 29] [Eq. (13)], phtalans [19], indanones [20], indanes [21], phenanthridines [22], benzoproline and tetrahydroisoquinoline derivatives [30, 31], C-arylglycosides and C-arylribosides [32-35]. Recently, this ruthenium-catalyzed [2+2+2] cycloaddition between a diyne and a monoalkyne was also used as reaction step in total syntheses [20, 23, 24, 36]. 

Borkowski PR, Horn JS, Rapoport H (1978) Role of 1,2-dehydroreticulinium ion in the biosynthetic conversion of reticuline to thebaine. J Am Chem Soc 100 276-281 Brossi A (1982) Mammalian TIQ s products of condensation with aldehydes or pyruvic acids In Bloom F, Barchas J, Sandler M, Usdin E (eds) Progress in clinical and biological research Beta-carbolines and tetrahydroisoquinolines,vol 90. Liss, New York, p 125 Cramer CL, Ristow JL, Paulus TJ, David RH (1983) Methods for mycelial breakage and isolation of mitochondria and vacuoles of Neurospora. Anal Biochem 128 384-392 Fahn A (1979) Secretory tissues in plants. Academic, London New York, pp 223-243 Fairbairn JW, Kapoor LD (1960) Laticiferous vessels of Papaver somniferum, Planta Med 8 49-61... 

Simple tetrahydroisoquinoline alkaloids are obtained upon condensation of phenylethylamines and catecholamines with carbonyl compounds. In a subsequent Mannich-hke reaction, the biosynthetic equivalent to a Pictet-Spengler reaction, the heterocyclic ring system is established. Numerous examples of simple tetrahydroisoquinoline alkaloids have been isolated from different plant sources. Several of these tyrosine-derived secondary metabolites exhibit intriguing biological and physiological properties, due to their structural relationship to catecholamines and phenylethylamines. 

Tetrahydroisoquinolines bearing a chiral center at the Cl position constitute a structural motif found in many biologically active compounds. For instance, (5)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-l-carboxylic acid 114 is a precursor of the natural product (5)-calycotomine (Scheme 57.31). Kanerva, Fiilbp, et al. have described the preparation of both enantiomers of 114 by enzymatic hydrolysis of the ethyl ester derivative rac-113. Considering this substrate undergoes spontaneous racemization in an aqueous medium, these authors carried out an exhaustive study of the reaction variables in order to find the optimal conditions and thus achieve the DKR of this substrate. Two enzymes with opposite enantiopreferences were used CAL-B and... 

Chemistry and biology of the tetrahydroisoquinoline antitumor antibiotics. Scott, J.D., Williams, R.M. 

Cyclization of iminium ions onto arenes were first described by Pictet and Spengler in 1911, with the formation of tetrahydroisoquinoline 152 (Equation 10) [125]. This versatile transformation has been widely used in the diastereoselective synthesis of polycyclic aromatic alkaloids of biological interest, in particular of tetrahydro-/5-carbolines 154 (Equation 11) [126]. A few selected examples that highlight stereoselective Pictet-Spengler reactions are discussed below [9, 103, 127]. 

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