Direct Coupling of Catharanthine and Vindoline to Provide Vinblastine:  Total Synthesis of (+)- and ent-(−)-Vinblastine

Abstract

A direct coupling of cantharanthine with vindoline to provide vinblastine is detailed along with key mechanistic and labeling studies. Following an Fe(III)-promoted coupling reaction initiated by generation of a presumed cantharanthine amine 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'-C21' double bond and reduction of the intermediate iminium ion directly providing vinblastine (43%) and leurosidine (23%), its naturally occurring C21' 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 C21' alcohols is 66%.Vinblastine (1) 1 is the most widely recognized member of the class of bisindole alkaloids as a result of its clinical use as an antitumor drug. Originally isolated in trace quantities (0.00025% of dry leaf weight) from Cantharanthus roseus (L.) G. Don, 2 its biological properties were among the first to be shown to arise from inhibition of microtubule formation and mitosis that today is still regarded as one of the more successful targets for cancer therapeutic intervention. 3Presently, the clinical supplies of 1 and related drugs 3c are derived from natural sources. Fortunately, the doses are so small that the production amounts are manageable even with the trace natural abundance of 1. Nonetheless, the effort required even for this limited quantity suggests that an efficient synthetic approach might provide a viable alternative. More significantly, an effective synthetic approach would provide access to analogues that incorporate deep-seated structural changes not yet explored. 4As a consequence, a number of pioneering studies have defined methods for coupling the lower half, vindoline (2), with appropriate precursors to the upper velbanamine subunit. These include the seminal Potier 5 and Kutney 6 disclosures of a coupling protocol enlisting a Polonovski reaction of catharanthine N-oxide 3) in which its embedded olefin controls the regioselectivity and coupling efficiency of the resulting iminium ion and necessarily provides anhydrovinblastine (4), Scheme 1. Conducting the reaction at low temperature was found to improve the C16' coupling diastereoselectivity (≥ 5:1 at −78 °C vs 1:1 at 0 °C), 4 and the subsequent conversion of anhydrovinblastine to vinblastine was addressed by conversion to 7 or with direct generation 8 of the enamine 6 which in turn was oxidized to the C20' alcohol. This indirect conversion of anhydrovinblastine to vinblastine via the enamine was necessitated

Ultrapotent vinblastines in which added molecular complexity further disrupts the target tubulin dimer–dimer interface

“…The exceptions to these generalizations are the behavior of 14, bearing the (R)-3-methoxypyrrolidine, and the two isomers of the 3-fluoropyrrolidine urea (17 and 18). As interesting as these latter observations are, these compounds only approach (14) or slightly surpass (17 and 18) the activity of 8, which bears no substituent. As a consequence, and rather than ascribing productive roles to the substituents, it appears that most detract from the properties of the parent compound 8 and a few (14, 17, and 18) constitute benign substitutions.…”

“…In the development of a total synthesis of vinblastine and vincristine, we introduced an Fe(III)/NaBH 4 -mediated freeradical oxidation of the anhydrovinblastine trisubstituted alkene for penultimate installation of the C20′ tertiary alcohol found in the natural products (14)(15)(16). This now-powerful hydrogen atom transfer (HAT)-initiated free-radical reaction was subsequently developed to provide a general method for functionalization of alkenes through use of a wider range of free-radical traps (17,18) beyond O 2 (air) and was explored specifically for the purpose of providing the late-stage, divergent (19) preparation of vinblastine analogs that bear alternative C20′ functionality at a site previously inaccessible for systematic exploration (Fig.…”

Evaluation of Biosynthetic Pathway and Engineered Biosynthesis of Alkaloids

“…Physostigmine is an antidote of anticholinergic toxicity and is used primarily for treating glaucoma [41]. However, these structurally complex compounds can be difficult to synthesize chemically [42,43]. To supply these compounds through biosynthetic routes, the biosynthetic pathway for a target compound must be elucidated.…”

Acidity-Controlled Indolylation of 3, 3-Bis(ethylthio)acrylate

“…吲哚衍生物是重要的一类有机化合物, 它们中有些 不仅具有良好的生物活性, 被用作治疗疾病的临床药 物 [1] , 而且有些结构简单的衍生物也是合成复杂吲哚衍 生物的重要合成中间体 [2,3] . 有机化合物的吲哚化反应 是合成吲哚衍生物的重要方法, 例如过渡金属催化的卤 代烃吲哚化能合成 2-或 3-烃基吲哚 [4,5] , 酸催化的联 烯 [6] 、 炔醇 [7] 和 α,β-不饱和羰基化合物 [8～10] 等吲哚化反应 能合成 3-烷基吲哚衍生物, 经过 C-H 活化偶联方式的 烯烃吲哚化可有效合成 2-或 3-烯基化吲哚 [11,12] , 酸酐或 酰氯的吲哚化反应能合成 3-酰基吲哚衍生物等 [13] .…”