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Bannucine is an Aspidosperma alkaloid isolated from the dried leaves of Catharanthus roseus. The molecule is a derivative of vindoline bearing a C10 substituent, a pattern common to the antineoplastic dimeric indole alkaloids of C. roseus. In bannucine, a 2-pyrrolidone moiety is attached at C5′ to the aromatic ring of the vindoline core at C10. In the present work we report the synthesis of bannucine and its 5′-epimer from natural (−)-vindoline using a cyclic N-acyliminium ion intermediate whose N-acylaminocarbinol precursor is synthesized by the partial reduction of succinimide. We also describe the separation and the structural analysis of the two epimers, using among others, single crystal X-ray diffraction methods, in order to clarify the orientation of the proton attached to the C5′ carbon. The in vitro antineoplastic activity of the pure epimers was also investigated, but none of the two substances showed significant activity on the examined tumour cell lines.

New derivatives of natural compounds, galanthamine using in treatment of Alzheimer’s disease and antitumor dimer alkaloids vinblastine and vincristine were synthesized. In the course of the reaction between galanthamine and diazomethane in the presence of a catalyst, such as palladium(II) acetate or copper(I) bromide, methylene insertion into the aromatic ring was observed instead of the expected cyclopropanation of the carbon-carbon double bond. New vindoline derivatives conjugated with amino acid esters were prepared. In Simmons-Smith reaction vinblastine and vincristine cyclopropanated in the carbon carbon double bond in position 14 and 15 of the vindoline monomer were obtained. New dimer alkaloids showed significant inhibiting effects in several tumor cell lines.

Sessiline is an alkaloid which is recently isolated from the fruits of Acanthopanax sessiliflorus. The molecule contains two five-membered heterocyclic units joined together by an acylaminocarbinol-ether type bond. Here, we describe the first, simple synthesis of sessiline from 5-hydroxypyrrolidin-2-one and 5-hydroxymethylfurfural, which are prepared from succinimide and furfuryl alcohol, respectively. The coupling reaction takes place on moderate heating under neat conditions.

We hereby report the biomimetic synthesis of three flavonoid alkaloids, namely 8-(2″-pyrrolidinon-5″-yl)quercetin, 6-(2″-pyrrolidinon-5″-yl)-(–)-epicatechin and 8-(2″-pyrrolidinon-5″-yl)-(–)-epicatechin. These known natural products were prepared via an acid-catalysed regioselective phenolic Mannich reaction involving the electrophilic attack of an N-acyliminium ion on the corresponding flavonoidal precursors. The products were purified by preparative HPLC. The reactions showed high C8-regioselectivity. The major isomers of the synthesized flavonoid alkaloids were further characterized in terms of their medicinal-chemical properties.

The synthetic investigation of biologically active natural compounds serves two main purposes: (i) the total synthesis of alkaloids and their analogues; (ii) modification of the structures for producing more selective, more effective, or less toxic derivatives. In the chemistry of dimeric Vinca alkaloids enormous efforts have been directed towards synthesizing new derivatives of the antitumor agents vinblastine and vincristine so as to obtain novel compounds with improved therapeutic properties.

Vinblastine is a widely used anticancer drug with undesired side effects. Its conjugation with carrier molecules could be an efficient strategy to reduce these side effects. Besides this, the conjugate could exhibit increased efficiency against resistant cells, e.g., due to the altered internalization pathway. Oligoarginines, as cell-penetrating peptides, can transport covalently attached compounds into different kinds of cells and enhance the efficiency of those compounds. We report here the coupling of vinblastine through its carboxyl group at position 16 with the N-terminal amino function of L-Trp methyl ester. After hydrolysis of the ester group, 17-desacetylvinblastineTrp was conjugated to the N-terminal amino group of oligoarginine via the C-terminal carboxyl group of the Trp moiety in solution. The antitumor effect of conjugates was studied on sensitive and resistant human leukemia (HL-60) cells in vitro. Our data suggest that all conjugates investigated possess an antiproliferative effect against the studied cells. However, the effect was dependent on the number of Arg residues in the conjugates: Arg₈ > Arg₆ ≫ Arg₄. The conjugate with Arg₈ exhibited similar efficicacy as compared with free 17-desacetylvinblastineTrp. The in vitro studies also showed that the tubulin binding ability of vinblastine was essentially preserved even in the octaarginine conjugate. We also observed that two isomers were formed during conjugation. These isomers showed different levels of activity against tubulin polymerization in vitro and in vivo. The 17-desacetylvinblastineTrp-Arg₈-1 isomer conjugate possessed high selectivity against the mitotic spindles. HRMS and NMR data suggest that 17-desacetylvinblastineTrp-Arg₈-1 and 17-desacetylvinblastineTrp-Arg₈-2 are epimers at the tryptophan α carbon atom.

