Tetrahy droisoquinolines

Reaction of tetrahydropyridin-4-one 119 and l,r-carbonyldiimidazole furnished l,3,4,4n,5,6-hexahydropyrido[l,2-c][l,3]oxazine-l,6-dione 120 (99JA2651). Similarly, pyrido[l,2-c][l,3]oxazine-l-one 121 and [1,3] oxazino[4,3-n]isoquinoline-4-one 122 were prepared from the respective 2-(2-hydroxypropyl)piperidine and l-(2-hydroxypropyl)-1,2,3,4-tetrahy-droisoquinoline (99JOC3790). Reaction of a 2 1 diastereomeric mixture of l-(l,2-dihydroxyethyl)-6,7-dihydroxy-l,2,3,4-dihydroisoquinolines 123 and 124 with l,l -carbonyldiimidazole gave a 2.7 1 mixture of 1,9,10-trihy-droxy-l,6,7,ll/)-tetrahydro-2//,4//-[l,3]oxazino[4,3-n]isoquinoline-4-ones 125 and 126, which were separated on preparative TLC plate (99BMC2525). 

Another common structural component of the isoquinoline alkaloids, particularly in the protoberberines, is the 7,8-disubstituted 1,2,3,4-tetrahy-droisoquinoline unit. The spectrum of 7,8-dimethoxy-l,2,3,4-tetrahydroiso-quinoline (4) showed two interesting chemical shift changes other than the expected shifts in the aromatic carbon atoms (14). First, it was found that C-l was shielded relative to the corresponding carbon atom of 2 by —4.6 ppm. This was attributed to the y steric effect of the C-8 methoxyl group on... 

In recent years, the Stevens rearrangement applied to cyclic systems has resulted in the formation of a variety of novel heterocycles. For example, benzylammonium salt 7 was found to undergo a facile [1,21-benzyl shift in aqueous sodium hydroxide at 5 °C to form the tetrahy-droisoquinoline derivative 8.11... 

Heating ethyl 6-methylpicolinate and ethylene oxide in methanol in a pressure bottle afforded 6-methylperhydropyrido[2,l-c][l,4]oxazin-l-one (66JMC311 68USP3388128). Similarly, l,3,4,6-tetrahydro[l,4]oxazino[4,3- >]isoquinolin-l-ones were prepared in the reactions of ethyl 1,2,3,4-tetrahy-droisoquinoline-3-carboxylates and ethylene oxide (85MI2). 

Irradiation of 1 -(2, 5 -dibromo-3 -thenyl)-2-acetyl-6,7-dimethoxy-1,2,3,4-tetrahy-droisoquinoline (208) in methanol/water (9/1) and sodium hydroxide yielded 6-acetyl-l,2-dimethoxy-4i/-5,6,6a,7-tetrahydrobenzo[bromine atoms are eliminated during the photolysis (equation 151). 

The peptides (17)-(22) were prepared by the usual solid-phase method of peptide synthesis utilizing different resins. The structures of D-Phe (22a) and its conformationally restricted phenylalanine analogue D-Tic (tetrahy-droisoquinoline-3-carboxyIic acid, 22b) positioned at the A-terminal position of the somatostatin analogues are shown. 

The pathways outlined in Scheme 3.3 overcome low yields encountered when 4-methoxybenzylmagnesium halides react with 5,6,7,8-tetrahy-droisoquinolinium salts (e.g., 2). Other routes were devised to achieve the same objective. Grewe et a/.(21) exploited the 1-lithium derivative of the tetrahy-droisoquinoline derived via the 1-amino intermediate, Scheme 3.4. 

Reaction of 17 with an anisaldehyde gave 18, which was readily converted to the morphinan precursor, 19. In a similar manner, l-chloro-5,6,7,8-tetrahy-droisoquinoline (20) gave the 1-benzyloctahydroisoquinoline amide (21)<22,23) that cyclized with the loss of the amide function to the corresponding morphinan. 

While the 4 -chloro analog (3, R = H, R2 = Cl) is only one tenth as active as morphine, a 5-nitro group in the benzimidazole nucleus raises activity by a factor of 30 (see 5) nitro groups placed elsewhere in this nucleus are ineffective. The only other active analgesics with nitro functions are a tetrahy-droisoquinoline and some N02-Phe4-enkephalins (p. 346). 

