Syntheses of analgesics. Part XXX.. Conformational studies of diastereoisomeric quaternary ammonium salts of 1,2,3,4,5,6-Hexahydro-2,6-methano-3-benzazocines

The configuration of the quaternary ammonium salts (Va and Vb) from 3-benzyl-1,2,3,4,5,6-hexahydro-8-hydroxy-6,11-dimethyl-2,6-methano-3-benzazocine. (II) and 3-methyl-2-butenyl bromide was determined spectroscopically. Moreover, configurational studies on 3-benzyl (VIa and VIb) and 3-(3-methyl-2-butenyl)benzazocinium bromides (VIIa and VIIb) were also achieved.     

Syntheses of benzomorphan and related compounds. Part III. An alternate synthesis of 3-substituted-1,2,3,4,5,6-hexahydro-8-hydroxy-2,6-methano-6,11-dimethyl-3-benzazocine

Reduction of the appropriate Schiff bases gave 5-benzylamino-3-methyl-2-pentene (XVII) and l-benzylamino-3-methylpentane (XVIII), the condensation of which with methyl 3-(4-methoxyphenyl)-2,3-epoxypropionate afforded a mixture of the isomeric 1-benzyl-2-(4-methoxy-benzyl)-3,4-dimethyl-4-hydroxypiperidines (XIXa and XIXb). The piperidinols were heated with hydrobromic acid, respectively, to afford 3-benzyl-1,2,3,4,5,6-hexahydro-8-hydroxy-2,6-methano-6,11-dimethyl-3-benzazocine (II). Since the conversion of II to pentazocine (Ic) had already been accomplished, an alternate synthesis of Ic was achieved.     

Circular dichroism spectra of 1,2,3,4,5,6-Hexahydro-2,6-methano-3-benzazocines

Circular dichroism curves of levorotatory 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocin-8-ol derivatives have been determined and correlated with stereochemical features. Compounds with the rectus configuration at C-6 were found to exhibit negative extrema for the long wavelength phenolic π → π* transition. The remaining Cotton effects have been ascribed to specific aromatic π → π* transitions.     

Studies on the syntheses of heteroeyelie compounds. Part DV. Cyclization products of i-substituted 2-benzyl-1,2,5,6-tetrahydropyridines [syntheses of analgesics. Part XXXV]

Treatment of 1,2,5,6-tetrahydro-2-(4-hydroxy- and/or 4-methoxybenzyl)-3,4-dimethyl-I-(3-methyl-2-butenyl)pyridines (IV and V) and 2-(4-methoxybenzyl)-3,4-dimethyl-1-(3-methyl-2-butenyl)-4-piperidinol (X) with acid afforded 9-(4-hydroxy- and/or 4-methoxybenzyl)-4,4,5,6-tetramethyl-1-azabicyelo[3,3,1]non-6-ene (XIII and XIV). In contrast, the corresponding 1-allyl-substituted derivatives VI, VII, and XI were converted into the expected 3-allyl-1,2,3,4,5,6-hexahydro-8-hydroxy- and/or 8-methoxy-6,11-dimethyl-2,6-methano-3-benzazocine (II and III).     

Snytheses of analgesics. Part XXXVII. An alternative synthesis of 1,2,3,4, 5, 6-hexahydro-8-hydroxy-2,6-methano-6, h-dimethyl-3-phenethyl-3-benzazoeine [studies on the syntheses of heterocyclic compounds. Part DXXI]

Acid treatment of the alkylated products of (Va, Vb, and VIII) of piperidinols IVa and IVb, and tetrahydropyridine VII with β-bromoethylbenzene, afforded 1,2,3,4,5,6-hexahydro-8-hydroxy-2,6-methano-6,1 1-dimethyl-3-phenethyl-3-benzazocine (la) in good yield. Piperidinols Va and Vb were also obtained from the reaction of N-(3-methyl-3-pentenyl)-β-phenethylamine (IIb) with methyl 3-(4-methoxyphenyl)-2,3-epoxypropionate.     

Studies on the syntheses of analgesics. Part XXXI. Synthesis of 1,2,3,4,5,6-Hexahydro-3-methyl-6-phenyl-2,6-melhano-2,3-benzo[g] diazocine [studies on the syntheses of heterocyclic compounds. Part CDLXXIX]

1,2,3,4,5,6 Hexahydro-8-methoxy-3-methyl-6-phenyl-2,6-methano-2,3-benzo[g]diazocine (IIa) was synthesized from 1-(3-methoxyphenyl)phenylaeetonitrile (III), readily available by the benzyne reaction of o-chloroanisole with phenylacetonitrile, through several steps. Treatment of IIa with 47% hydrobromic acid afforded 1,2,3,4,5,6-hexahydro-8-hydroxy-3-methyl-6-phenyl-2,6-methano-2,3-benzo[g]diazocine (IIb).     

