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Contiguous quaternary carbons in terpene natural products remain a major challenge in total synthesis. Synthetic strategies to overcome this challenge will be a pivotal prerequisite to the medicinal application of natural products and their analogs or derivatives. In this review, we cover syntheses of natural products that exhibit a dense assembly of quaternary carbons and whose syntheses were uncompleted until recently. While discussing their syntheses, we not only cover the most recent total syntheses but also provide an update on the status quo of modern syntheses of complex natural products. Herein, we review (±)-canataxpropellane, (+)-waihoensene, (-)-illisimonin A and (±)-11- O -debenzoyltashironin as prominent examples of natural products bearing contiguous quaternary carbons.

Background: Hepatocellular carcinoma (HCC) represents a major health burden with limited curative treatment options. There is a substantial unmet need to develop innovative approaches to impact the progression of advanced HCC. Haprolid is a novel natural component isolated from myxobacteria. Haprolid has been reported as a potent selective cytotoxin against a panel of tumor cells in recent studies including HCC cells. The aims of this study are to evaluate the antitumor effect of haprolid in HCC and to understand its underlying molecular mechanisms., Methods: The efficacy of haprolid was evaluated in human HCC cell lines (Huh-7, Hep3B and HepG2) and xenograft tumors (NMRI-Foxn1 nu mice with injection of Hep3B cells). Cytotoxic activity of haprolid was determined by the WST-1 and crystal violet assay. Wound healing, transwell and tumorsphere assays were performed to investigate migration and invasion of HCC cells. Apoptosis and cell-cycle distribution were measured by flow cytometry. The effects of haprolid on the Rb/E2F and Akt/mTOR pathway were examined by immunoblotting and immunohistochemistry., Results: haprolid treatment significantly inhibited cell proliferation, migration and invasion in vitro. The epithelial-mesenchymal transition (EMT) was impaired by haprolid treatment and the expression level of N-cadherin, vimentin and Snail was downregulated. Moreover, growth of HCC cells in vitro was suppressed by inhibition of G1/S transition, and partially by induction of apoptosis. The drug induced downregulation of cell cycle regulatory proteins cyclin A, cyclin B and CDK2 and induced upregulation of p21 and p27. Further evidence showed that these effects of haprolid were associated with Rb/E2F downregulation and Akt/mTOR inhibition. Finally, in vivo nude mice experiments demonstrated significant inhibition of tumor growth upon haprolid treatment., Conclusion: Our results show that haprolid inhibits the growth of HCC through dual inhibition of Rb/E2F and Akt/mTOR pathways . Therefore, haprolid might be considered as a new and promising candidate for the palliative therapy of HCC., Competing Interests: The authors declare that they have no competing interests.

It is a challenging objective in synthetic organic chemistry to create efficient access to biologically active compounds. In particular, one structural element which is frequently incorporated into the framework of complex natural products is a β-hydroxy ketone. In this context, the aldol reaction is the most important transformation to generate this structural element as it not only creates new C-C bonds but also establishes stereogenic centers. In recent years, a large variety of highly selective methodologies of aldol and aldol-type reactions have been put forward. In this regard, the vinylogous Mukaiyama aldol reaction (VMAR) became a pivotal transformation as it allows the synthesis of larger fragments while incorporating 1,5-relationships and generating two new stereocenters and one double bond simultaneously. This review summarizes and updates methodology-oriented and target-oriented research focused on the various aspects of the vinylogous Mukaiyama aldol (VMA) reaction. This manuscript comprehensively condenses the last four years of research, covering the period 2016-2019.