Macrocarpamin,ein neues Bisindolalkaloid aus Alstonia macrophylla WALL. 167. Mittelung über organische Naturstoffe

Macrocarpamine, a new bisindole alkaloid from Alstonia macrophylla WALL . A new bisindole alkaloid give the name (?)-macrocarpamine ( 3 ) was isolated from the bark of Alstonia macrophylla WALL . Under pyrolytic conditions 3 is cleaved into the two known bases (+)-pleiocarpamine ( 2 ) and (?)-anhydro macrosalhin-methin ( 5 ) (Scheme 1). The structure of 3 (including relative configuration) was deduced on the basis of chemical evidence and from its UV.-, IR.-, NMR.- and mass spectroscopic data.     

Synthesis of the Carbon Framework of Scholarisine A by Intramolecular Oxidative Coupling

Scholarisine A, isolated from the leaves of Alstonia scholaris, is a monoterpene indole alkaloid with an unprecedented cage‐like structure. In this paper, preparation of the distinctive cage‐like core skeleton of scholarisine A is described. The key feature of this synthetic strategy is an intramolecular oxidative coupling reaction at the late stage to construct a 10‐oxa‐tricyclo[5.3.1.0^{3, 8}]undecan‐9‐one structure fused with indolenine. Intramolecular oxidative coupling by using N‐iodosuccinimide gave the carbon framework of scholarisine A in moderate yield, which is the first example of intramolecular oxidative‐coupling reaction between non‐activated enolate and indole. This study lays the foundation for continued investigations towards the total synthesis of scholarisine A.     

Targeted quantitative analysis of monoterpenoid indole alkaloids in Alstonia scholaris by ultra-high-performance liquid chromatography coupled with quadrupole time of flight mass spectrometry

Monoterpene indole alkaloids exhibit structural diversity in herbal resources and have been developed as promising drugs owing to their significant biological activities. Confidential identification and quantification of monoterpene indole alkaloids is the key to quality control of target plants in industrial production but has rarely been reported. In this study, quantitative performance of three data acquisition modes of ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry including full scan, auto-MS² and target-MS², was evaluated and compared for specificity, sensitivity, linearity, precision, accuracy, and matrix effect using five monoterpene indole alkaloids (scholaricine, 19-epi-scholaricine, vallesamine, picrinine, and picralinal). Method validations indicated that target-MS² mode showed predominant performance for simultaneous annotation and quantification of analytes, and was then applied to determine monoterpene indole alkaloids in Alstonia scholaris (leaves, barks) after extraction procedures optimization using Box-Behnken design of response surface methodology. The variations of A. scholaris monoterpene indole alkaloids in different plant parts, harvest periods, and post-handling processes, were subsequently investigated. The results indicated that target-MS² mode could improve the quantitative capability of ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry for structure-complex monoterpene indole alkaloids in herbal matrices. Alstonia scholaris, monoterpene indole alkaloids, quadrupole time of flight mass spectrometry, qualitative and quantitative analysis, ultra-high-performance liquid chromatography     

Meloslines A and B,two novel indole alkaloids from Alstonia scholaris

An unprecedented indole alkaloid melosline A (1), with 6/5/6/6 tetracyclic ring skeleton, together with a new alkaloid melosline B (2) and one known compound (3) were isolated from the leaves and twigs of Alstonia scholaris. The new structures were elucidated by comprehensive spectroscopic analysis. The absolute configuration of compound 1 was confirmed by comparison of experimental data with calculated electronic circular dichroism (ECD). Compound 1 exhibited moderate cytotoxicity against MCF-7 cancer cell lines.     

On the constitution of the macralstonidines

The alkaloid macralstonidine, which was originally isolated from Alstonia macrophylla WALL . by T. M. SHARP in 1934, has the molecular formula C₄₁H₄₈O₃N₄. The hydrolysis of this dimeric alkaloid yielded the macroline derivative 5 , N_(a)-methyl-sarpagine ( 6 ) and formaldehyde. Partial acid cleavage under deuterating conditions gave 5 -d₉, 6 -d₃ and decadeuterated macralstonidine. On the basis of spectral data, particularly an analysis of the mass spectra of macralstonidine and its decadeutero derivative, structure 2 has been elucidated for this alkaloid.     

Alstobrogaline,an unusual pentacyclic monoterpenoid indole alkaloid with aldimine and aldimine-N-oxide moieties from Alstonia scholaris

Alstobrogaline (1), an unusual monoterpenoid indole alkaloid incorporating a third N atom and possessing two aldimine functions, with one being in the form of N-oxide, was isolated from the leaves of Alstonia scholaris. Its structure and relative configuration were determined by extensive NMR spectroscopic analysis, while its absolute configuration was established by X-ray diffraction analysis. A possible biogenetic pathway to 1 was proposed. Compound 1 displayed weak cytotoxic effects against MDA-MB-231 and MCF7 breast cancer cells.     

