Total synthesis of (±)-fangchinoline

(±)-Fangchinoline was synthesized by condensation of (±)-1-(3-bromo-4-methoxy-benzyl)-2-methyl-6-methoxy-7-hydroxy-8-bromo-1,2,3,4-tetrahydroisoquinoline ( 2 ) and (±)-1-(4-hydroxy-benzyl)-2-methyl-6-methoxy-7-hydroxy-1,2,3,4-tetrahydroisoquinoline ( 3 ) in the presence of copper, pyridine and potassium carbonate.     

Studies on Debenzylation and Photolysis of 1-Benzyl- and 1-(β-Phenethyl)-1,2,3,4-tetrahydroisoquinolines

Debenzylation of 1-(3-benzyloxybenzyl)-1,2,3,4-tetrahydroisoquinolines 1 , 6 , 7 with hydrochloric acid and ethanol gave the corresponding phenolic isoquinolines 2 , 8 , 9 and tetrahydroprotoberberines 4 , 12 , 13 . Compounds 2 , 8 , 9 on photolysis also gave, besides the expected noraporphines 3 , 10 , 11 , the tetrahydroprotoberberines 4 , 12 , 13 [1–4] (Schemes 1 and 2). 6-Benzyloxy-1-(5-benzyloxy-2-bromo-benzyl)-1,2,3,4-tetrahydroisoquinoline (27a) containing no methoxy or methylenedioxy groups either in ring A or C does not give protoberberine during debenzylation; but 28 , the debenzylation product of 27a , on photolysis gives both the noraporphine 29 and the tetrahydroprotoberberine 30 (Scheme 6), proving that during debenzylation of 1-(3-benzyloxybenzyl)-1,2,3,4-tetrahydroisoquinolines containing additional methoxy or methylenedioxy groups, the necessary formaldehyde comes from the latter groups. During photolysis both the methoxy groups (methylenedioxy groups) and the C(3) atom of the tetrahydroisoquinoline moiety provide the formaldehyde. Veratrole under debenzylation and photolytic conditions and tetrahydroisoquinoline under the latter condition also give rise to formaldehyde (Schemes 8 and 10). The novel bromohomoprotoberberine 43 along with 42 was formed during debenzylation of the 1-phenethyl-1,2,3,4-tetrahydroisoquinoline 41 . Photolysis of 42 yielded the novel nor-homoaporphine 44 , in addition to 43 ; the latter was debrominated to give the homoberbine 45 .     

Reaction of N-nitroaryl-1,2,3,4-tetrahydroisoquinoline derivatives with oxygen

Heating N-4′-methyl-2′-nitrophenyl-1,2,3,4-tetrahydroisoquinoline ( 1 ) in the presence of oxygen gave both products derived from cleavage of the C8a? Cl bond and oxidation at the 1-position. Under similar conditions N-4′-nitrophenyl-1,2,3,4-tetrahydroisoquinoline ( 4 ) gave only the oxidation product.     

Synthesen in der Isochinolinreihe: Zur Ätherspaltung 6,7,8-trimethoxy-substituierter Isochinolinverbindungen mit wässeriger Salzsäure

Zusammenfassung Die Behandlung des 6,7,8-trimethoxy-substituierten 1,2,3,4-Tetrahydroisochinolins (I) mit 20proz. wäßr. HCl ergibt zur Hauptsache das entsprechende 6,7,8-Trihydroxyderivat II. Die Behandlung des analog substituierten 3,4-Dihydroisochinolins IV und Isochinolins XXI führt hauptsächlich zu den 6,8-dimethoxy-7-hydroxy-substituierten Isochinolinverbindungen V und XXII, unter selektiver Spaltung der in 7-Stellung befindlichen Methoxyl-gruppe. Die Konstitution von V und XXII konnte durch Synthese und Abbau bewiesen werden.

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Treatment of the 6,7,8-trimethoxy-substituted 1,2,3,4-tetrahydroisoquinoline I with 20% aqueous HCl yields predominantly the corresponding 6,7,8-trihydroxy derivative II. The analogously substituted 3,4-dihydroisoquinoline IV and isoquinoline XXI are converted into their 6,8-dimethoxy-7-hydroxy derivatives V and XXII under these conditions. The constitution of these phenols was established by synthesis and degradation.

