Microwave-assisted direct biaryl coupling: first application to the synthesis of aporphines

We have investigated the use of microwaves in a direct biaryl coupling reaction for the synthesis of analogs of the aporphine alkaloid nantenine. Our study shows that the aporphine core may be rapidly accessed from benzyl-tetrahydroisoquinoline substrates with this method. This is the first report of a microwave-assisted direct biaryl coupling reaction in the synthesis of aporphine molecules.     

Natural Aporphine Alkaloids with Potential to Impact Metabolic Syndrome

The incidence and prevalence of metabolic syndrome has steadily increased worldwide. As a major risk factor for various diseases, metabolic syndrome has come into focus in recent years. Some natural aporphine alkaloids are very promising agents in the prevention and treatment of metabolic syndrome and its components because of their wide variety of biological activities. These natural aporphine alkaloids have protective effects on the different risk factors characterizing metabolic syndrome. In this review, we highlight the activities of bioactive aporphine alkaloids: thaliporphine, boldine, nuciferine, pronuciferine, roemerine, dicentrine, magnoflorine, anonaine, apomorphine, glaucine, predicentrine, isolaureline, xylopine, methylbulbocapnine, and crebanine. We particularly focused on their impact on metabolic syndrome and its components, including insulin resistance and type 2 diabetes mellitus, endothelial dysfunction, hypertension and cardiovascular disease, hyperlipidemia and obesity, non-alcoholic fatty liver disease, hyperuricemia and kidney damage, erectile dysfunction, central nervous system-related disorder, and intestinal microbiota dysbiosis. We also discussed the potential mechanisms of actions by aporphine alkaloids in metabolic syndrome.     

An efficient synthesis of an 8-phenoxy aporphine derivative utilizing mono-ligated palladium ortho-phenol arylation

8-Aryloxy aporphines are a structurally diverse subset of alkaloids that display an array of biological activities. An efficient synthesis of an 8-phenoxy aporphine model compound has been developed utilizing Pictet-Spengler cyclization followed by biaryl bond formation using Pd-XPhos catalyzed ortho-phenol arylation. Biaryl bond formation using direct arylation is also compared. Finally, the stability of the 8-phenoxy aporphine model compound is discussed with potential implications for the isolation, structure elucidation and pharmacognosy of 7-dehydroaporphine natural products.     

Intramolecular ortho-arylation of phenols utilized in the synthesis of the aporphine alkaloids (±)-lirinidine and (±)-nuciferine

A palladium-mediated intramolecular phenol ortho-arylation reaction applied to the construction of aporphine alkaloids is reported. Most significantly, the efficiency of this transformation was enhanced by the utilization of trialkylphosphine (i.e. tricyclohexylphosphine) or trialkylphosphonium salts (i.e. di-tert-butylmethyl-phosphonium tetrafluoroborate) as co-catalysts in the presence of cesium carbonate. This methodology was employed in the syntheses of the aporphine alkaloids (±)-lirinidine and (±)-nuciferine.     

Aporphine alkaloid contents increase with moderate nitrogen supply in Annona diversifolia Saff. (Annonaceae) seedlings during diurnal periods

Aporphine alkaloids are secondary metabolites that are obtained in low levels from species of the Annonaceae family. Nitrogen addition may increase the alkaloid content in plants. However, previous studies published did not consider that nitrogen could change the alkaloid content throughout the day. We conducted this short-term study to determine the effects of nitrogen applied throughout the diurnal period on the aporphine alkaloids via measurements conducted on the roots, stems and leaves of Annona diversifolia seedlings. The 60-day-old seedlings were cultured with the addition of three levels of nitrogen (0, 30 and 60 mM), and alkaloid extracts were analysed using high-performance liquid chromatography. The highest total alkaloid content was measured in the treatment with moderate nitrogen supply. Further, the levels of aporphine alkaloids changed significantly in the first few hours of the diurnal period. We conclude that aporphine alkaloid content increased with moderate nitrogen supply and exhibited diurnal variation.     

Structural analogues of aporphines. Part II: Synthesis of some isomers of lysergic acid derivatives

Isomers of lysergic acid derivatives ( 3 , 22 , 23 and 24 ). analogous to aporphine, have been synthesized from the key intermediate ketone 12 .     

