Tetrahydroisoquinolines, 4-substituted

Optically active 4-substituted tetrahydroisoquinolines have been formed regio- and stereo-selectively via formation of aziridinium ions which then ring expand through action as electrophiles in intramolecular Friedel-Crafts reactions (Scheme 204). 

An enzyme-catalyzed appHcation has been used to prepare the enantiomers of hydroxy-substituted tetrahydroisoquinolines (160). The synthesis of ( V)-reticuline [485-19-8] (30) has been reported using similar methodology (161). The substitution of formic acid and paraformaldehyde in this method leads to lower reaction temperatures, freedom from hydrolysis of protective groups, and improved yields (162). 

The chiral (V-camphanoyl iminium ion 7, prepared by hydride abstraction from 2-camphanoyl-l,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline 6 (see Appendix) with triphenylcarbenium te-trafluoroborate, reacts with silyl enol ethers to give 1-substituted tetrahydroisoquinoline derivatives with reasonable diastereoselectivity, 0°. On addition of titanium(IV) chloride, prior to the addition of the silyl enol ether, the diastereoselectivity gradually rises to an optimum at 2.5 equivalents of the Lewis acid, but the yield drops by 20%. 

Chiral tetrahydroisoquinoline derivatives can be obtained by diastereoselective or enatioselective protonation. Deprotonation of lactam 87 with n-BuLi followed by addition of H2O and NH4CI afforded 88 in 92% yield and 97% ee. The stereoselectivity was highly dependent upon the proton source. Further elaboration afforded tetrahydroisoquinoline 89 in >97% ee . The enantioselective protonation of 1-substituted tetrahydroisoquinoline 90 in the presence of chiral amine 91 proceeded in 90-95% yield and 83-86% ee. This methodology was used in an asymmetric synthesis of salsolidine <00SL1640>. 

Special cases concerning the reactivity of intermediate 331 with electrophiles involve the use of A -silylimine or epoxides. In the first case, aminoalcohol 333 was prepared, which was easily cyclized (thionyl chloride followed by basic treatment) to the corresponding substituted tetrahydroisoquinoline 334 (Scheme 98) . ... 

Gawley and coworkers showed that oxazolines can be used in place of formamidines for asymmetric alkylations of tetrahydroisoquinolines. A number of substituted oxazolines were evaluated as chiral auxiliaries, and one derived from valinol was found to be optimal. Interestingly, the same enantiomer of valinol affords the opposite enantiomers of the substituted tetrahydroisoquinoline when incorporated into formamidine or oxazoline auxiliaries. An example is shown in Scheme 58, as applied to a synthesis of laudanosine and the morphinan 9-7 -0-methylflavinantine. ° ... 

The prefix "seco" is an unusual term occasionally encountered in the literature of natural products. Just as the term "ortho-attack" indicates the generation of a new ring, the term "seco" indicates the destruction of a ring. A secoisoquinoline is formed from a 1-substituted tetrahydroisoquinoline by the loss of the 1,2-bond. Transferring a hydrogen atom from the a-carbon to the nitrogen, and reshuffling the electrons, results in the formation of a new double bond. 

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. 

The Meisenheimer rearrangement of substituted tetrahydroisoquinoline IV-oxides <1996CHEC-II(9)183> has been further exploited as a convenient approach for the synthesis of 2,3-benzoxazepine derivatives <1997MI13>. 

Dihydroisoquinolines. The N-chlorination-dehydrochlorination sequence with K02 (8, 417) can be used to convert 1,2,3,4-tetrahydroisoquinoline (1) to 3,4-dihydroisoquinoline (2) and 1-substituted tetrahydroisoquinolines (3). ... 

Ortwine DF, Malone TC, Bigge CF, Drummond JT, Humblet C, Johnson G, Pinter GW (1992) Generation of N-methyl-D-aspartate agonist and competitive antagonist pharmacophore models. Design and synthesis of phosphonoalkyl-substituted tetrahydroisoquinolines as novel antagonists. J Med Chem 35 1345-1370. 

The palladium-based coupling to 1-substituted tetrahydroisoquinolines has been reported using standard conditions (Equation 54) <2002JOC465>, with the asymmetric versions reported to be part of ongoing studies. 

Ring cleavage of hydroxyalkyl-substituted tetrahydroisoquinoline 551 followed by ring closure to their corresponding isochromans 552 is affected by chlorothiono-, chlorothiol-, and chlorodithiolformates in moderate yield (Scheme 119, Table 26) <2003BKC256>. 

The synthesis of 1-substituted tetrahydroisoquinolines using an intramolecular Pd-catalyzed a-enolate arylation was described. Treatment of a-amino esters such as 71 and 73 with LiOr-Bu, Pd2(dba)3 and ligand 75 or 76 afforded the corresponding isoquinolines 72 and 74. Investigations to develop an asymmetric version of this reaction were reported to be ongoing <02JOC465>. 

