Synthesis of vinca alkaloids and related compounds part 94. Epimerization of compounds with aspidospermane and D‐secoaspidospermane skeleton

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.     

Synthesis of compounds related to vinca alkaloids : Stereoselective synthesis of (±) homoeburnamine

Base catalysed addition of acrolein to 1-ethyl-2,3,4,6,7,12-hexahydroindolo[2,3a] quinolizine (perch-lorate) 5b gives a pentacyclic alcohol 6b, which can be reduced in excellent yield to (±) homoeburnamine 7, a convenient precursor of (±) homoeburnamenine 9 and (±) homoeburnamonine 11.     

Synthesis of vinca alkaloids and related compounds. XLVI. . Formation of a new ring system

In the Pictet-Spengler reaction of indole-3-propanamine 1 and diethyl-(2-formyl-cyclopropane-1,1-dicar-boxylate) 2 the formation of ethyl (1a,2,4,5,6,11,11b,11c-octahydro-2-oxo-1H-cycloprop[3′,4′]pyrrolo[1,2′:1,2]-azepino[3,4-b]indole-1a-carboxylates) 3 and 4 was observed. Compounds 3 and 4 represent a new ring system.     

Synthesis of vinca alkaloids and related compounds—II: Stereoselective and enantioselective synthesis of (+)-vincamine

Addition of α-acetoxy acrilic acid (-)-menthyl ester to enamine 1 produces about 40% asymmetric induction. The compound obtained, 9b, can be converted into (+)-vincamine with ease and in good yield. The catalytic effect of metal ions on the epimerisation of the vincamine-epivincamine system was investigated.     

Synthesis of vinca alkaloids and related compounds. Part 102: Simple synthesis and ring transformation of (±)-minovincine. First synthesis of (±)-vincaminine

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.     

Synthesis of vinca alkaloids and related compounds XII an unusual racemization. Chromic effect.

Oxidation of the quinolizine derivative 1a by sodium dichromate is accompanied by racemization not observable with other oxidizing agents.     

Synthesis of vinca alkaloids and related compounds LXXXV. Studies with azepino[3,4-b]indoles

The synthesis of some new pyrido[1′,2′:1,2]azepino[3,4-b]indoles starting from indole-3-propanamine 1 is described. Stereochemistry and observed side reactions are discussed.     

Synthesis of vinca alakaloids and realated compounds 98. Oxidation with dimethyldioxirane of compounds containing the aspidospermane and quebrachamine ring system. A simple synthesis of (7S,20S)‐(+)‐rhazidigenine and (2R,7S,20S)‐(+)‐rhazidine

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.     

Synthesis of vinca alkaloids and related compounds XXVII formation of a stable 3-acylindolenine

A stable 3-acylindolenine derivative (2) has been prepared $\text{via}$ intramolecular electrophilic acylation. The reactivity of 2 has been studied.     

Syntheses of vinca alkaloids and related compounds. 104. A concise synthesis of (-)-vincapusine

beta-Iodo-enamines with an eburnane skeleton (5a and 5c) were obtained with the aid of iodine from compounds 2a and 2c and were then transformed into hydroxyl lactams (6a and 6c) with CuSO4.5H2O in a mixture of DMF and water. Lactams (6a and 6c) were reduced selectively with BH3.SMe2 to result in the first synthesis of (-)-vincapusine (4a) as well as its natural 14-decarbomethoxy analogue (4c).     

The synthesis of compounds related to the indole-indoline core of the vinca alkaloids (+)-vinblastine and (+)-vincristine

A series of α′-aryl-α′-carbomethoxycycloalk-2-en-1-ones, 16, has been prepared using the Pinhey arylation methodology for introducing the aromatic residue. Subjection of these compounds to Johnson iodination and Pd[0]-catalyzed Ullmann cross-coupling of the resulting α-iodocycloalkenones 11 with 2-iodonitrobenzene (5, X = I) then affords α,α′-diaryl-α′-carbomethoxycycloalk-2-en-1-ones of the general form 10. Reductive cyclization of this last type of compound gives the corresponding indoles 9a-f (n = 1-3), some of which resemble the indole-indoline cores of the clinically important alkaloids (+)-vinblastine (1) and (+)-vincristine (2).     

Synthesis of vinca alkaloids and related compounds 99<Superscript>1</Superscript>. A new heterocyclic system

Utilising our earlier intermediate obtained by the umpolung reactivity of quinolizidine enamines, a new heterocyclic system: (11bSR, 15aSR)-1,2,3,6,11,14,15,15a-Octahydro-5H-indolo [2′,3′:3,4]pyrido[2,1-j]-1,6-naphthyridin-13(12H)-one was synthesised and its biological effects evaluated. Although modest, significant and selective effects were detected.     

Synthesis of vinca alkaloids and related compounds. Part 108: Efficient convergent synthetic pathway to the ibophyllidine skeleton IV. First synthesis of (±)-18-hydroxy-20-epiibophyllidine

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.     

Stereoselective synthesis of the indolizinoindole ring system

We report a novel, facile and stereoselective approach to the indolizino[8,7-b]indole ring system from a readily available, non-racemic chiral template.     

Synthesis of vinca alkaloids and related compounds. Part 110: A new synthetic method for the preparation of pandoline-type alkaloid-like molecules

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.     

Stereoselective synthesis of the ABC ring system of norzoanthamine

[reaction: see text] An efficient synthesis of enone 4, representing the ABC ring motif of norzoanthamine, is presented. The crucial C22 quaternary center was introduced via a stereoselective methylation of enone 8. The trans-anti-trans relative configuration of the ABC framework of 4 was installed via a sequence of reactions that included a hydroboration and a modified Robinson annulation.     

Stereochemistry of reactions in the 1,2-dimethylsilacyclopentane ring system. II. Stereoselective transformation

A number of stereoselective reactions of 1-substituted-1,2-dimethylsilacyclopentanes are described. Reactions of the silyl chloride (II) with ZnF₂ and with alcohols catalyzed by amines are stereoselective as a result of rapid isomerization of II. Alcoholysis of silicon hydride (I) catalyzed by transition metals is apparently an inversion reaction regardless of the nature of the catalyst, but can appear to be stereoselective because of isomerization of alkoxysilane product. Reduction of silyl fluoride (IV) by lithium aluminum hydride is nonstereoselective, a result which is proposed to arise through rapid isomerization of intermediates with expanded coordination.