Catharanthine synthesis

Nef, C., Rio, B. and Chrestin, H. 1991. Induction of catharanthine synthesis and stimulation of major indole alkaloid production by Catharanthus roseus cells under non-growth-altering treatment with Pythium vexans extracts. Plant Cell Reports, 10 26-29. 

In 1999 Fnkuyama s group described a new indole ring construction based on < -alkenylthioanilides and their radical addition, followed by indolization (Scheme 4, equations 1 and 2) [21], Fukuyama apphed this variant indole synthesis to the synthesis of ( )-catharanthine [22], (H-)-vinblastine [23-25], (+)-vincristine [26], and (-)-strychnine [27], The catharanthine synthesis required hypophosphorous acid and AIBN to achieve indole formation (equation 3). 

After the stmcture and absolute stereochemistry of cleavamine (111), C22H24N2, was estabUshed, its synthesis was shortly completed and impetus to unravel the stmcture of the dimeric bases (22) was bolstered (77). Again, the fragment, now only slightly modified from that originally present in secologanin (102), is readily seen in catharanthine (107). 

Imanishi, T., Shin, H., Yagi, N., Hanaoka, M. (1980) l,6-Dihydro-3(2H)-Pyridinones as Symmetric Intermediates. Formal Synthesis of ( )-Tabersonine and ( )-Catharanthine. Tetrahedron Letters, 21, 3285-3288. 

Two RCM reactions were employed in a new and efficient route to a key chiral intermediate, isoquinuclidine 150, in the synthesis of alkaloid (-F)-catharanthine <06AG(I)5334>. The first RCM makes use of chiral enone 151, derived from L-serine, to generate a chiral dihydropyridinone 152. Intramolecular alkene metathesis of dialkenyl piperidine 153 generates 150, which represents the first example of the use of RCM in the generation of an azabicyclo[2.2.2]alkene system. 

A similar strategy was reported soon after by Atta-ur-Rahman for the synthesis of 16 -epianhydrovinblastine (Scheme 5) (27). Reductive cleavage of catharanthine (21) provided a mixture of epimeric carbomethoxy-cleavamines (22) which, without separation, was transformed to a mix-... 

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. 

DiCosmo, F., Quesnel, A., Misawa, M. and Tallevi, S. G. 1987. Increased synthesis of ajmalicine and catharanthine by cell suspension cultures of Catharanthus roseus in response to fungal culture-filtrates. Applied Biochemistry and Biotechnology, 14 101-106. 

The Polonovski reaction on catharanthine Nb-oxide (170) leads to fission of the 5,6-bond and re-cyclization with formation of (171) 106 in the presence of other nucleophiles (e.g. vindoline), this reaction forms the basis of the synthesis of the vinblastine group of alkaloids (q.v.). The formation of (171) is reversible in acid solution, and under appropriate conditions the methylene group (C-5) is lost as formaldehyde re-cyclization by the Mannich reaction then gives 5-norcatharan-thine (173) (Scheme 23).106"... 

Trost has continued his remarkable series of palladium-catalysed syntheses in this area with a neat seven-stage synthesis of the catharanthine intermediate (174) (Scheme 24).108a Since (174) has already been converted into ( )-catharanthine by Biichi et al.,10Sb this constitutes a nine-step synthesis of ( )-catharanthine. 

Over seven-hundred references are concerned with the isolation and chemistry of alkaloids, and approximately one-third of these are devoted to synthesis and biosynthesis. It is perhaps in these areas that the most notable research is to be found. Although it is probably invidious to attempt the exercise, a personal selection of highlights would include new results on the biosynthesis of quinoliz-idine alkaloids (p. 4), the first synthesis of an eleven-membered macrocyclic pyrrolizidine diester (p. 49), the synthesis of Poranthera alkaloids (p. 68), and, in the indole field, the synthesis of tryptoquivalines G and L (p. 152), of a chiral intermediate in the construction of heteroyohimbine alkaloids (p. 167), and of a catharanthine intermediate, using palladium catalysts (p. 186). 

This method can be used for the stereocontrolled synthesis of (+)-catharanthine, an anticancer alkaloid, shown in eq. 3.74... 

The same sequence of reactions has also been accomplished by Kutney et a/.,162 from the j3-epoxide (239) the process is described as efficient, but the yield of leurosine obtained is unspecified. In the course of this synthesis, an improved preparation of the epoxide (239) from catharanthine (236) via the lactam epoxide (265) was developed (Scheme 26).162... 

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... 

Details have been published of Sundberg s synthesis of desethylcatharanthine,121 and an independent new synthesis has also been reported.122" This new approach relies, for the formation of the complete skeleton, on a biogenetically patterned cycloaddition of an indole-2-acrylate to a 1,2-dihydropyridine derivative, and has immediately been applied to the synthesis of ( )-catharanthine (263) itself (Scheme 37).122 For this purpose, an iV-substituted 3-ethyl-1,2-dihydropyridine (264) was required, and since no reliable method for the synthesis of this compound was available, the route shown was devised. Addition of the indole-2-acrylate (265) to (264) gave (266) (major product) and the desired tetracyclic base (267) formation of the bond between Nb and C-5 then gave the quaternary bromide (268), and the... 

The formal synthesis of ( )-catharanthine by Imanishi et al.l09a consists in a new preparation of the pentacyclic ketoamide (269), which has previously been converted into catharanthine by Biichi et a/.123 The critical stage in this synthesis (Scheme 38) was the preparation of the quinuclidine ketone (270) by an intramolecular aldol reaction on the keto-aldehyde derived from the piperidine bis-acetal (271). 

Synthesis of [methyl-2H]-labelled ajmalicine, yohimbine, tabersonine and catharanthine... 

This chemistry was part of a synthesis of the aikaioirf catharanthine by S. Raucher anrf R. F. Lawrence, Tetrahedron Lett., 1983, 24, 2927. 

C. roseus is, therefore, an amazing chemical factory, which produces more than 100 different monoterpenoid indole alkaloids, many of them possessing notable pharmacological activity [158-159]. The main alkaloids present in C. roseus plants are catharanthine, vindoline and a-3 ,4 -anhydrovinblastine. Ajmalicine and serpentine are also present in significant amounts in the plant [160-165]. Class III plant peroxidases have been involved in the synthesis of many of these monoterpenoid indole alkaloids. 

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