Selective separation of structure-related alkaloids in Rhizoma coptidis with "click" binaphthyl stationary phase and their structural elucidation with liquid chromatography-mass spectrometry

It is a new task to separate structure-related compounds into a fraction according to their structural characteristics in a complex traditional Chinese medicine (TCM). This method makes separation of the components of the sample simple and structural elucidation easy. In this study, selective separation of alkaloids in Rhizoma coptidis was realized on a "click" binaphthyl column possessing a planar conjugate structure. Three kinds of alkaloids, aporphine, tetrahydroprotoberberine and protoberberine in Rhizoma coptidis showed better retention than other compounds by virtue of π-π interactions with the stationary phase. Moreover, the "click" binaphthyl column could distinguish the aporphine and tetrahydroprotoberberine alkaloids possessing two benzene rings from the protoberberine alkaloids possessing three benzene rings. After separating on the "click" binaphthyl column, the fractions containing the alkaloids were collected and then analyzed with liquid chromatography-mass spectrometry (LC-MS). Totally, 23 alkaloids were identified, and among these alkaloids, three tetrahydroprotoberberine, two aporphine and seven protoberberine alkaloids were first found in Rhizoma coptidis. These newly found alkaloids are minor compounds, and they are always neglected without eliminating the interference of compounds in large amounts by pre-separation on the "click" binaphthyl column. The typical fragmentation pathways of each class of alkaloids were summarized to illustrate their structures. In the MS(2) spectrum, the loss of a molecule of dimethylamine ((CH(3))(2)NH) was observed as the characteristic loss of aporphine alkaloids. All the tetrahydroprotoberberine alkaloids would undergo the Retro-Diels-Alder (RDA) fragmentation reaction in the MS(2) fragmentation. For protoberberine alkaloids, different characteristic fragmentations were observed with different skeleton structures.     

Studies on the Alkaloids of Illigera Luzonensis (Presl.) Merr

From the non-phenolic base part of Illigera luzonensis (Presl.) Merr. launobine belonging to the aporphine type base was isolated.     

Chemical constituents of Talauma arcabucoana (Magnoliaceae): their brine shrimp lethality and antimicrobial activity

A new aporphine alkaloid, (-)-arcabucoine [(6aR)-N-formyl-1,2-methylenedioxy-9,10-dimethoxy-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline] 1 was isolated from the leaves of Talauma arcabucoana (Magnoliaceae), along with the known compounds (-)-erythro-saccharinic acid lactone 2 and (-)-shikimic acid 3. Furthermore, the known aporphine alkaloids (-)-dicentrine 4, (-)-nordicentrine 5 and dicentrinone 6 were isolated from the stem bark. The alkaloids 4 and 5 were found to be the most active compounds in a brine shrimp lethality assay. In addition, alkaloids 1, 4 and 5 showed moderate growth inhibition against Staphylococcus aureus and Candida albicans.     

An improved photochemical aporphine synthesis : New syntheses of dicentrine and cassameridine

An improved non-oxidative photochemical synthesis of aporphine derivatives has been developed, in which o-halobenzylidenetetrahydroisoquinolines are irradiated in the presence of potassium t-butoxide. The yield (72%) of one such product, N-carbethoxynorneolitsine (25) is the highest ever reported for any cyclization producing the aporphine ring system. Compound 25 was converted in two steps to cassameridine (4), confirming the suggested structure of this oxoaporphine. The natural bases dehydrodicentrine (26) and dicentrine (3) were also synthesized using the improved photochemical approach.     

Concise total synthesis of the aporphine alkaloid 7,7''-bisdehydro-O-methylisopiline by an InCl3 mediated cycloisomerization reaction

A novel InCl3 mediated cycloisomerization reaction leading to 10-halophenanthrene derivatives constitutes the key step of the first total syntheses of O-methyldehydroisopiline 10 and 7,7'-bisdehydro-O-methylisopiline 11, two prototype members of the aporphine family of alkaloids.     

Fremy's salt oxidation of some isoquinoline alkaloids. Biogenetic considerations

Fremy's salt oxidation of benzyl isoquinoline and aporphine alkaloids to isoquinolones and oxoaporphines is described. Aminium radicals are suggested to account for the observed results. Their possible involvement in alkaloid biosynthesis is considered.     

Characterization and simultaneous quantification of biological aporphine alkaloids in Litsea cubeba by HPLC with hybrid ion trap time‐of‐flight mass spectrometry and HPLC with diode array detection

The root and rhizome of Litsea cubeba (Lour) Pers., named ‘Dou‐chi‐jiang’ in Chinese, has been traditionally used for treatment of cardiovascular and cerebrovascular diseases, rheumatic arthralgia, and other diseases in China. Aporphine alkaloids are its characteristic ingredients and responsible for its bioactivities, especially anti‐inflammatory and analgesic effects. A sensitive and reliable high‐performance liquid chromatography with diode array detection‐tandem mass spectrometry method was developed for characterization and simultaneous determination of biological aporphine alkaloids in ‘Dou‐chi‐jiang’. The optimized chromatographic conditions were performed on an Eclipse XDB C₁₈ column with a gradient of acetonitrile/water containing 0.1% formic acid as the mass spectrometry mobile phase and acetonitrile/water containing 0.2% diethylamine (pH 3.10, adjusted by acetic acid) as the liquid chromatography mobile phase. The fragmentation pathways by loss of CO, ·CH₃, ·NH₃, and ·NH₂CH₃ were detected as characteristic for aporphine alkaloids. Based on these characteristics, total 12 analogues were identified. The quantification method was validated in terms of linearity, precision, and accuracy for six major aporphine alkaloids, which was successfully applied for simultaneous determination in ten batches of samples. The established method is simple, rapid, and specific for characterization and quantitation of aporphine alkaloids in ‘Dou‐chi‐jiang’ and other traditional Chinese medicines rich in this kind of ingredient.     