The structure of the quaternary alkaloid macrosalhine

From the stem bark of Alstonia macrophylla Wall. a new quaternary alkaloid macrosalhine, C₂₁H₂₇O₂N, has been isolated in small amounts as chloride or thiocyanate. On the basis of its chemical transformations and particularly its spectral properties (NMR., mass) the structure 1 has been proposed for it. Macrosalhin therefore represents a new skeletal type in the alkaloid field.     

Cage-like monoterpenoid indole alkaloids with antimicrobial activity from Alstonia scholaris

Three new cage-like monoterpenoid indole alkaloids, scholarisines T–V (1–3), together with three known analogues 4–6 were isolated from the leaves of Alstonia scholaris. Among them, 2 represents a unique degraded derivative, whereas 3 shares a rare 5,16-seco lactone scaffold. The structures were mainly established by extensive spectroscopic data analyses, and their plausible biosynthesis pathway from picrinine were proposed. Compared with positive control cefotaxime, alkaloid 2 showed remarkable antibacterial activity against Bacillus subtilis with an MIC value of 3.12?μg/mL, whereas 1–3 exhibited significant antibacterial effects on Escherichia coli with an MIC value of 0.78?μg/mL.     

Die Struktur des Spermin-Alkaloides Aphelandrin aus Aphelandra squarrosa NEES. 170. Mitteilung über organische Naturstoffe

The structure of the spermine alkaloid aphelandrine from Aphelandra squarrosa NEES The new spermine alkaloid aphelandrine ( 2 ) has been isolated from Aphelandra squarrosa NEES . By oxidation of 2 with KMnO₄ followed by methylation (CH₂N₂) 12 and 14 could be prepared (Scheme 2). Fusion of 2 with KOH yielded spermine ( 1 ) whereas hydrolysis of 2 in hot hydrochloric acid results in lacton 17 , the structure of which could be elucidated by comparison with a synthetically prepared model compound (Scheme 3). The benzylic bonds N (10), C(11) as well as O(16), C(17) of 2 could be cleaved by hydrogenolysis (compare 23 and 26 ; Scheme 4). The elucidation of the correct linkage of the spermine moiety with the aromatic dicarboxylic acid is based mainly on chemical and spectroscopic evidence of the tetrahydro derivative 26 , the Hofmann-degradation products 28 , 30 and 31 (Scheme 6) as well as the ester 35 , prepared by partial hydrolysis of 2 (Scheme 7).     

Indolalkaloids of Pleiocarpa talbotii Wernham. 145. Alkaloids

Besides talbotine ( 1 ) three new indole alkaloids, talpinine ( 2 ), talcarpine ( 3 ) and 16-epi-affinine ( 4 ) were isolated from the stem bark of Pleiocarpa talbotii Wernham. The structure of 2 was deduced by chemical degradation and by analyses of the spectra of the alkaloid and its derivatives. One of these derivatives is identical with talcarpine ( 3 ). The structures 2 and 3 are similar to that of macroline ( 14 ), a splitting product of the bisindole alkaloid villalstonine from Alstonia species. 16-epi-Affinine ( 4 ) was chemically correlated with the known alkaloid vobasine ( 19 ). Talpinine ( 2 ) and 16-epi-affinine ( 4 ) were also isolated from the root bark of Pleiocarpa talbotii.     

Caulerpin

The crystal structure of caulerpin (di­methyl 6,13‐di­hydro­dibenzo­[b,i]­phenazine‐5,12‐di­carboxyl­ate, C₂₄H₁₈N₂O₄), an indole alkaloid, reported in space group Cc with an acute β angle, has been redetermined in the correct space group, C2/c. The mol­ecule has twofold crystallographic symmetry and is composed of two essentially planar indole groups fused to an eight‐membered cyclo­octatetraene ring which adopts a boat conformation. The molecular dimensions are normal. The structure is stabilized by intermolecular and intramolecular interactions involving the indole N—H atom and carbonyl O atom [N?O 3.211 (4) and 2.836 (4) Å].     