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Herrn Prof. Dr.H. Bretschneider zum 60. Geburtstag gewidmet.     

Synthesis and pharmacological evaluation of 2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinoline derivatives as specific bradycardic agents

Novel 1,2,3,4-tetrahydroisoquinoline derivatives bearing directly a cyclic amine at the 2-position were prepared and examined for their bradycardic activities in isolated right atria and in anesthetized rats. The structure-activity relationships (SAR) study revealed that the 2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinoline skeleton is essential for the appearance of potent in vitro activity, and that the presence of at least one methoxy group at the 6- or 7-position of the 1,2,3,4-tetrahydroisoquinoline ring is important to exert potent in vitro activity. In vivo tests of selected compounds demonstrated that 2-(1-benzyl-3-piperidyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (6c) exhibited potent bradycardic activity with negligible influence on mean blood pressure in rats, although its potency is a half of that of Zatebradine.     

Enantioselective addition of organolithium reagents to 3,4-dihydroisoquinoline in the presence of (−)-sparteine as an external ligand. Application for the synthesis of isoquinoline alkaloids

Three isoquinoline alkaloids, (−)-salsolidine 2, (+)-carnegine 6 and (−)-1-phenyl-2-methyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 7, were obtained in high yield and with 17–46% e.e. by the enantioselective additions of organolithium reagents to dihydroisoquinolines 1 and 5, in the presence of (−)-sparteine as a chiral ligand.     

A synthesis of 3-phenyl-1,2,3,4-tetrahydroisoquinoline and 2-phenyl-1,2,4,5-tetrahydro-3H-3-benzazepine via Pummerer-type cyclization: enhancing effect of boron trifluoride diethyl etherate on the cyclization

A synthesis of 6,7-dimethoxy-3-phenyl-1,2,3,4-tetrahydroisoquinoline (14a) and 7,8-dimethoxy-2-phenyl-1,2,4,5-tetrahydro-3H-3-benzazepine (14b) was achieved via the cyclization of N-(3,4-dimethoxyphenyl)methyl-1-phenyl-2-(phenylsulfinyl)ethylformamide (6a) and N-2-(3,4-dimethoxyphenyl)ethyl-1-phenyl-2-(phenylsulfinyl)-ethylformamide (6b) using the Pummerer reaction as a key step, respectively. The Pummerer reaction of 6a,b under usual conditions using trifluoroacetic anhydride yielded the vinyl sulfides (8a, b), non-cyclized products, as a major product. The cyclization proceeded when boron trifluoride diethyl etherate was used as an additive reagent, thus giving rise to the corresponding cyclized products (7a) and (7b) in moderate yields. We propose that the enhancing effect of the Lewis acid on the cyclization may be attributable to the involvement of a dicationic intermediate, sulfonium-carbenium dication (23).     

An effective method for the preparation of mono N-alkyl derivatives of 1,1′-bis(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline)

The condensation of 1,1′-bis(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline) with alkyl, aralkyl and aryl aldehydes, but not ketones, in ethanol or chloroform provides useful cyclic aminal [8-substituted 5,6,10,11,15b,15c-hexahydro-2,3,13,14-tetramethoxy-8H-imidazo[5,1-a:4,3-a′]diisoquinoline] intermediates that when subsequently treated with sodium cyanoborohydride in ethanol, followed by the addition of 2 M hydrochloric acid, gave monosubstituted N-alkyl 1,1′-bis(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline) derivatives in very high yields. The rates of the initial condensation with four different aldehydes were measured, and the entire sequence was successfully applied in one example to a ‘one-pot’ process; this signals a versatile route to differentially N-substituted 1,1′-bis(1,2,3,4-tetrahydroisoquinoline) derivatives.     

