Total Synthesis of Vinblastine, Vincristine, Related Natural Products, and Key Structural Analogues

Abstract

Full details of the development of a direct coupling of catharanthine with vindoline to provide vinblastine are described along with key mechanistic and labeling studies. Following an Fe(III)-promoted coupling reaction initiated by generation of a presumed catharanthine radical cation that undergoes a subsequent oxidative fragmentation and diastereoselective coupling with vindoline, addition of the resulting reaction mixture to an Fe(III)-NaBH 4 /air solution leads to oxidation of the C15′-C20′ double bond and reduction of the intermediate iminium ion directly providing vinblastine (40-43%) and leurosidine (20-23%), its naturally occurring C20′ alcohol isomer. The yield of coupled products, which exclusively possess the natural C16′ stereochemistry, approaches or exceeds 80% and the combined yield of the isomeric C20′ alcohols is >60%. Preliminary studies of Fe(III)-NaBH 4 /air oxidation reaction illustrate a generalizable trisubstituted olefin scope, identified alternatives to O 2 trap at the oxidized carbon, provides a unique entry into C20′ functionalized vinblastines, and affords initial insights into the observed C20′ diastereoselectivity. The first disclosure of the use of exo-catharanthine proceeding through Δ 19′,20′ -anhydrovinblastine in such coupling reactions is also detailed with identical stereochemical consequences. Incorporating either a catharanthine N-methyl group or a vindoline N-formyl group precludes Fe(III)-promoted coupling, whereas the removal of the potentially key C16 methoxy group of vindoline does not adversely impact the coupling efficiency. Extension of these studies provided a total synthesis of vincristine (2) via N-desmethylvinblastine (36, also a natural product), 16-desmethoxyvinblastine (44) and 4-desacetoxy-16-desmethoxyvinblastine (47) both of which we can now suggest are likely natural products produced by C. roseus, desacetylvinblastine (62) and 4-desacetoxyvinblastine (59), as well as a series of key analogues bearing systematic modifications in the vindoline subunit. Their biological evaluation provided additional insights into the key functionality within the vindoline subunit contributing to the activity and sets the foundation on which further, more deep-seated changes in the structures of 1 and 2 will be explored in future studies.

Modifications on the Basic Skeletons of Vinblastine and Vincristine

“…Kutney et al [41] and Ishikawa [42] synthesized 14,15-dihydrovindoline (78), and its coupling with catharanthine resulted in 14,15-dihydroanhydrovinblastine (79) (Scheme 29). Meanwhile 14,15-dihydrovinblastine was simply prepared by catalytic hydrogenation of vinblastine, and its mechanism of action was different from that of the original vinblastine and the antitumor activity was rather low [43].…”

“…The anhydro intermediates 90 were then oxidized to the expected target molecules, which are vinblastines 91 substituted in the catharanthine monomer (Scheme 34). Ishikawa and his research group [42] elaborated the preparation of vinblastine by coupling catharanthine and vindoline in one step (Scheme 35). Depending the kind of Fe salt and the solvents used, products [vinblastine (1), anhydrovinblastine (32), leurosidine (65) and desoxyleurosidine (92), respectively] and their yields could be changed Scheme 35.…”

Effects of Ultraviolet A Supplemented with Red Light Irradiation on Vinblastine Production in <i>Catharanthus roseus</i>

“…A coupling reaction of vindoline and catharanthine rarely occurs in nature. Although many researchers have studied total or semi-synthetic techniques for DIAs production by chemical and enzymatic methods Misawa et al, 1988;Kuehne et al, 1991;Yokoshima et al, 2002;Shirahama et al, 2006;Ishikawa et al, 2009), these techniques have not resulted in sufficient benefit. These drugs, derived from DIAs, can still be extracted and purified from large amounts of C. roseus plants, which are cultivated in large fields (Roepke et al, 2010).…”

Screening and kinetic studies of catharanthine and ajmalicine accumulation and their correlation with growth biomass inCatharanthus roseushairy roots

“…This presents a serious challenge to improve the performance and reduce the unit cost. Recently, it has been shown that vinblastine and vincristine can be semi-synthesized by using catharanthine and vindoline as precursors (Ishikawa et al 2009). For several years, plant tissue culture has been considered as a promising biotechnological approach to improve the secondary metabolites production (Malik et al 2011(Malik et al , 2014.…”