High-performance liquid chromatographic enantioseparation of methanobenzazocines

Chiral recognition and resolution of methanobenzazocines was investigated by HPLC using polysaccharide, Pirkle-type, native and derivatized β-cyclodextrin chiral stationary phases. Enantioseparation of phenyl substituted 2,6-methanobenzazocines was achieved with multiple chiral stationary phases throughout the classes described. Chiral resolution of the enantiomers of 1,5-methano-3-methyl-6-oxo-1,2,3,4,5,6-hexahydro-3-benzazocine was produced on both polysaccharide and Pirkle-type phases. In the case of 1,5-methano-3-methyl-6-phenyl-1,2,3,4,5,6-hexahydro-3-benzazocine only a dinitrophenyl substituted β-cyclodextrin produced a separation of enantiomers.     

Syntheses of the opioid substructures 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine and 2,3,4,5-tetrahydro-1,5-methano-1H-2-benzazepine

Concise syntheses of 1,2,3,4,5,6-hexahydro-2,6-methano-3-benzazocine (12) and 2,3,4,5-tetrahydro-1,5-methano-1H-2-benzazepine (18) are described and involve an intramolecular Friedel-Crafts alkylation and an intramolecular Heck cyclization as their respective key ring-forming steps.     

Novel rearrangement of a 2-aryl-3-alkyl-3H-indol-3-ol to a 1,4,5,6-tetrahydro-2,6-methano-1-benzazocin-3(2H)-one with implications for the biosynthesis of aspernomine

[reaction: see text] Nominine (1) and aspernomine (2) are two biologically important indole diterpenoids that arise from a common digeranylindole precursor. The skeletal relationship of these two natural products was not heretofore understood. We have observed a novel rearrangement of 2-(2-bromophenyl)-3-(3-butenyl)-3H-indol-3-ol (5) to 7, which contains the uncommon 1,4,5,6-tetrahydro-2,6-methano-1-benzazocin-3(2H)-one ring system, under acidic conditions. This rearrangement suggests that aspernomine (2) may arise biosynthetically from nominine (1).     

Synthesis of a phosphotyrosyl analogue having χ1, χ2 and φ angles constrained to values observed for an SH2 domain-bound phosphotyrosyl residue

Src homology 2 (SH2) domains provide connectivity in protein-tyrosine kinase (PTK)-dependent signaling through their high affinity association with phosphotyrosyl (pTyr)-containing peptide sequences. Because recognition of pTyr residues is central to SH2 domain-binding affinity, design of pTyr-mimicking residues has been one component of SH2 domain signaling antagonist development. Reported herein is the synthesis of (±)-(rel-1R,2R,5S)-3-acetyl-1,2,3,4,5,6-hexahydro-8-O-phosphoryl-1,5-methano-3-benzazocine-2-carboxylic acid methyl ester (3c) as a monomeric pTyr-mimicking analogue that constrains three torsion angles (χ₁=168°; χ₂=−85°; φ₁=−113°) to values approximating those observed for a pTyr residue bound to the Grb2 SH2 domain (χ₁=182°; χ₂=−89°; φ₁=−132°). Compound 3c differs from our previously reported analogue, (±)-(rel-1R,2R,5S)-3-acetyl-1,2,3,4,5,6-hexahydro-1-methyl-1,5-methano-3-benzazocin-8-ol, in lacking a methyl substituent at the bridgehead 1-position. Molecular modeling studies had indicated that this methyl group could potentially hinder SH2 domain binding. Synthesis of the desmethyl derivative was achieved by formation of the methanobenzazocine ring system using an intramolecular electrophilic cyclization that proceeds through an activated acyliminium intermediate. Importantly, the correct relative (2R) stereochemistry at the ‘α-carboxyl’-bearing carbon is obtained through base-catalyzed equilibration of a (2S/2R) diastereomeric mixture that results from intramolecular ring closure. Comparison of Grb2 SH2 domain-binding affinity of 3c (IC₅₀=1167 μM) with conformationally flexible phosphorylated (±)-N-acetyl-tyrosine methyl ester (15; IC₅₀=1469 μM) revealed no apparent enhancement in affinity. This apparent ineffectiveness of ‘local conformational constraint’ on SH2 domain-binding affinity of the monomeric pTyr mimetic is consistent with previous reports obtained by conformationally constraining pTyr-mimicking residues that were contained within peptide platforms. Although not providing high binding affinity in its current form, the novel 1,5-methano-3-benzazocine ring system may afford a novel platform for further elaboration and development of small molecule SH2 domain signaling antagonists.     