Amide rotamers of N-acetyl-1,3-dimethyltetrahydroisoquinolines: synthesis, variable temperature NMR spectroscopy and molecular modelling

Mercury(II)-mediated ring closure of N-[1-(2-allyl-3-benzyloxy-4,6-dimethoxyphenyl)ethyl]acetamide 9 afforded N-acetyl-5-benzyloxy-6,8-dimethoxy-1,3-trans-dimethyl-1,2,3,4-tetrahydroisoquinoline 8. The product was shown to exist as a mixture of amide rotamers by NMR spectroscopy, since signals coalesced at higher temperatures. Variable temperature NMR spectroscopy and molecular modelling were used to investigate these rotamers and gave average values for the barrier of rotation in the range of 15-16 kcal mol⁻¹. 2-[2-[1-(Acetylamino)ethyl]-6-(benzyloxy)-3,5-dimethoxyphenyl]-1-methylethyl methanesulfonate 17 was also cyclized with sodium hydride to afford the same rotameric products with the same tetrahydroisoquinoline skeleton, but as a mixture of 1,3-trans- and cis-dimethyl isomers.     

A contribution to the asymmetric synthesis of isoquinolines: Concise stereoselective approach to (3S,4S)-6,7-dimethoxy-4-hydroxy-3-phenyl-1,2,3,4-tetrahydroisoquinoline

A highly efficient stereoselective synthesis of (3S,4S)-6,7-dimethoxy-4-hydroxy-3-phenyl-1,2,3,4-tetrahydroisoquinoline 8 (e.e.=96%) starting from enantiomerically pure imine 3 is reported.     

Methyl trifluoropyruvate in the Pictet-Spengler reaction

Condensation of methyl trifluoropyruvate with 2-(3,4-dimethoxyphenyl)ethylamine, tryptamine, and (D, L)-tryptophan yielded 1-methoxycarbonyl-1-trifluoromethyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, 1-methoxycarbonyl-1-trifluoromethyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole, and Z-1-methoxycarbonyl-1-trifluoromethyl-3-carboxy-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole, respectively. The Z configuration of the latter was determined by x-ray structural analysis.A. N. Nesmayanov Institute of Organoelemental Compounds, Russian Academy of Sciences, 117813 Moscow, Russia. Translated from Izvestiya Akademii Nauk, Seriya Khimicheskaya, No. 8, pp. 1831–1836, August, 1992.     

Versuche zur enantiomerenreinen Synthese des Chatancins, 1. Mitt. Synthese von (1R,2S,6S,7R,8S,3′S)-2-(4′-Benzyloxy-3′-methylbutoyl)-7-hydroxy-8-isopropyl-1-methylbicyclo [4.4.0]decan-4-on

Summary Our first target on the way towards the synthesis of enantiomerically pure chatancin is the preparation of the title compound. The cycloadduct of 5,5-dimethoxy-1,2,3,4-tetrachlorocyclopentadiene and thymoquinone is stereo- and regioselectively reduced to the tricyclic ketoalcohol4, which by nucleophilic cyclisation and reductive removal of the keto group as well as the chlorine atoms yielded a tetracyclic dimethoxyketal. Acidic hydrolysis freed the keto group, which now was treated with a chiral lithium alkyl compound derived from methyl (R)-2-methyl-3-hydroxypropionate in few steps. The resulting stereomeric tertiary alkohols were fragmented and the decalinones thus obtained separated. X-ray analysis permitted the determination of the absolute configuration of these decalinone derivatives.

     

Complete assignments 1H and 13C NMR spectral data of four anabaseine derivatives

The anabaseine derivatives 6-methoxy-7-hydroxy-1-(pyridin-3-yl)-3,4-dihydroisoquinoline, 6,7-dimethoxy-1-(pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline and 6,7-dimethoxy-1-(piperidin-3-yl)-1,2,3,4-tetrahydroisoquino- line were prepared either by demethylation with HBr or by reduction with different reagents, NaBH4 and H2/PtO2 from 6,7-dimethoxy-1-(pyridin-3-yl)-3,4-dihydroisoquinoline, as starting material. The structures have been fully assigned by the combination of one- and two-dimensional experiments.     