A practical ligand-free palladium-catalyzed intramolecular reductive Heck cyclization was developed by Liu et al. <07TL2307>. The authors found that water was an essential component of the reaction mixture. Using a series of aryl halide intermediates this cyclization resulted in the desired 1,2,3,4-tetrahydroisoquinolines in high yields. Cook and co-workers found that InCU was an efficient catalyst for an intramolecular Friedel-Crafts cyclization of Ar-(4-bromobut-2-enyl)-A-(bcnzyl)-4-methylbcnzcncsulfonamidc to form the desired 3-substituted tetrahydroisoquinolines <07OL1311>. 

The aromatic, tetramethoxy-substituted, tetrahydroisoquinoline alkaloid weberine has been isolated recently from extracts of the Mexican cactus Pachycereus weberi (38). The rare occurrence of four adjacent methoxy groups on an aryl moiety prompted the synthesis and examination by crystal-structure analyses of analogs and derivatives with four and five adjacent methoxy groups on the phenyl ring. In contrast to the problem with... 

This method of asymmetric alkylation has been performed in a number of other systems with equally good enantioselectivity. Tetrahydroisoquinolines have been alkylated (Eq 1) with various alkyl halides to give l substituted tetrahydroisoquinolines in 50-70% overall yields and with excellent ee s. Several naturally occurring isoquinoline alkaloids have also been prepared (compounds A-C) in 95-98.5% ee. A number of chiral auxiliaries other than the valine-based tert-butyl ether also have been examined and gave 80-99% ee s after alkylation. However, the authors consider the chiral auxiliary used in the present procedure to be superior to the others. 

Hegedues, A., Hell, Z. One-step preparation of 1-substituted tetrahydroisoquinolines via the Pictet-Spengler reaction using zeolite catalysts. Tetrahedron Lett. 2004, 45, 8553-8555. 

An example of a Hansch analysis (see section III. B. 2.a) using MLR is a study on substituted tetrahydroisoquinolines with affinity for both phenylethanolamine iV-methyltrans-ferase (PNMT) and the a2-adreno-receptor " (see Figure 23.10). The multiple regression equations obtained were ... 

The absolute configurations of (If , 4R)-l,2,3,4-tetrahydro-4-hydroxy-6-methoxy-2-methyl-l-phenylisoquinoline (31) and its epimer (IS, 4R), synthesised fromD-(+)-2-amino-l-(3-hydroxyphenyl)ethanol, have been determined with the aid of n.m.r. spectral and o.r.d. and c.d. measurements.42 These results may prove to be useful in the determination of the absolute configuration of 1-phenyl-isoquinoline alkaloids. In this regard, another report on the conformation and configuration of differently substituted tetrahydroisoquinolines may be consulted.43... 

Preparation of 1-substituted tetrahydroisoquinolines via the Pictet-Spengler reaction using a natural zeolite catalyst... 

The reduction of imines such as 3,4-dihydroisoquinolines with chiral sodium triacyloxyborohydrides [NaB(0acyl)3H] has been effected in optical yields of up to 1 % Two new methods for the preparation of 1-substituted tetrahydroisoquinolines have been reported. These both involve directed 1-lithiation and subsequent reaction with electrophiles. The directing groups on nitrogen are CH=N-R and P(0)(NMe2)2 (see above) respectively, both of which are readily removable. 

The number of alkaloids based on the 1-substituted tetrahydroisoquinoline skeleton is legion and the structural variation which this skeleton affords, particularly in the case of 1-benzylisoquinolines, is rich. The 1-substituted isoquinoline skeleton of each kind probably arises by the common step of condensing a j8-arylethylamine with an appropriate carbonyl compound, for which the Pictet-Spengler reaction provides an analogy. In some cases the participation of a carbonyl compound is established but in others it is still speculative. Recently progress has been made in this area in studies on the biosynthesis of lophocerine, the Papaver alkaloids, and to some extent the cryptostyline alkaloids with their novel 1-phenylisoquinoline structures. 

Phosphonoalkyl-substituted tetrahydroisoquinolines have been proposed as competitive antagonist models. Their structures were derived from an agonist pharmacophore model for NMDA. The most active was l,2,3,4-tetrahydro-5-(2-phosphonoethyl)-3-isoquinolinecarboxylic acid (9, R = H, = COOH, R = S-CHjCHjPOjHj). Less potent were V-(phosphonoalkyl)phenyl-(10) m or =1, R = H) and V-(phosphonoalkyl)-a-amino acids The subject has been reviewed ". ... 

Humblet, C., Johnson, G., Malone, T. and Ortwine, D. F (1990) Design, synthesis and molecular modeling of phosphonoalkyl-substituted tetrahydroisoquinolines as competitive NMDA antagonists. In Proceedings of the Xlth International Symposium on Medicinal Chemistry, Jemsalem, Israel. 

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