Total Synthesis of Indole and Dihydroindole Alkaloids. IX Studies on the synthesis of bisindole alkaloids in the vinblastine‐ vincristine series. The biogenetic approach

Kutney, James P.; Hibino, Toshihiko; Jahngen, Edwin; Okutani, Tetsuya; Ratcliffe, Arnold H.; Treasurywala, Adi M.; Wunderly, Stephen

doi:10.1002/hlca.19760590824

Cited by 101 publications

(53 citation statements)

References 15 publications

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“…The point of attachment of the indole unit at C15 of the vindoline ring system was readily ascertained from the 'Hmr spectrum (singlets at F 6.48 and 6.12 for the C14 and C,, protons, respectively). As in the previous studies (6,9), this spectrum was highly informative, being essentially a summation of the appropriate signals for the indole and dihydroindole portions, and virtually on its own established the postulated structure 5. Although the normal proton signals attributed to the vindoline unit were clearly evident in the 'Hmr spectrum of 5, several important differences in For personal use only.…”

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confidence: 53%

“…the signal patterns for the indole unit were noted. The absence of the indole N H signal, so characteristic in all the previous bisindole products isolated previously (5,6,9) and in leurosine prepared above, was immediately noted and a new two-proton AB quartet centered at 6 5.02 ( J = 11 Hz) never observed in any of the 'Hmr spectra of the previously studied bisindole products, was noted. This quartet was attributed to the methylene group at C,' in 5, a product arising from a rearrangement of the N-oxide 4 prior to coupling with vindoline (see later).…”

mentioning

confidence: 51%

“…Consequently our initial studies with the oxygenated catharanthine derivatives (4,14) were directed toward this objective. The two possible 3,4-epoxydihydrocatharanthine derivatives available from the previous studies (4,14) were utilized in coupling experiments with vindoline (2) according to procedures developed independently in our laboratories (5,6) and elsewhere (7,8).…”

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confidence: 99%

“…oxygen functionality at the C,-C4 positions (5,6), other bisindole products, particularly those bearing unnatural configuration at C,,,, are not isolated. The other byproducts obtained are monomeric in nature clearly arising from transformations of the catharanthine and indole systems.…”

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Total synthesis of indole and dihydroindole alkaloids. XI.^1,2 The synthesis of leurosine and the coupling of 3α,4α-substituted catharanthine derivatives with vindoline

Kutney¹,

Joshua²,

Liao³

et al. 1977

Can. J. Chem.

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A detailed study involving the Polonovski-type coupling of vindoline (2) with several novel catharanthine derivatives is described. Coupling of vindoline (2) with the N-oxide intermediate of 3β,4β-epoxydihydrocatharanthine (1) provides a laboratory synthesis of the bisindole alkaloid leurosine (3, R=CO2CH3) and an unambiguous proof of the stereochemistry of the epoxide function in that alkaloid. The coupling of 2 with the N-oxides of 3α,4α-epoxydihydrocatharanthine (4) and 4α-hydroxydihydrocatharanthinic acid lactone (6) provide the rearranged bisindole products 5, 7, and 8.

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confidence: 53%

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confidence: 51%

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confidence: 99%

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confidence: 99%

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Total synthesis of indole and dihydroindole alkaloids. XI.^1,2 The synthesis of leurosine and the coupling of 3α,4α-substituted catharanthine derivatives with vindoline

Kutney¹,

Joshua²,

Liao³

et al. 1977

Can. J. Chem.

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“…Our previous investigations (1)(2)(3)5) involved studies in which appropriate indole and dihydroindole units were coupled to provide the desired bisindole systems. In another study we have tion, we turned our attention t o oxygen and hydroperoxide oxidation of alkenes, a reaction which is not generally utilized by synthetic chemists (6)(7)(8)(9).…”

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confidence: 99%

Total synthesis of indole and dihydroindole alkaloids. XII. Selective functionalization of various bisindoles. Efficient syntheses of leurosine and related bisindole alkaloid derivatives

Kutney¹,

Balsevich²,

Bokelman³

et al. 1978

Can. J. Chem.

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. Can. J. Chem. 56,62 (1978).Studies involving selective functionalization of the indole unit in a number of bisindole alkaloids and related synthetic derivatives are described. These investigations include such reagents as tert-butyl hydroperoxide, which provides an efficient procedure for epoxidation of olefinic linkages, mercuric acetate, osmium tetroxide, and iodine under basic conditions and oxygenation under acidic conditions. Efficient syntheses of leurosine (8) In a continuiilg research program directed at the laboratory synthesis of bisindole alkaloids of the vinblastine-vincristine series, we have considered various approaches in the hope of developing efficient procedures for the preparation of these clinically important agents. Our previous investigations (1-3, 5) involved studies in which appropriate indole and dihydroindole units were coupled to provide the desired bisindole systems. In another study we have tion, we turned our attention t o oxygen and hydroperoxide oxidation of alkenes, a reaction which is not generally utilized by synthetic chemists (6-9).The intermediate chosen for this study was N,-carbomethoxy-18P-carbomethoxycleavainine (1) since this compound was expected to exhibit properties similar to those of the indole unit present in the bisindole alkaloids. The preparation of this intermediate was accomplished by reacting the readily considered the development of selective^ reactions available 18~-carbo~ethoxycleavamine (1, 10) with which would allow specific functionalization of strong base to remove the indolic hydrogen and appropriate bisindole systems already available from treating the resultant anion with methyl chloroprevious experiments. The results presented herein formate. illustrate the success of such an approach.Oxidation of 1 with oxygen in a tetrahydrofuran It has already been noted (Part XI, ref. 4) that solution containing trifluoroacetic acid provided electrophilic addition to the olefinic linkage of the two main products, which on the basis of their catharanthine system is complicated by competitive spectral data, were assigned the structures 2 and 3. side reactions at the indole or the basic nitrogen site The major component (51% yield) was the lactam in the molecule. A similar difficulty was observed epoxide 3 while the desired N,-carbomethoxy-lSPwith the cleavamine system, the indole unit normally carbomethoxy -3P,4P -epoxydihydrocleavamine (2) present in the bisindole alkaloids. After much was isolated in only 10-15% yield. Of particular frustration with the more common electrophilic importance in allowing the structural assignment for reagents generally employed in olefin functionaliza-2 was the characteristic fragmentation pattern in the mass spectrum. The most significant fragmentation For personal use only.