N-Hydroxymethylation occurs upon the catalytic decomposition of dimethoxymethane generating formaldehyde followed by Picket-Spengler cyclization forming the tetrahy-droisoquinoline. A review of the Pictet-Spengler synthesis in the preparation of tetrahydroiso-quinolines is provided (1). 

An attempt to utilize this conversion of amines into aldehydes in an isoquinoline synthesis was not successful. Instead, reaction between 2-(3,4-dimethoxyphenyl)ethylamine and isatin afforded only the spiro compound 150. Reaction between isatin and 2-(3-hydroxy-4-methoxyphenyl)ethylamine gave a mixture of two spiro compounds, while a reaction of isatin, this amine, and benzylamine gave 6-hydroxy-7-methoxy-1 -phenyl-1,2,3,4-tetrahy droisoquinoline. ... 

Section II,A,3) (73JOC1947). Isoquinoline-4-carboxylic acid, 5,6,7,8-tetrahy-droisoquinoline, and 7-methoxyisoquinoline have also been successfully aminated (78RCR1042). 

Several other biomimetic approaches to the synthesis of cephalotaxine have also been reported. In 1977, Kupchan etal. (72,73) prepared tetrahy-droisoquinoline 214, which underwent intramolecular oxidative coupling to 215 by means of vanadium(V) oxytrifluoride and trifluoroacetic acid/ trifluoroacetic anhydride (Scheme 38). Treatment of 215 with 1 N sodium hydroxide in methanol yielded the ring-expanded product, imine 216, which was converted in five steps to amine 217. Transannular cyclization of 217... 

Ohta, S., Tachikawa, O., Makino, Y., Tasaki, Y. and Hirobe, M. (1990) Metabolism and brain accumulation of tetrahy-droisoquinoline (TIQ) a possible parkinsonism inducing substance, in an animal model of a poor debrisoquine me-tabolizer. Life Sci. 46 599-605. 

Su W, Yu J, Li Z, Jiang Z. Solvent-free cross-dehydrogenative coupling reactions under high speed ball-milling conditions applied to the synthesis of functionahzed tetrahy-droisoquinolines. J Org Chem 2011 76 9144-50. 

The El spectrum of 0-methylpellotine (Af = 251) in Figure 4.10a reflects a problem that is encountered in the interpretation of the mass spectra of tetrahy-droisoquinoline alkaloids in general. A molecular ion peak is not observed, but an intense peak in the high-mass region occurs at m/z 236, and a weak peak is seen 14 mass units higher at m/z 250. There are two possible interpretations for these data. 

Anhalonium alkaloick isoquinoline alkaloids found primarily in cacti. They all have a tetrahy-droisoquinoline skeleton carrying several phenolic hydroxyl groups (which may be etherified) on Ring B. 

For alternative approaches to tetrahy-droisoquinoline derivatives employing this same methodology, see ... 

Similarly, arylalkynes with ortAo-substituted carbamates cyclized via either 6-endo-dig or 6-exo-dig mode to form hydroisoquinolines.Interestingly, the addition of EtOH (5 equiv) substantially accelerated the reactions (eq 16). This general strategy was used in the construction of the CDE ring system of tetrahy-droisoquinoline alkaloids. ... 

Synthetic Studies Toward Saframycin B and Ecteinascidin 743 (Yondelis) Tetrahy-droisoquinoline alkaloids are a broad family of biologically active natural products. Takemoto et al. [39] have carried out a concise synthesis of the CDF ring system present in this kind of alkaloids (Scheme 2.36). Both An(I)-catalyzed intramolecnlar hydroamination of alkynyl amide and NBS-mediated oxidative FC cyclization were utilized as key reactions. By rednctive alkylation of a-amino acid derivative 235 with aldehyde 236, the conpling prodnct 237 was obtained... 

Wang et al. reported the synthesis of several tetrahy-droisoquinolines 311 by the reaction of N-protected... 

With Copper In 2008, Basle and Li reported [107] a copper-catalyzed oxidative sp C-H bond arylation with aryl boronic acids (Scheme 4.19). This method provides access to biologically active tetrahy-droisoquinoline products. Either peroxide or molecular oxygen can be used as the oxidant. On using PhPyBox ligand, an enantioselectivity as high as 44% ee using CuOTf was obtained. 

---