A practicable synthesis of a pandoline-type alkaloid-like molecule is reported through an efficient preparation of carbinolamine ether intermediates (9a and 9b). The key step of the synthesis consists of an intramolecular cycloaddition of the secodine-type intermediate (2), which was formed from the tryptamine derivative (3) and lactol (4). The mechanism of the cycloaddition reaction was investigated by quantum chemical calculations and it was found to follow a step-wise mechanism involving a zwitterionic intermediate (15). By employing this strategy, other members of the family of pandoline alkaloids or alkaloid-like molecules could be synthesized by reacting the tryptamine derivative with appropriately functionalized aldehydes.

Starting from racemic naringenin ((±)-1), a mixture of dracocephin A stereoisomers 6-(2”-pyrrolidinone-5”-yl)naringenin (±)-2a–d and its regioisomer, dracocephin B 8-(2”-pyrrolidinone-5”-yl)naringenin (±)-3a–d originally isolated from Dracocephalum rupestre, have been synthesized in a one-pot reaction. The separation of 2a–d and 3a–d was achieved by preparative HPLC. The four stereoisomers of each natural product were separated by analytical chiral HPLC and their absolute configuration was studied by the combination of HPLC–ECD measurements and TDDFT–ECD calculations. The synthesized flavonoid alkaloids were further characterized by physicochemical and in vitro pharmacological studies.

The first total synthesis of the pentacyclic alkaloid (±)-18-hydroxy-20-epiibophyllidine was realized via an efficient preparation of the d -seco-pseudoaspidospermane molecule. The key step of the sequence involves an intramolecular [4+2] cycloaddition reaction of the dihydrosecodine intermediate, which was built up from the reaction of a tryptamine derivative with an aldehyde–ester. After full epimerization, the intramolecular N-alkylation of the tetracyclic ester gave the pentacyclic compound. Reduction of the latter molecule led to the title compound.

Starting from methyl-5-oxohexanoate we produced the appropriately functionalized aldehyde, which, after having been allowed to react with the tryptamine derivative in a [4+2] cycloaddition reaction as the final step, yielded the molecule containing a D-seco-aspidospermane skeleton. From the latter we could successfully produce a 1:1 mixture of protected epimers, the desilylation reaction of the protected molecules gave the alkaloids (±)-19-hydroxy-ibophyllidine and (±)-19-hydroxy-20-epiibophyllidine in good yield.

Transformation of β-carboline derivatives into optically active entities were studied and the de and ee values of the resulted compounds were detected.

A molecule with an indole skeleton, containing a latent acrylic ester function—acting as a diene—readily reacted with benzoic acid (4-bromomethylene-5-oxo)hexyl ester that had been built up from pentane-2,4-dione. Dehydration of the enamine and subsequent [4+2] cycloaddition supplied epimers having the d -secoaspidospermane skeleton. These compounds directly or after epimerization gave (±)-minovincine. Oxidative ring transformation of (±)-minovincine under different conditions led to (±)-16-acetyl-16-deethylapovincamine and (±)-vincaminine.

A molecule with an indole skeleton, containing a latent acrylic ester function—acting as a diene—was produced from Nb-trityl-2-(hydroxy-methyl)-tryptamine and reacted with esters containing an aldehyde or aldehyde-equivalent structural unit, yielding 3-oxo-16,17-dihydro-Δ20-secodin-17-ol type intermediates from which dehydration, followed by [4+2]cycloaddition, furnished 3-oxovincadifformine and 3-oxominovincine. We also wished to apply the method to produce 15β-hydroxyvincadifformine, however, the appearance of a dimeric product with indole skeleton was observed instead of the expected cycloaddition.

The first syntheses of the alkaloids (−)-mehranine (3), (+)-voaphylline/conoflorine (4), (+)-Na-methylvoaphylline/hecubine (5), and (−)-lochnericine (2) were achieved by stereoselective epoxidation starting from (−)-tabersonine (1), through intermediates with the aspidospermane and quebrachamine skeleton.

The oxidation of (-)-tabersonine (1) with dimethyldioxirane (DMD) in neutral and acidic medium gave 16-hydroxytabersonine-N-oxide (3) and the didehydrovincamine isomers 4 and 5, respectively. (+)-14,15-Didehydro-quebrachamine (7) furnished the hydroxyindolenine 9, and the pentacyclic derivative 11. (+)-Quebrachamine (8) and DMD in neutral medium gave (7S,20S)-(+)-rhazidigenine (12) which was converted to (2R,7S,20S)-(+)-rhazidine (13b) with hydrochloric acid.