The synthesis of ventiloquinone L, the monomer of cardinalin 3

Readily available ethyl-4-acetoxy-6,8-dimethoxynaphthalene-2-carboxylate was converted into 1-[3-allyl-4-(benzyloxy)-6,8-dimethoxy-2-naphthyl)-1-ethanol in seven steps. Subjection of this compound to Wacker oxidation conditions provided 5-benzyloxy-7,9-dimethoxy-1,3-dimethyl-1H-benzo[g]isochromene in good yield. Hydrogenation of the isochromene afforded (+/-)-cis-7,9-dimethoxy-1,3-dimethyl-1H-benzo[g]isochroman-5-ol as the major product, which was readily converted into ventiloquinone L.     

Rearrangements of 4-(2-Aminophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid diethyl ester

The treatment of 4-(2-aminophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinecarboxylic acid diethyl ester (III) with refluxing toluene or pyridine afforded 1,2,3,6-tetrahydro-2,4-dimethyl-2,6-methano-1,3-benzodiazocine-5,11-dicarboxylic acid diethyl ester (IV) as the major product. In addition, the following minor products were isolated: 2-methyl-3-quinolinecarboxylic acid ethyl ester (V), 3-(2-aminophenyl)-5-methyl-6-azabicyclo[3,3,1]-hept-1-ene-2,4-dicarboxylic acid diethyl ester (VI), and 5,6-dihydro-2,4-dimethyl-5-oxobenzo[c][2,7]naphthyridine-1-carboxylic acid ethyl ester (VII). In contrast, acidic conditions caused the conversion of III into V in a 95% yield. The formation of the latter appears to involve IV as an intermediate, since IV degraded rapidly in acid to give V in a quantitative yield.     

Study on the base-catalyzed reverse vinylogous aldol reaction of (4abeta,5beta)-4,4a,5,6,7,8-hexahydro-5-hydroxy-1,4a-dimethylnaphthalen-2(3H)-one under Robinson annulation conditions

[reaction: see text] We have proposed a pathway for the base-catalyzed reverse vinylogous aldol reaction of (-)-(4abeta,5beta)-4,4a,5,6,7,8-hexahydro-5-hydroxy-1,4a-dimethylnaphthalen-2(3H)-one [(-)-8] under Robinson annulation conditions. For confirmation, 4-(2,6-dimethyl-3-oxocyclohex-1-enyl)butanal (11) and 4-(2,6-dimethyl-5-oxocyclohex-1-enyl)butanal (12), both of which potentially produce enolate I, were synthesized regioselectively. Unexpectedly, 11 gave a complex mixture, including only a trace amount of (+/-)-8 (less than 5% yield), under these basic conditions. To the contrary, 12 cleanly afforded (+/-)-8 in 66% yield. This result provides evidence for our proposed mechanism of the above reaction.     

Electronic and infrared spectroscopy of jet-cooled (+/-)-cis-1-amino-indan-2-ol hydrates

The role of conformational isomerism in molecular interaction has been studied using the example of jet-cooled complexes of (+/-)-cis-1-amino-indan-2-ol with water. The two formerly evidenced conformers of (+/-)-cis-1-amino-indan-2-ol easily form hydrates and dihydrates, which have been studied by means of laser-induced fluorescence and IR/UV double resonance spectroscopy, as well as ab initio calculations. All the 1 : 1 and 1 : 2 complexes with water evidenced in this work involve "ring" structures, in which the water monomer or dimer acts as an acceptor from the NH(2) and a donor to the OH groups of (+/-)-cis-1-amino-indan-2-ol. However, the water lies externally to the indan frame in the hydrates of conformer I of (+/-)-cis-1-amino-indan-2-ol, which possesses axial NH(2) and equatorial OH groups, and above it for the hydrates with the less stable conformer II, with equatorial NH(2) and axial OH groups. Consequently, the different steric constraints which exist in the two conformers result in different hydrogen bond topologies, with an additional OH[dot dot dot]pi interaction for the hydrates of conformer II.     