Synthesis of bridged azabicycles from isoquinolines via a tandem of allylboration and intramolecular metathesis

A method for the synthesis of bridged azabicyclic compounds from isoquinolines was developed. The method is based on a combination of allylboration and ruthenium-catalyzed intramolecular metathesis. Reductive 1,3-diallylation of bromoisoquinolines with triallylborane gave trans-1,3-diallyl-1,2,3,4-tetrahydroisoquinolines. When heated with triallylborane, these compounds yielded mixtures of cis-and trans-isomers in the ratio ∼1: 1. The structure of cis-1,3-diallyl-5-bromo-1,2,3,4-tetrahydroisoquinoline was confirmed by X-ray diffraction analysis. In a similar way, trans-3-allyl-1-vinyl-1,2,3,4-tetrahydroisoquinoline synthesized by sequential vinylation (with vinyllithium) and allylboration of isoquinoline, yielded a mixture of cis-and trans-isomers in the ratio 1.6: 1. Intramolecular metathesis reactions of N-Boc derivatives of cis-isomers in the presence of the Grubbs catalyst (2.0–2.5 mol.%) afforded 7,8-benzo-10-azabicyclo[4.3.1]dec-2-enes or 7,8-benzo-9-azabicyclo[3.3.1]non-2-ene in nearly quantitative yields. Dedicated to Academician V. A. Tartakovsky on the occasion of his 75th birthday. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1510–1515, August, 2007.     

Substituent effects in the ring-chain tautomerism of 4-aryl-1,3,4,6,7,11b-hexahydro-2H-pyrimido[6,1-a]isoquinolines

By condensation of 1-(2′-aminoethyl)-1,2,3,4-tetrahydroisoquinoline derivatives with substituted benzaldehydes, 1,6-unsubstituted and diastereomers of 1-methyl- or 6-methyl-substituted 4-aryl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrimido[6,1-a]isoquinolines were prepared. The ring-chain tautomeric equilibria of most of these compounds in CDCl₃ at 300 K were found to be shifted nearly totally towards either the cyclic or the open tautomeric forms, while the (6R*,11bR*)-6-methyl substituted compounds proved to be three-component tautomeric mixtures, the equilibria of which could be characterized by a Hammett-type equation. The conformational equilibria of the cyclic forms turned out to be strongly influenced by the 1- and 6-methyl substituents and the configurations of the substituted carbons (C-1 or C-6 and C-4) relative to C-11b.     

On the Alkaloids of Nelumbo Nucifera Gaertn. Studies on the Alkaloids of Loti Embryo

A new tertiary tetrahydroisoquinoline alkaloid, methylcorypalline (V) and biscoclaurine base, neferine (II) were isolated from a Formosan lotus embryo (embryo of the seed of Nelumbo nucifera Gaertn.) (Nymphaeaceae), besides the earlier reported isoliensinine (I) and lotusine (IV). Characterization of this new base, methylcorypalline (I), mp. 58–59° (n-hexane), , by spectral data and direct comparison with synthetic sample prepared from vanillin have proved to be 6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (V). Methylcorypalline (V) is the first instance occurring in nature having coronary dilator action.     

Isolation and X-ray crystal structure of tetrahydroisoquinoline alkaloids from Calycotome villosa Subsp. intermedias

Two tetrahydroisoquinoline alkaloids were extracted from the alkaloid fraction of a methanol extract of the seeds of Calycotome Villosa Subsp. intermedia. Their structures were established as (R)-1-hydroxymethyl-7-8-dimethoxy-1,2,3,4-tetrahydro- isoquinoline (1) and (S)-7-hydroxymethyl-2-3-dimethoxy-7,8,9,10-tetrahydroisoquinoline chloride (2) by spectroscopic techniques and X-ray diffraction analysis.     

A convenient and highly stereoselective synthesis of 14-substituted 8,13-diazaoestrone analogues by domino ring closures

By means of convenient domino ring closure reactions of 1-(2-aminoethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline 2 and γ-oxo-acids, 14-substituted 8,13-diazaoestrone derivatives (5 and 6) were formed with ∼100% diastereoselectivity.     

The synthesis of 1,4-ethano-1,2,3,4-tetrahydroisoquinolines as rigid analogues of adrenergic agents

The Diels-Alder addition of benzyne and 4,5-dimethoxybenzyne to 1-(2-trans-phenylvinyl)-2-pyridone and 1-benzyl-3-benzyloxy-2-pyridones provided members of the 1,4-etheno-3-oxo-1,2,3,4-tetrahydroisoquinoline system. Catalytic reduction of these adducts yielded the corresponding tricyclic lactams. Lithium aluminum hydride reduction of these lactams produced a number of 1,4-ethano-1,2,3,4-tetrahydroisoquinolines.