The collective synthesis of pentacyclic stemoamide-type alkaloids is recognized as a daunting task despite high demand for a comprehensive biological profiling of these natural products. In this Letter, we report a unified synthesis of seven pentacyclic alkaloids and two unnatural derivatives. The keys to success are (1) the chemoselective assembly of four five-membered building blocks, (2) the direct oxidation of pyrrolidine natural products to pyrrole derivatives, and (3) the stereodivergent construction of totally E- or Z-substituted butenolides.

In order to enhance berry coloration of bright-red grape cultivars, the effects of abscisic acid (ABA) treatment on the quantity and composition of anthocyanins as well as the expression of genes related to flavonoid biosynthesis in the berry were examined. Exogenous ABA treatment increased anthocyanin content, especially petunidin-and malvidin-type anthocyanins. Quantitative realtime PCR analysis revealed that ABA treatment around véraison resulted in the upregulation of genes encoding enzymes responsible for both general flavonoid and anthocyanin biosynthesis. On the other hand, the gene expressions of enzymes involved in proanthocyanidin synthesis were drastically decreased at véraison and remained extremely low even with ABA treatment. Thus, increases in the total amount and composition ratios of petunidin-and malvidin-type anthocyanins were mainly caused by ABA-induced upregulation of uridine diphosphate glucose flavonoid glucosyl transferase, glutathione S-transferase 4, O-methyl transferase and flavonoid 3', 5' hydroxylase expression, resulting in the deep coloration of berry of skin.

Our research group has been exploring a lactam strategy for the concise total synthesis of complex alkaloids. In this article, we report full details of the unified total synthesis of stemoamide-type alkaloids by chemoselective assembly of five-membered rings based on the lactam strategy. First, the concise and gram-scale synthesis of tricyclic stemoamide was achieved by vinylogous Michael addition-reduction sequence of an unsaturated γ-lactam with an unsaturated γ-lactone, followed by N-alkylation to form the seven-membered ring. From stemoamide as a common intermediate, chemoselective nucleophilic addition of unsaturated lactone derivatives provides tetracyclic natural products. While stemonine is obtained by an Ir-catalyzed lactam-selective reductive Mannich reaction, saxorumamide and isosaxorumamide are produced through the lactone-selective nucleophilic addition of the lithiated 2-silyl furan. The developed conditions for the lactam-selective nucleophilic reactions are highly general, and were found to be applicable to the total synthesis of pentacyclic stemocochinin and isostemocochinin. The strategy enables the concise and unified total synthesis of tricyclic, tetracyclic and pentacyclic stemoamide-type alkaloids within 12 steps from a commercially available compound.

The totally substituted butenolide including two tetrasubstituted olefins is a distinct structural motif seen in Stemona alkaloids, but efficient methods for its synthesis are not well developed. As an ongoing program aimed at the collective total synthesis of the stemoamide group, we report a stereodivergent method to give either (E)- or (Z)-totally substituted butenolide from the same intermediate. While the AgOTf-mediated elimination via the E1-type mechanism results in the formation of the kinetic (Z)-tetrasubstituted olefin, the subsequent TfOH-mediated isomerization gives the thermodynamic (E)-tetrasubstituted olefin. The pyrrole ring is another important structure found in Stemona alkaloids. The direct oxidation of pyrrolidine rings with MnO2 and careful purification give the pyrrole groups without isomerization of the stereocenter in the lactone group. These two methods enable us to synthesize a series of stemoamide-type alkaloids including tricyclic, tetracyclic and pentacyclic frameworks. The anti-inflammatory activities by inhibition of iNOS expression in macrophage cell line RAW264.7 indicate that the most potent anti-inflammatory compounds without cytotoxicity are protostemonines, which consist of pentacyclic frameworks including the totally substituted butenolide.