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.

The selective cleavage of carbon-carbon bonds is a significant challenge in synthetic chemistry, yet this strategy can be a powerful way to generate reactive intermediates. We have discovered that, through the facile release of trifluoroacetate which occurs by C-C bond scission, difluoroenolates can be generated under very mild reaction conditions. Unlike existing reactions, this method is not limited to a small group of fluorinated building blocks. We have applied this process to the aldol reaction to install difluoromethylene groups.

The success of fluorinated molecules in drug design has led medicinal chemists to search for new fluorine-containing substituents. A major recently developed group is the pentafluorosulfanyl group. This group is stable under physiological conditions and displays unique physical and chemical properties. There are currently few synthetic methods to install the SF group, yet efforts to integrate this group into lead optimization continue unabated. Typically, the SF group has been used as a replacement for trifluoromethyl, tert-butyl, halogen, or nitro groups. In this review, the use of the SF group as a bioisosteric replacement for each of these three functionalities is compared and contrasted across various groups of biologically active molecules. The organization and presentation of these data should be instructive to medicinal chemists considering to design synthetic strategies to access SF -substituted molecules.

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

The palladium-catalyzed arylation of different alpha-methylene-gamma-lactone-containing sesquiterpene lactones was shown to produce E-olefin coupling products selectively in moderate to excellent yields. Biological evaluation of these semisynthetic sesquiterpene lactone derivatives in HeLa cells showed interesting antiproliferative profiles and provided initial structure-activity data.

The medicinal chemistry of amino-derivatives of the sesquiterpene lactones is described, beginning with synthetic development, moving into pharmacological applications, and finishing with clinical translation.

Three series of α-halo-α,α-difluoromethyl ketones are prepared from highly α-fluorinated gem-diols by exploiting the facile release of trifluoroacetate, followed by immediate trapping of the liberated α,α-difluoroenolate with an electrophilic chlorine, bromine, or iodine source. The products are typically isolated in good yields, even in the case of sensitive, α-iodo-α,α-difluoromethyl ketones. Also, we demonstrate that an α-iodo-α,α-difluoromethyl ketone will participate in a copper-promoted reaction to forge a new carbon–carbon bond.

Multiple myeloma (MM) is an incurable plasma cell malignancy where nearly all patients succumb to a relapse. The current preclinical models of MM target the plasma cells, constituting the bulk of the tumor, leaving the cancer stem cells to trigger a relapse. Utilizing a three-dimensional tissue culture system where cells were grown in extracellular matrix designed to reconstruct human bone marrow, we tested the anti-multiple myeloma cancer stem cell (MM-CSC) potential of two natural product inhibitors of nuclear factor κB (NFκB). Here we show that parthenolide and andrographolide are potent anti-MM-CSC agents. Both natural products demonstrated preferential toxicity toward MM-CSCs over non-tumorigenic MM cells. Addition of the bone marrow stromal compartment abrogated andrographolide activity while having no effect on parthenolide cytoxicity. This is the first report of a natural product with anti-CSC activity in myeloma, suggesting that it has the potential to improve the survival of patients with MM by eliminating the relapse-causing MM-CSCs.