Über die Struktur eines neuartigen Indolalkaloids,des Talbotins. 141. Mitteilung über Alkaloide [1]

From the leaves of the African Apocynacea Pleiocarpa talbotii Wernham a novel indole alkaloid, talbotine, C₂₁H₂₄N₂O₄, has been isolated. Talbotine ( 1 ) contains a secondary N_(b)-atom and a cyclic hemiacetal group. Catalytic hydrogenation leads to 19, 20-dihydrotalbotine ( 6 ), hydrogenation in the presence of formaldehyde gives N_(b)-methyl-19, 20-dihydrotalbotine ( 8 ). In the presence of sodium methoxide and methanol, 1 is converted into the lactone 12 and the methyl ester 13 . In these reactions carbon 17 is lost as formic acid. These data, together with the analyses of the NMR. spectra of talbotine and its derivatives as well as the interpretation of the various types of the mass spectral fragmentation, lead to formula 1 for the alkaloid. Dehydrogenation of talbotine methyl ether ( 3 ) with palladium and maleic acid gives the ß-carboline derivative 26 . The N_(b)-methiodide of the latter is converted into N_(b)-methyl-talbotine methyl ether on reduction with sodium borohydride. From these data as well as from the analyses of NMR. and IR. spectra the complete relative stereochemistry of talbotine could be derived. Application of the Horeau method to the nitrogen atom b of the methyl ether 3 on the one hand and to the hydroxyl group on C17 in N_(b)-methyl-19, 20-dihydrotalbotine ( 8 ) on the other hand gives consistent results and establishes S configuration of centre 15.     

Three New Indole Alkaloids from the Leaves of Alstonia scholaris

Three new akuamillan‐type indole alkaloids, i.e., 5‐methoxystrictamine (=methyl (5β,16R,19E)‐5‐methoxyakuammilan‐17‐oate; 1 ), methyl (16R,19E)‐1,2‐dihydro‐16‐(hydroxymethyl)‐5‐oxoakuammilan‐17‐oate ( 2 ), and methyl (2β,16R,19E)‐4,5‐didehydro‐1,2‐dihydro‐2‐hydroxy‐16‐(hydroxymethyl)akuammilan‐4‐ium‐17‐oate chloride ( 3 ), have been isolated from the leaves of Alstonia scholaris, together with ten known compounds. Their structures were determined by spectroscopic means. None of the constituents showed significant cytotoxic activity towards WT cells.     

Réarrangements en milieu acide trifluoroacétique de deux alcaloïdes indoliques: la desformocorymine et la dihydrocorymine

The rearrangement in trifluoroacetic acid of two indole alkaloids of the echitamine series, desformocorymine (14) and dihydrocorymine (9) , has been investigated. Desformocorymine (14) was tranformed into a mixture of carbinolamines 17a , b , with the akuammiline skeleton, which were reduced (Et₃SiH, CF₃CO₂H) into an isomer 12 of cathafoline (6). This sequence constitutes the first example of an interconversion of the corymine skeleton into the akuammiline skeleton (Scheme 2). In the case of dihydrocorymine (9) , the rearrangement followed a different pathway owing to the formation of a hemiacetal between the primary alcohol CH₂(17)-OH and a carbonyl formed at C(3). Treatment of this hemiacetal 26 with aqueous base led to its opening with concomitant formation of a lactam. ¹³C-NMR seems to indicate that this lactam exists under a hydrated form 27. This highly unstable intermediate was cleanly transformed (MeONa-MeOH) into a 2-acyl indole 30 (Scheme 4), the structure of which was determined by X-ray crystallography. The formation of this acylindole involves the rupture of the C(7)? C(16) bond; it is the reverse of the reaction generally postulated as occurring in the biogenesis of the pentacyclic alkaloids. The structure of a by-product 34 was established as 17-hydroxymethylvincoridine by X-ray crystallography. The acid-catalyzed rearrangements involve the rupture of the Ph-N? C? N chromophore, with formation of a carbonyl at C(3). The reversibility of these steps is used in an easy correlation of dihydrocorymine and of 3-epidihydrocorymine via their trifluoroacetates.     

Synthesis of Substituted Pyrrolo[3,4‐a]carbazoles

The cycloaddition between N‐protected 3‐{1‐[(trimethylsilyl)oxy]ethenyl}‐1H‐indoles and substituted maleimides (= 1H‐pyrrole‐2,5‐diones) yielded substituted pyrrolo[3,4‐a]carbazole derivatives bearing an additional succinimide (= pyrrolidine‐2,5‐dione) moiety either at C(5a) or C(10b) depending on the type of the protection group at the indole N‐atom. Derivatives substituted at C(10b) were isolated when the protection group, Me₃Si or Boc (^tBuOCO), was eliminated during the reaction (Schemes 2 and 3), whereas a substitution at C(5a) was observed when an electron‐withdrawing group, Tos (4‐MeC₆H₄SO₂) or pivaloyl (Me₃CCO), was not eliminated (Scheme 1). Complex results were found in reactions between 1‐(trimethylsilyl)‐3‐{1‐[(trimethylsilyl)oxy]ethenyl}‐1H‐indole, in contrast to formerly reported results (Scheme 3). Some derivatives of 1H,5H‐[1,2,4]triazolo[1′,2 : 1,2]pyridazino[3,4‐b]indole‐1,3(2H)‐dione were obtained from reactions with 4‐phenyl‐3H‐1,2,4‐triazole‐3,5(4H)‐dione (Scheme 2). All structures were established by spectroscopic data, by calculations, and one representative structure was confirmed by an X‐ray crystallographic analysis (Fig.). Finally, the formation of the different structure types was discussed, and compared with similar reactions reported in the literature.     

