Polonovski reaction modified

Also, a mixture of ( )-3-epi-18,19-dihydroantirhine (203) and its C-20 epimer (204) has been obtained (138) by hydrogenation and subsequent deacetylation of 206, prepared earlier via a modified Polonovski reaction (101). 

The observed acid-catalysed conversion of complestatin (289) into chloropeptin L (291) has been envisioned" " as proceeding through a cyclopropyl intermediate (290) (see Scheme 94). An intramolecular oxygen-transfer reaction illustrated in Scheme 95 has been proposed" to explain hydroxylation of the aromatic nucleus, viz. formation of (292), during the course of a modified Polonovski reaction on galanthamine. 

Application of the modified Polonovski reaction to catharanthine p-ep-oxide (73) afforded leurosine (74) in 6% (75) or 20% yield (70-74), thus... 

The relatively facile formation of anhydrovinblastine (42) by the modified Polonovski reaction, and the poor yields experienced on coupling of other catharanthine derivatives, made anhydrovinblastine an attractive precursor for the preparation of additional binary alkaloids, including vinblastine itself (50,57). Hydrogenation to 20 -deoxyleurosidine (61a), formation of its Af -oxide (78), and reaction with trifluoroacetic anhydride led to the enamine 59 (Scheme 23). Oxidation of this enamine with thal-... 

In another search for an alternative to Potier s modified Polonovski reaction of catharanthine A-oxide (45), it has now been found that anhy-drovinblastine (42) can be generated directly, in 77% yield, from a reaction of catharanthine and vindoline in 0.01 N acid, promoted by ionized ferric salts, followed by reduction with sodium borohydride (Scheme 30) (Wl). Remarkably, the cation radical 106 generated by Fe(III), in accord with other simple amine oxidations by Lindsay Smith and Mead (102), resulted in isoquinuclidine fragmentation and coupling to vindoline at 0°C, without the conformational inversion observed in the modified Polonovski reaction at that temperature (see Scheme 15). Other metal oxidants or ligand-bound Fe(lll) did not promote the coupling reaction. It will be of interest to see if the overwhelming competition of C-5-C-6 bond... 

Another example is provided by the application of the modified Polonovski reaction to A3-piperideines. Treatment of amine oxides (141) with trifluoroacetic anhydride results in the formation of iminium ion (142). These compounds can behave as useful synthetic intermediates, reacting with a number of nucleophiles such as cyanide ion (80JA1064). 

A second group of 5 -nor-derivatives has been obtained by the coupling of vindoline with 5-norcatharanthine (173), prepared as described above.1066 Under the usual modified Polonovski reaction conditions, loss of a proton from C-6 or C-3 in the quaternary ion (214) derived from norcatharanthine Nb-oxide (213) was followed by coupling with vindoline, with formation of the bis-indole bases (215) and (216) (Scheme 26). In this reaction, cleavage of the 16,21 bond in the norcatharanthine component is not observed, in contrast to the behaviour of... 

The critical dependence of the stereochemical and regiochemical course of the modified Polonovski reaction on the oxygen functionality in the catharanthine derivative has been well exemplified in recent synthetic studies. Indeed, in the reaction that ultimately provided the first synthesis of anhydrovinblastine, a minor product proved to be the result of an alternative fragmentation of the catharanthine Nb-oxide derivative in which the 5,6-bond was cleaved [->(266)] and subsequent coupling of vindoline occurred at position 6, with formation of the dimeric species (267).159 When an attempt was made to couple the N-oxide of the lactone (238) with vindoline under Polonovski conditions, this type of coupling occurred exclusively, and the products were the lactone (268) (major product)163-165, the... 

Further use of the modified Polonovski reaction has been made166 in the synthesis of four model vinblastine derivatives (271)—(274) from the vindoline relatives mentioned earlier 117 all four products have the natural stereochemistry at C-16. ... 

Scheme 18.3 Chemical transformation of daphnicyclidin Dto daphnicyclidins E and J by a modified Polonovski reaction.