(+)‐N‐Formylnorglaucine Rotamers from Unonopsis stipitata Diels

(+)‐N‐formylnorglaucine ( 1 ), an aporphine alkaloid containing a formyl group linked to the heterocyclic nitrogen, was isolated from the leaves of Unonopsis stipitata, an Amazon medicinal plant. The chemical structure was characterized based on 1D‐ and 2D‐NMR spectroscopy and HR‐ESI‐MS. NMR spectra revealed that 1 is composed of two rotamers ( 1a and 1b ) in a ratio of approximately 2:1. In addition, the fragmentation behavior of 1 displayed an unusual fragmentation pattern compared to regular aporphine alkaloids. Thus, this compound is reported for the first time as a natural product in this study.     

新的醚链双生物碱尖叶唐松草阿原碱的结构测定

从尖叶唐松草〔Thalictrumacutifolium(Hand.Mazz.)Boivin〕根分离得到一种新生物碱(尖叶唐松草阿原碱).通过IR,MS,¹HNMR,¹³CNMR,2DNMR(包括¹H-¹HCOSY,¹³C-¹HCOSY,NOESY和HMBC)测定了其化学结构,发现由阿朴菲和原小蘖碱通过醚链连接.对多种肿瘤细胞的生长有抑制作用,并有凋亡现象出现,而且对正常细胞的毒性较小     

Die Kristallstruktur des (−)-O-Methyllaurepukins (1, 2-Methylendioxy-11-methoxy-6a, β-aporphin-6β-oxid)

The crystal and molecular structure of the O-methyl derivative of the aporphine alkaloid laurepukin has been determined by direct methods, which are described. A short discussion of the structure is given.     

Synthesis and dopamine receptor binding affinity of 4H-thiochromenoapomorphines

Abstract  The synthesis of 4H-thiochromene derivatives of apomorphines, a novel class of isoquinoline alkaloid-related compounds, has been achieved by different O-dealkylation methods applied on previously published heteroring-fused aporphinoids. Detailed DFT study has been presented regarding the mechanism of the L-selectride-mediated multiple O-dealkylation of a seven-ring aporphine analogue. Dopamine-binding tests confirmed the essential function of 11-hydroxy moiety of the aporphine skeleton and revealed a remarkable D₁ over D₂ specificity for the derivative having the 4H-thiochromene ring system attached to positions 2 and 3 of the aporphine backbone. Graphical Abstract  

Sesquiterpenes and alkaloids from Lindera chunii and their inhibitory activities against HIV-1 integrase

Three new eudesmane type sesquiterpenoid lindenanolides E (1), F (2) and G (3), and two new aporphine alkaloid lindechunines A (18) and B (20) were isolated from roots of Lindera chunii MERR., together with seven known sesquiterpenes including a new naturally-occurring lindenanolide H (4) and eight known aporphine alkaloids. The structures of these compounds were determined by spectroscopic means. Of the isolated compounds, hernandonine (14), laurolistine (16), 7-oxohernangerine (17) and lindechunine A (18) showed significant anti-human immunodeficiency virus type 1 (HIV-1) integrase activity with IC(50) values of 16.3, 7.7, 18.2 and 21.1 microM, respectively. The major alkaloids presented in the roots of L. chunii were quantitatively analyzed by an HPLC method.     

Two New Aporphine Alkaloids from Amoora cucullata and their Antibacterial Activity

Chemistry of Natural Compounds - Two new aporphine alkaloids, amocurines D and E (1 and 2), together with five known compounds (3–7), were isolated from the stems of Amoora cucullata. The...     

Alkaloids ofLiriodendron tulipifera

The alkaloids of the tulip treeLiriodendron tulipifera L., family Magnoliaceae, are considered. More then 20 alkaloids have been isolated during different vegetation periods from various organs of the plant growing in Uzbekistan, and these have been assigned to the aporphine alkaloids and their dehydro, oxo, and 7-hydroxy derivatives; only two alkaloids proved to be derivatives of proaphorphine and of tetrahydroberberine. On the basis of the results of a comparative study of the NMR spectra of aporphines unsubstituted in ring D and some chemical transformations, the structure and configuration of the (R)-3-hydroxy-1,2-dimethoxyaporphine have been proposed for the new alkaloid lirinine. The absolute configurations, possible biogenetic interconnections, and mutual transitions of the alkaloids ofL. tylipifera that are derivatives of aporphine, oxoaporphine, and dehydroaporphine are discussed. A summery table is given which includes 41 alkaloids found in this plant.