Beitrag zum Reaktionsmechanismus der Synthese von Seychellen [1]

New Mechanistical Details Concerning the Synthesis of Seychellen [1] In the last step of our synthesis of Seychellen ( 2 ) [1], the solvolysis of 1 , only one side-product was formed, namely 3 (Scheme 1). Now the structure of 3 has been elucidated, mainly by spectroscopic studies of its derivatives 7 and 9 (Scheme 2). In order to differentiate between two different solvolytic pathways from 1 to 3 (see Scheme 1 and 3) d₃- 1 was prepared. Solvolysis of d₃- 1 proved the mechanism shown in Scheme 1. Solvolysis of 1 and of 2-epi- 1 , respectively, furnished the same product distribution, which makes a common intermediate a very probable. In both cases 10 is an intermediate, which is slowly converted into 2 and 3 . 2-epi- 1 was prepared from 1 (Scheme 5). Kinetic measurements with 1 , d₃- 1 and 2-epi- 1 are also in agreement with the mechanism drawn in Scheme 4: k₁(72°) = (5,2±0,5) · 10^?5 sec^?1, k₁(H)/k₁(D)(72°) = 1,4±0,15; k₂(H)/k₄(H) = 0,66 and k₂(H)/k₂(D) = 2,2 if k₄(H) ≈ k₄(D) is assumed.     

Synthesis and Structure of Carbonyliron Complexes of Allenecarboxylates and Allenic Lactones

On irradiation in the presence of Fe(CO)₅, the allenecarboxylates 1 afforded binuclear carbonyliron complexex 6 (Scheme 3), whereas the allenic lactone 7 under similar conditions gave a mixture of one binuclear and two mononuclear carbonyliron complexes ( 9 , 8 , and 10 ; Scheme 4). The structure of the complexes has been elucidated by X-ray crystallography. The structure of the binuclear complex 9 corresponds to that of 6 , while 8 has been shown to be a 1,3-butadiene(tricabonyl)iron complex. The unique structure of the 10 represents a new type of allenic complex. A stepwise formation of the complexes via intermediate allene(tetracarbonyl) iron complexes type 11 and 13 is suggested. Treatment of the binuclear complex 6b with FeCl₃ led to the formation of the free ligand and a mixture of mononuclear complexes 13 and 14 (Scheme 5). On heating, the 1,3-diene complex 8 yielded the free ligand 15 , the prouduct of a (1,3) H shift in the allene 7 ; the complex 10 on the other hand liberates 7 on treatment with ethylenetracarbonitrile (TCNE) (Scheme 6).     

Synthesis of Aristotelia-type alkaloids. Part IX. Synthesis of (±)-alloaristoteline

The probably most straightforward plan to synthesize the indole alkaloid alloaristoteline ( 5 ) failed, because– in marked contrast to the regular Aristotelia series-electrophilic reagents attack with preference C(3) of the indole moiety in the key intermediate allohobartine ((?)- 12 ), instead of C(18). The only product that could be isolated when (?)- 12 was treated with mineral acid was isomer (+)- 15 of 5 (Scheme 2). As a consequence, the crucial electrophilic site at C(17) was created by taking recourse to the preparation of the stabilized allylic cation VI . Gratifyingly, this alleged intermediate, obtained from precursor (±)- 18 , cyclized smoothly to protected (±)-18,19-didehydroalloaristoteline (±)- 17 , which was transformed in two high-yield steps into the racemic form of the target molecule 5 (Scheme 4). This successful alternative provides unambiguous evidence that the recently revised structure of 5 is indeed correct.     

An unusual indole alkaloid with anti-adenovirus and anti-HSV activities from Alstonia scholaris

A novel alkaloid, 17-nor-excelsinidine (1), possessing an unusual 1-azoniatricyclo [4.3.3.0] undecane moiety was isolated from the twigs and leaves of Alstonia scholaris alongside its biogenetically related strictamine (2). The structure and absolute stereochemistry of compound 1 were rigorously determined by a combination of NMR spectroscopy and X-ray crystallography. The 17-nor-excelsinidine (1) and strictamine (2) showed significant inhibitory activity against herpes simplex virus (HSV) and adenovirus (ADV).     

Iridoids from the Bark of Alstonia scholaris

Four new 11‐noriridoids named scholareins A–D ( 1 – 4 ), along with three known derivatives, isoboonein ( 5 ), alyxialactone ( 6 ), and loganin ( 7 ), were isolated from EtOH extracts of the bark of Alstonia scholaris by chromatographic methods. Their structures were identified by extensive mass‐spectrometric and spectroscopic (especially 2D‐NMR) experiments.