In principle, any reagent capable of activating the N-oxide oxygen can promote the Polonovski reaction. However, acid anhydrides, and in particular trifluoroacetic anhydride (the modified Polonovski reaction), are usually employed. The discussion in this chapter will therefore be limited mainly to the use of acid anhydrides. Brief mention is made in Sections 4.7.2.5 and 4.7.2.6 of the use of iron salts, sulfur dioxide and organo-silicon and -selenium derivatives as activating agents. 

The Polonovski reaction (see Volume 6, Chapter 4.7) — the action of an acid anhydride on an V-oxide — can give rise both to elimination or fragmentation reactions. Potier has modified the fragmentation by use of TFAA rather than AC2O and has applied this version to a useful synthesis of compounds related to antitumor alkaloids of Catharanthus roseus, e.g. vinblastine and vincristine. 

Potier, P. Is the modified Polonovski reaction biomimetic Annu. Proc. Phytochem. Soc. Eur. 1980, 17, 159-169. 

Lounasmaa, M., Koskinen, A. Modified Polonovski reaction, a versatile synthetic tool. Heterocycles 1984, 22, 1591-1612. 

Morita, H., Kobayashi, J. i. A Biomimetic Transformation of Serratinine into Serratezomine A through a Modified Polonovski Reaction. J. 

A new synthesis" of ( )-dihydroantirhine (104) (Scheme 12) makes use of the modified Polonovski reaction for the construction of the indoloquinolizidine ring system in model experiments it had been established that the preferred stereochemistry of the product formed on closure of ring c was C-3, C-15 trans, in contrast to the other available methods of synthesis. However, the product obtained was proved to be an inseparable mixture of (104) and its C-20 epimer. 

The partial synthesis of vinblastine itself makes use of 20-acetoxycatharanthine (223), prepared from catharanthine as described earlier. The modified Polonovski reaction in the presence of vindoline gave an intermediate immonium ion, which was reduced to 20 -acetylvinblastine (Scheme 37). Mild alkaline hydrolysis afforded deacetylvinblastine, the secondary hydroxy-group of which could be re-acetylated preferentially, with formation of vinblastine (271). ... 

The chemical conversion of alkaloids of the vobasine type into those of the ervatamine type can readily be effected, using a modified Polonovski reaction. This involves formation of an N-oxide and its rearrangement, using trifluoroacetic anhydride as reagent. Dregamine (65) has been converted into 20-epi-ervatamine... 

Deacetylcathovaline (168) has been found to occur together with cathovaline (169) in C. ovalis, and the structures of these two alkaloids have been established by correlation with vindorosine (170) the structure previously proposed " for cathovaline is thus confirmed, and the stereochemical detail also becomes evident. Vindorosine (170) (and vindoline) apparently do not give an Nb-oxide under the usual conditions, owing to the presence of a strong hydrogen bond between the tertiary hydroxy-group and the lone electrons on Ny,. The acetyl derivative (171), however, behaves normally and from the product deacetylvindorosine JVb-oxide (172) can be obtained, and transformed into deacetylcathovaline by a modified Polonovski reaction, "" presumably via the enamine (173) (Scheme 31). 

In 1975, Potier and collaborators proposed that, in planta, the dimeric vinblastine type alkaloids resulted from the coupling of catharanthine and vindoline and, in light of this hypothesis, they reported for the first time the chemical synthesis of a dimer with the natural configuration through a modified Polonovski reaction [18, 19]. This reaction resulted in the formation of an iminium dimer which, after reduction with NaBH4, yielded a-3 ,4 -anhydrovinblastine, Fig. (2), later proved to be the first dimeric biosynthetic precursor of vinblastine in the plant. The group of Potier investigated possible modifications of anhydrovinblastine and produced vinorelbine, Fig. (1), which was the first active derivative with an altered cleavamine (catharanthine) moiety [20, 21]. 

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