Attempted cyclisation of N-methylated spiro benzazepine–cyclohexenone ( 5 ) into the corresponding N -methyl tetracyclic unit of galanthamine-type alkaloids ( 6 ) instead gave an unexpected rearrangement to yield a cyclopentanoisoquinolinone derivative ( 7 ). Methylation of the tetrahydrobenzofurobenzazepine tetracycle resulted in the expected N -methyl derivative 6 , and the anomalous product 8 , with structure similar to that of 7 .

The individual epimerization steps of vincadifformine (1), deethylvincadifformine isomers (2,3), their synthetic intermediates (4–13) as well as that of simpler compounds with D-secoaspidospermane skeleton (15–17) were studied a) in protic medium (boiling deuteroacetic acidic) and b) under reductive (with sodium borodeuteride in boiling acetic acid, or with sodium borohydride in boiling deuteroacetic acid) conditions.

Subjection of tryptamine 1 to the action of aldehyde 2d a substantial amount of dimeric naphthyridine 5 was formed along with the indolo-quinolizidine derivatives 6a and 6b.

The synthesis of the natural alkaloids (+)-Vincine and (+)-Apovincine has been achieved for the first time.

Reaction of compound (4) with (5) give a mixture of the isomers (7) and (8) through the intermediate (1). Further conversions led through the oxo- (9), (10) and thioxo (11), (12) derivatives to (±)-19-ethoxycarbonyl-19-demethylvincadifformine (3), and (±)-18-methoxycarbonyl-D(14)-norvincadifformine (13). The preparation of the former compound constitutes the formal synthesis of (±)-12-demethoxy-N(1)-acetylcylindrocarine (2). Oxidative ring transformation of the latter gave (±)-21-methoxycarbony 1-D(18)-norapovincamine (14).

The reaction of the key compound 14 with methyl 4-formyl-butanoate (9) or with 5-benzoyloxypentanal (13) gave the D-seco-aspidospermane derivatives 17 and 18, respectively. Compound 17 was indirectly and 18 was directly converted to (±)-20-deethylvincadifformine (7) and (±)-20-deethyl-20-epivincadifformine (8). Epimerization occurred in both cases. The thioxo compound 23 was used for the synthesis of (±)-20-deethyltabersonine (28) and (±)-20-deethyl-3-oxotabersonine (27). Oxidative ring transformation of the (±)-20-deethylvincadifformine (7) gave (±)-16-deethylapovincamine (29).

The synthetic investigation of biologically active natural compounds serves two main purposes: (i) the total synthesis of alkaloids and their analogues; (ii) modification of the structures for producing more selective, more effective, or less toxic derivatives. In the chemistry of dimeric Vinca alkaloids enormous efforts have been directed towards synthesizing new derivatives of the antitumor agents vinblastine and vincristine so as to obtain novel compounds with improved therapeutic properties.

Several methods2a-g are known for the enantioselective syntheses of (+)-vincamine [1*]# and (+)-apovincaminic acid esters [2*].

Using our previously reported convergent synthetic strategy, secondary amine, methyl 2-[3-(2-[benzylamino]ethyl)indol-2-yl]-3-hydroxypropionate (6), and aldehyde, ethyl 2-ethyl-4-formylbutanoate (9), reacted to give tetracyclic esters ,pyrrolo[2,3-d]carbazole derivatives 10 and 11, which readily led to pentacyclic lactams indolizino[8,1-cd]carbazole derivatives 14-16. Selective reduction of these products gave (±)-pseudovincadifformine (4), (±)-20-epipseudovincadifformine (5), and (±)-14-epipseudovincadifformine (20). 2-ethyl-4-formylbutyl benzoate 23 was also prepared and could be directly used for synthesizing (±)-20-epipseudovincadifformine (5). The introduction of the double bond into ring D of the pseudoaspidospermane skeleton was successfully achieved to obtain 21-oxopseudotabersonine (30)

Compound 3, which has an indole skeleton containing a masked acryl ester function, was synthesized from the hydrochloride of 2-(ethorycarbonyl)tryptamine (2). The cycloaddition of 3 with methyl 4-formylhexanoate (21) or with 5-(benzoylocy)-2-ethylpentanal (33) yielded the starting materials for beget compounds (±)-vincadifformine (4), (±)-3-oxotabersonine (42), and (±)-tabersonine (43). The synthesis of vincadifformine (4) was achieved in two different ways: via 3-oxovincadifformine (7) and via tetracyclic benzoate esters 37 and 38. The double bond requiredin tabersonine (43) and 3-oxotabersonine (42) was introducedby treatment of 3-thioxovincadifformine (39) with p-toluenesulfinyl chloride

Publisher Summary This chapter discusses the synthesis of Aspidosperma and related alkaloids. Aspidosperma alkaloids constitute the largest group of indole alkaloids and number well over 220 entities. Dealing with these bases is not only important in order to gain more knowledge about their nature, but some members are also of commercial value. The transformation of aspidospermas such as vincadiflformine to the vincamine, vincamone, and Cavinton is carried out on a large scale. The chapter presents a convergent synthetic pathway that is suitable for the convenient and efficient preparation of a number of compounds having the aspidospermane skeleton. Under this strategy, a compound is prepared from an indole derivative, which on reaction with suitably substituted aldehydes, gives–via the unisolated intermediates (R 1 =Bn)–tetracyclic compounds. Formation of the fifth ring affords the target compounds and as the aldehyde component could be varied, this strategy allows the preparation of many analogous compounds. This enables a convenient synthesis of aspidosperma alkaloids and related compounds.