丁酸氯维地平降解杂质的合成

以4-(2,3-二氯苯基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸(2-氰基乙基)（甲基）酯(5)为起始原料,合成了丁酸氯维地平的5种降解杂质：4-(2,3-二氯苯基)-1,4-二氢-2,6-二甲基-3,5-吡啶二羧酸单甲酯(A), 4-(2,3-二氯苯基)-1,4-二氢-2,6-二甲基-3-吡啶羧酸甲酯(B), 4-(2,3-二氯苯基)-2,6-二甲基-3,5-吡啶二羧酸单甲酯(C), 4-(2,3-二氯苯基)-2,6-二甲基-3,5-吡啶二羧酸（丁酰氧基甲基）（甲基）酯(D)和4-(2,3-二氯苯基)-2,6-二甲基-3-吡啶羧酸甲酯(E)。其中A由5水解制得;B由A脱羧制得;C由5氧化后再经水解制得;D由C和丁酸氯甲酯缩合制得;E由C脱羧制得,化合物结构经¹H NMR和MS（ESI）确证。     

Synthesis of 1,5-methano-2-benzazocines from 3-hydroxy-1,3-dimethyl-6-phenyl-4-piperidone

Reaction of 3e-hydroxy-1e,3a-dimethyl-6e-phenyl-4-piperidone with cyanoacetic ester affords 6e,8a-dimethyl-2-oxo-5e-phenyl-3-cyanofuro[2,3-c]piperidine, the epoxide of which undergoes intramolecular cyclization on treatment with 80% H₂SO₄, to give 1,2,5,6-tetrahydro-2-endo-4-dimethyl-1,5-methano-6-oxo-2-benzazocin-3-ene. It has been found that the latter is formed via the intermediate 3-hydroxy-6e,8a-dimethyl-2-oxo-5e-phenylfuro[2,3-c]piperidine.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1371–1374, October, 1986.     

2,6-二-O-戊基-β-环糊精涂渍Symmetry C8柱拆分扁桃酸及其类似物对映体

利用合成的2,6-二-O-戊基-β-环糊精涂渍Symmetry C8色谱柱,研究了扁桃酸及其类似物等6 种外消旋对映体的反相高效液相色谱拆分。优化了色谱分离条件,探讨了扁桃酸的手性拆分机理。结果表明,采用优化后的甲醇-水或甲醇-0.5%三乙胺-乙酸缓冲液流动相等色谱条件,扁桃酸、扁桃酸甲酯、苯基甘氨酸、苯基琥珀酸和安息香等5种外消旋对映体达到或接近基线分离,其中前4种对映体均为(S)-构型先出峰。该法可用于实际样品的对映体纯度测定。     

Studies on the syntheses of analgesics. Part XXXVI. Synthesis of 1,2,3,4,5,6-ilexahydro-2,6-methano-6-phenyl-2 henzazocine [studies on the syntheses of heterocyclic compounds. Part D XI]

An attempt to obtain 2,3,4,5,6,7-hexahydro-lH2,7-methano-9-methoxy-3-rnethyl-7-phenyl-2,3-benzodiazonine (II) by the Pictet-Spengler reaction of 2,3,4,5,6,7-hexahydro-lH-4-(3-meth-oxyphenyl)-l-methyl-4-phenyl-1,2-diazepine (XI) prepared through several steps from 1-(3-methoxyphenyl)phenylaeetonitrile (IV) resulted instead, in the formation of 1,2,3,4,5,6-hexa-hydro-2,6-methano-8-methoxy-6-phenyl-2-benzazocine (XIV).     

Syntheses of benzomorphan and related compounds. Part 1. Synthesis of N-substituted-l,2,3,4,5,6-hexahydro-8-hydroxy-2,6-methano-6,11-dimethyl-3-benzazocine [studies on the syntheses of heterocyclic compounds. Part CCLXXXII ]

A modified synthesis of pentazocine, l,2,3,4,5,6-hexahydro-8-hydroxy-2,6-methano-6, H-dimethyl-3-(3-methyl-2-butenyl)-3-benzazocine (III), has been achieved and catalytic hydro-genation has been found to be effective for the debenzylation of quaternary ammonium salts.     

The acyclic dienamine-indoloacrylate addition route to catharanthine

Condensation of methyl 3-benzyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate (3) with methyl Z-4-formylhex-3-enoate (6) gave cis-fused dimethyl 5-benzyl-4-ethyl-2,4a,5,6,7,12-hexahydro-1H-benzo[2,3]azepino[4,5-b]indole-2,12b-dicarboxylate and its trans-fused diastereomer. Selective reduction of the less hindered ester group with sodium borohydride to an alcohol ester, tosylation, debenzylation, and cyclization gave racemic catharanthine (1).