Tabersonine synthesis

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. 

Scheme 6.17 gives some examples of the orthoamide and imidate versions of the Claisen rearrangement. Entry 1 applied the reaction in the synthesis of a portion of the alkaloid tabersonine. The reaction in Entry 2 was used in an enantiospecific synthesis of pravastatin, one of a family of drugs used to lower cholesterol levels. The product from the reaction in Entry 3 was used in a synthesis of a portion of the antibiotic rampamycin. Entries 4 and 5 were used in the synthesis of polycyclic natural products. Note that the reaction in Entry 4 also leads to isomerization of the double bond into conjugation with the ester group. Entries 1 to 5 all involve cyclic reactants, and the concerted TS ensures that the substituent is introduced syn to the original hydroxy substituent. 

Rawal and Kozmin have utilized a Reissert type reaction in the total synthesis of tabersonine. The requisite nitro ketone is prepared by SNAr reaction of o-nitrophenylphenyliodonium fluoride with ketone silyl enol ether (Scheme 10.10).96... 

Vincamine, vinblastine and vincristine are very important clinic alkaloids. They are produced naturally by plants vincamine by Vinca minor, and vinblascine and vincristine by Madagascar periwinkle Catharanthus roseus). The vindoline synthesis pathway starts with strictosidine and, via dehydrogeissoschizine, preakuammicine, stemmadenine and tabersonine, is converted to vindoline and vincristine (Figure 42). Conversion from vindoline to vinblastine is based on the NADH enzyme activity. Vinblastine and vincristine are very similar alkaloids. The difference is that vincristine has CHO connected to N, whereas vinblastine in the same situation has only CO3. This synthetic structural differences influence their activity. Vinblastine is used to treat Hodgkin s disease (a form of lymphoid cancer), while vincristine is used clinically in the treatment of children s leukaemia. Vincristine is more neurotoxic than vinblastine. 

Finally, one has to mention the work of Levy and co-workers who described the semi-synthesis of D-ring seco-rhazinilam analogues from (-)-tabersonine using an Emde degradation and /nCPBA oxidation [90]. The. veco-analogue 50 is only twice less active than rhazinilam on the inhibition of microtubules disassembly, illustrating that the absence of the D-ring is not strictly deleterious to the antitubulin activity [91,92]. 

In a similar heterocyclic quinodimethane ring construction strategy, the hexacyclic adducts (64) were isolated in good yield upon condensation of appropriately functionalized indole imines with ( )-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid chloride (Equation (35)) (88JA2242). In a demonstration of the utility of this new method for indole alkaloid synthesis, further transformations conducted on compound (64 R = R2 = H, R3 = Et) were shown to lead to ( —)-16-methoxy-tabersonine. 

An independent synthesis109" of the ketolactam (235), which has already been converted into (+)-tabersonine,i09° constitutes a new formal synthesis of this alkaloid. 

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

The usefulness of aminosiloxy diene Diels-Alder chemistry to the preparation of different substituted cyclohexenones is demonstrated in Table 11.3 The functionality at the 4 and 5-positions of the cyclohexenones can be easily controlled by the substitution pattern in the dienophile. The differing endo-exo selectivity found in the initial cycloadducts does not impact the usefulness of this route to cyclohexenones, since the amino group is eliminated in the last step. Chiral versions of aminosiloxy dienes provide the opportunity for asymmetric synthesis. Indeed, the diphenylpyrrolidine-substituted diene allows the synthesis of a variety of cyclohexenones, with good to excellent ee s 2b The usefulness of aminosiloxy diene Diels-Alder reactions to natural product synthesis is exemplified through the stereocontrolled synthesis of the pentacyclic indole alkaloid tabersonine 2c... 

Other applications of the 6-exo Heck cyclization strategy can be found in Ihe synthesis of pentacyclic Strychnos alkaloids by Bosch et al. [98] and tabersonine by Kuehne et al. (99). As illustrated in Scheme 35, 6-exo Heck cyclization of substrate 20S was successful only when Grigg s [100] modified Heck conditions [Pd(OAc), LiCN] were employed to give the tricyclic intermediate 206. Another 6-exo reductive Heck reaction successfully cyclized tetracyclic substrate 207 into pentacyclic tabersonine (208). 

Other workers have concentrated on the introduction of functionality into ring C of tabersonine (78). Danieli et al. (252) introduced the 17-hydroxy group by oxidation of tabersonine by means of phenylseleninic anhydride. Presumably, the Va,17-didehydrotabersonine initially produced suffers nucleophilic attack by water during workup, the stereochemistry of attack being controlled by the adjacent ethyl group. Oxidation of the product, 377, at C-16 by means of peracid also proceeds preferentially at the /3-face to give the V-oxide 378 of the desired diol. Reductive methylation and acetylation then complete the partial synthesis of vindorosine (43) (Scheme 24) (252). 

The synthesis of vindoline (44) from 11-methoxytabersonine (82) is hampered by the lack of availability of starting material. Hence, Danieli et al. (253) have developed a method for the conversion of the much more abundant tabersonine into 11-methoxytabersonine and thence into vindoline. Since electrophilic substitution in tabersonine and 2,16-dihy-drotabersonine could not be effected cleanly and efficiently, IV-acetyl-... 

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. 

The anilinoacrylate alkaloids have been the subject of intensive study during the past two decades, and numerous syntheses of vincadifformine, tabersonine, and their relatives have been reported. This area has been dominated by the versatile biomimetic synthesis developed by Kuehne and... 

The early synthesis of ( )-vincadifformine and ( )-minovine, by Kutney et al, was discussed in Volume 17 (I) and details of this work have since been published (326). Details of the synthesis of tabersonine by Takano et... 

The next target for synthesis by Kuehne s group was tabersonine (78), and three syntheses were recorded (134,323,332-334). Following the synthesis of racemic tabersonine (332) from the indoloazepine ester 560 and the lactol chloride 563, the procedure was refined by use of the chiral epoxyaldehyde 564 (333,334), which eventually afforded enantioselective syntheses of both (-)-vincadifformine (76) and (-)-tabersonine (78). Subsequently (323),... 

Szdntay s later synthesis (343) of 3-oxovincadifformine consisted essentially of an independent synthesis (Scheme 75) of Kuehne s tetracyclic aminoester 562a, which on debenzylation cyclized to 3-oxovincadifformine (97). The double bond was then introduced at the 14,15-position via the thiolactam, in a procedure reminiscent of that adopted by Magnus in his synthesis of 3-oxotabersonine (107). Desulfurization of the intermediate unsaturated thiolactam 586 gave yet another synthesis of tabersonine, whereas oxidative removal of the si r atom gave 3-oxotabersonine (107). Alternatively, condensation of the starting tryptamine derivative 587 with... 

The most recent synthesis of vincadifformine, 3-oxovincadifformine, and tabersonine is described in yet another substantial contribution from... 

The intermediate 591a was also used in a synthesis of tabersonine. Alkylation of 591a by Z-l,3-di-iodopropene followed by elimination of the phenylselenyl group gave a ring C diene 594, which was cyclized by a reductive Heck reaction with palladium acetate, sodium formate, triphenyl-phosphine, and base, with formation of tabersonine (78) in 43% yield (Scheme 77) (346). 

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