A versatile method for introducing a functionalized side chain into enamines 9a and 11a is described. This procedure provides an easy access to 16-deethyl-vincamines 16, 17 and 16-deethyl-apovincamines 18–21.

The first syntheses of the alkaloids (-)-mehranine (3), (+)-voaphylline/conoflorine (4), (+)-N(a)-methylvoaphylline/hecubine (5), and (-)-lochnericine (2) were achieved by stereoselective epoxidation starting from (-)-tabersonine (1), through intermediates with the aspidospermane and quebrachamine skeleton.

Publisher Summary This chapter discusses the synthesis of Aspidosperma and related alkaloids. Aspidosperma alkaloids constitute the largest group of indole alkaloids and number well over 220 entities. Dealing with these bases is not only important in order to gain more knowledge about their nature, but some members are also of commercial value. The transformation of aspidospermas such as vincadiflformine to the vincamine, vincamone, and Cavinton is carried out on a large scale. The chapter presents a convergent synthetic pathway that is suitable for the convenient and efficient preparation of a number of compounds having the aspidospermane skeleton. Under this strategy, a compound is prepared from an indole derivative, which on reaction with suitably substituted aldehydes, gives–via the unisolated intermediates (R 1 =Bn)–tetracyclic compounds. Formation of the fifth ring affords the target compounds and as the aldehyde component could be varied, this strategy allows the preparation of many analogous compounds. This enables a convenient synthesis of aspidosperma alkaloids and related compounds.

10-Bromovindoline and its 14,15-dihydro- and 14,15-cyclopropano derivatives were coupled in the position 16 with (L)- and (D)-tryptophan methyl esters. The tryptophan derivatives of vindoline were synthesized starting from the 16-carboxylic acid hydrazides viathe corresponding azides which were allowed to react with the amino acidesters. The new compounds showed antitumor activity against human leukemia (HL-60) cells in vitro.

The pentacyclic alkaloid 1 could be synthesized by an intramolecular [4+2] cycloaddition reaction of intermediate 11, which had been obtained from tryptamine derivative 4 and aldehyde 5. After full epimerization of 13 the cyclization reaction furnished a mixture of 14a and 14b. Separation of the stereoisomers 14a and 14b and subsequent reduction with LiA1H 4 resulted in (±)-iboxyphylline (14a -> 1) and its epimer, (±)-20-epiiboxyphylline (14b -> 15).

Starting from 5-ethyldihydrofuran-2(3H)-one (9) we prepared aldehydes (6 and 7) which, in a [4+2] cycloaddition reactions with the tryptamine derivative (8) gave, as a final step, compounds (13 and 22) having D-seco-pseudoaspidospermane skeleton. We synthesized (±)-20-epiibophyllidine (4) via the benzoate ester (15) or the mesylate (17) of alcohol (14) which had been obtained from 13, while the catalytic hydrogenation of 22 led to (±)-ibophyllidine (3) via full epimerization, cyclization and reduction steps in one operation.

Reaction of tryptamine derivative (2b) and acetate ester (11) built up from 2-(chloromethylene)butanal (4) resulted in enamino ketone (14). Dehydration of 14 and subsequent intramolecular [4+2] cycloaddition led to 15-oxovincadifformine (15). Regio- and stereoselective reduction of the latter molecule supplied 15β-hydroxyvincadifformine (1).

Reaction of the enamine 5 with α-bromoacrylic esters or α-chloroacrylonitrile and subsequent reduction with NaBH4 yielded the pentacyclic D-noreburnamenine derivatives 8–10 or 11–14, respectively. Uber die Synthese von Vinca-Alkaloiden und verwandten Verbindungen, XXXVI. – Eine einfache Synthese einiger D-Noreburnamenin-Derivate Das Enamin 5 reagiert mit α-Bromacrylestern oder α-Chloracrylonitril und anschliesender Reduktion mit NaBH4 unter Bildung der pentacyclischen D-Noreburnamenin-Derivate 8–10 oder 11–14.

A stereoselective method has been elaborated for the synthesis of oxime esters, (-)-4a, b, from which, as common intermediates, (+)-apovincaminic acid esters (3a,b), (+)-vincamine (1) and (-)-vincamone (2) can be prepared.