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ThePolonovski Reaction

Grierson¹

1990

Organic Reactions

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In connection with their interest in the isolation and medicinal properties of the “gen alkaloids” ( N ‐oxides), Max and Michel Polonovski reported in 1927 their discovery that the treatment of a tertiary amine N ‐oxide with acetic anhydride or acetyl chloride results in a rearrangement in which one of the alkyl groups attached to nitrogen is cleaved, and the N ‐acetyl derivative of the corresponding secondary amine and aldehyde are obtained. As the original work by the Polonovskis was mainly carried out on bicyclic tropane N ‐oxide derivatives, the products of the reaction were the demethylated amides and formaldehyde. The reaction was thus looked upon as a means of effecting N ‐demethylation of tertiary amines. As such it was, and still remains, a viable alternative to the use of cyanogen bromide, alkyl chloroformates, azocarboxylic esters, or nitrous acid for this purpose. These methods often require more drastic conditions and/or promote unwanted side reactions. The central feature of the Polonovski reaction is the transformation of an N ‐oxide to an iminium ion intermediate. Depending on the structure of the substrate and the acid anhydride or other activating reagent employed, iminium ion formation can occur through loss of an α hydrogen, or through fragmentation of a Cαcarbon bond. Again, depending on conditions, the reaction will either stop at this stage and iminium ions become the Polonovski products, or proceed to give enamines or tertiary amides and/or secondary amines and aldehydes. The often close relationship between structure and reaction conditions, which determine both product types and reaction regiochemistry, is discussed. In its initial stages the Polonovski reaction resembles other reactions in which a tertiary amine is oxidized through interaction of the pair of electrons on nitrogen with an agent X followed by elimination of the elements of HX. Reagents like lead tetraacetate, N ‐bromosuccinimide and in particular mercuric acetate have been employed for this purpose. However, the Polonovski reaction can offer certain advantages in selectivity and experimental ease. In principle, any reagent capable of activating the N ‐oxide oxygen could promote the Polonovski reaction. However, three major types of activating agents, acid anhydrides and chlorides (including chloroformate esters), iron salts and complexes, and sulfur dioxide, are usually employed. Perhaps the most important contribution to the use of the Polonovski reaction in modern organic synthesis was the discovery in the 1960s that on replacing acetic anhydride by trifluoroacetic anhydride the reaction could be stopped at the iminium ion stage. Considering the rich chemistry of iminium ions, many applications of this modified, or Polonovski–Potier, reaction have appeared in the literature, the most spectacular of which was the first successful approach to the synthesis of the indole antitumor agents of the vinblastine group. In this chapter the discussion is limited to examples of the Polonovski reaction in which the abovementioned activating reagents are employed. The coverage is restricted to tertiary amine oxides in which at least one of the substituents on nitrogen is an alkyl group. Both acyclic and cyclic amine oxides such as piperidine N ‐oxide fall into this category, whereas heteroaromatic N ‐oxides do not. With the exception of one special case, nitrones are also omitted from the discussion. The literature coverage includes articles appearing before the end of August 1988.

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Total Synthesis of Indole and Dihydroindole Alkaloids. IX Studies on the synthesis of bisindole alkaloids in the vinblastine‐ vincristine series. The biogenetic approach

Cited by 101 publications

References 15 publications

Total synthesis of indole and dihydroindole alkaloids. XI.^1,2 The synthesis of leurosine and the coupling of 3α,4α-substituted catharanthine derivatives with vindoline

Total synthesis of indole and dihydroindole alkaloids. XI.^1,2 The synthesis of leurosine and the coupling of 3α,4α-substituted catharanthine derivatives with vindoline

Total synthesis of indole and dihydroindole alkaloids. XII. Selective functionalization of various bisindoles. Efficient syntheses of leurosine and related bisindole alkaloid derivatives

ThePolonovski Reaction

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Total Synthesis of Indole and Dihydroindole Alkaloids. IX Studies on the synthesis of bisindole alkaloids in the vinblastine‐ vincristine series. The biogenetic approach

Cited by 101 publications

References 15 publications

Total synthesis of indole and dihydroindole alkaloids. XI.1,2 The synthesis of leurosine and the coupling of 3α,4α-substituted catharanthine derivatives with vindoline

Total synthesis of indole and dihydroindole alkaloids. XI.1,2 The synthesis of leurosine and the coupling of 3α,4α-substituted catharanthine derivatives with vindoline

Total synthesis of indole and dihydroindole alkaloids. XII. Selective functionalization of various bisindoles. Efficient syntheses of leurosine and related bisindole alkaloid derivatives

ThePolonovski Reaction

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Total synthesis of indole and dihydroindole alkaloids. XI.^1,2 The synthesis of leurosine and the coupling of 3α,4α-substituted catharanthine derivatives with vindoline

Total synthesis of indole and dihydroindole alkaloids. XI.^1,2 The synthesis of leurosine and the coupling of 3α,4α-substituted catharanthine derivatives with vindoline