Vindoline total synthesis

Kobayashi, S., Ueda, T, Fukuyama, T. (2000) An Efficient Total Synthesis of (—)-Vindoline. Synlett, 883-886. 

Having an efficient total synthesis of the indole alkaloid vindoline in mind, the Boger group [47] developed a facile entry to its core structure using a domino [4+2]/[3+2] cycloaddition. Reaction of the 1,3,4-oxadiazoles 4-139 led to 4-140 in high yield and excellent stereoselectivity via the intermediates 4-141 and 4-142 (Scheme 4.29). 

A systematic exploration of the intramolecular [4+2]/[3+2] cycloaddition cascade of 1,3,4-oxadiazoles was described. The studies permit the use of unsymmetrical dienophiles, dipolarophiles, and oxadiazoles as well as to control the cycloaddition regioselectivity and diastereoselectivity. The scope and utility of the reaction were defined <2006JA10589>. The tandem intramolecular [4+2]/[3+2] cycloaddition cascade reaction of 1,3,4-oxadiazole was applied to the syntheses of a series of natural products including a total synthesis of (-)- and ent-(+)-vindoline <2006JA10596>. 

A total synthesis of (+ )-vinblastine widely used in cancer chemotherapy, has been reported. It includes the synthesis of (-)-vindoline. 1,3-Dipolar cycloaddition of a nitrile oxide has played an important role in the preparation of the indoloazacycloundecane moiety, whose coupling with (-)-vindoline occurs with the desired stereochemistry, leading to an intermediate readily transformed to the target (+ )-vinblastine (492). 

Although there are many examples of bisindole derivatives that are prepared by reaction of a naturally occurring alkaloid with various reagents, there are few examples of compounds that result from chemistry that alters the skeletal features of these compounds. Much interest has been directed at the synthesis of the dimeric compounds by the coupling of the monomer units vindoline (21) and catharanthine (38), in part because of the necessity of using this strategy to prepare bisindoles by total synthesis. 

Natural products have always been attractive targets for the application of newly developed synthetic strategies. In this field, only a few examples have been reported, in which intramolecular aryl radical addition reactions occur to non-activated carbon-carbon double bonds [69]. One of the early examples is the first total synthesis of (—)-y-lycorane [70]. More recently, formal total syntheses of aspidos-permidine [71] and vindoline [72] have been accomplished by an aryl radical... 

Langlois and co-workers (82CC1118 85JOC961) succeeded in the total synthesis of vindrosine (46) and vindoline (47) by the imino Diels-Alder cycloaddition using dihydro-)3-carbolines and the diene shown in Scheme 5. 

The total synthesis of vindoline (205) from the pentacyclic ketone (206), whose formation was discussed in last year s Report, has now been completed (Scheme 27), essentially according to the route adopted earlier in the synthesis of vin-dorosine. The reduction of the C-17 ketone function in the penultimate stage with normal hydride reducing agents was not stereospecific. However, this was circumvented by addition of aluminium chloride, which presumably formed a complex involving the C-16 hydroxy-group and N reduction by a bulky complex hydride then ensured preferential a-attack with formation of deacetylvindoline. ... 

The synthesis of vindorosine (43) and vindoline (44) by Kuehne and his collaborators is particularly notable, since it constitutes the first enantiosel-ective synthesis of these alkaloids (323). Essentially, this consists of an extension of the synthesis (4) of tabersonine (78) and 11-methoxytaberson-ine (82) by the same group of workers, the last stages being in principle very similar to those employed by Danieli et aL (vide supra. Scheme 24, Ref. 252). Since the starting materials for these syntheses are available in R, S, and racemic forms, both enantiomers and the racemates of these alkaloids are accessible by total synthesis. 

More recently, Langlois and co-workers have adapted this methodology to total synthesis of some complex indole alkaloids.56 Cyclic imines (Scheme 2-IX) reacted thermally in good yields with methylbutadiene-1-carboxylate to afford a mixture of Diels-Alder adducts. Alkylation of the enolate derived from the mixture of isomers gave a /3, y-unsaturated ester stereospecifically. This type of compound was coverted to vindoline (28, R = OMe) and vindorosine (28, R = H). These workers found that 1-cyanobutadiene is also useful in this sort of cycloaddition [Eq. (13)]... 

Buchi has presented an interim report " on progress towards the total synthesis of vinblastine. The general strategy involves the condensation of vindoline (174)... 

Ban and co-workers have recently reported (310) a total synthesis of 525, an intermediate in Biichi s synthesis of vindoline (101). Previous work (205) had succeeded in the synthesis of 417 beginning with 2-hydroxy-tryptamine (406) (Scheme 16). Now, these workers have reported a... 

Ishikawa H, Boger DL (2007) Total synthesis of (—)- and ent-(+)-4-desacetoxy-5-desethyl-vindoline. Heterocycles 72 95-102... 

Ishikawa H, Colby DA, Boger DL (2008) Direct coupling of catharanthine and vindoline to provide vinblastine total synthesis of (+)- and enr-(-)vinblastine. J Am Chem Soc 130 420 21... 

Since vinblastine is a dimeric alkaloid, consists of vindoline moiety and carbomethoxyvelbanamine part, schemes for the total synthesis of both are required followed by joining the two monomeric units to produce the dimeric alkaloid. 

Murphy has investigated domino radical cyclizations of iodoaryl azides. This reaction found several applications in the total synthesis of natural product, as for instance Murphy s synthesis of aspidospermidine (Scheme 8.34), ° vindoline, horsfiline, and coerulescine. ... 

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