Synthesis of antiproliferative Cephalotaxus esters and their evaluation against several human hematopoietic and solid tumor cell lines: uncovering differential susceptibilities to multidrug resistance

Deoxyharringtonine (2), homoharringtonine (3), homodeoxyharringtonine (4), and anhydroharringtonine (5) are reported to be among the most potent members of the antileukemia alkaloids isolated from the Cephalotaxus genus. Convergent syntheses of these four natural products are described, each involving novel synthetic methods and strategies. These syntheses enabled evaluation of several advanced natural and non-natural compounds against an array of human hematopoietic and solid tumor cells. Potent cytotoxicity was observed in several cell lines previously not challenged with these alkaloids. Variations in the structure of the ester chain within this family of alkaloids confer differing activity profiles against vincristine-resistant HL-60/RV+, signalling new avenues for molecular design of these natural products to combat multi-drug resistance.     

Total synthesis of dimeric pyrrole-imidazole alkaloids: sceptrin, ageliferin, nagelamide e, oxysceptrin, nakamuric acid, and the axinellamine carbon skeleton

The dimeric pyrrole imidazole natural products are a growing class of alkaloids with exotic connectivity, unique topologies, high nitrogen content, and exciting bioactivities. This full account traces the evolution of a strategy that culminated in the first total syntheses of several members of this family, including sceptrin, ageliferin, nagelamide E, nakamuric acid (and its methyl ester), and oxysceptrin. Details on the fascinating conversion of sceptrin to ageliferin, which has been used to produce gram quantities of this sensitive natural product, are provided. In addition, the first enantioselective total synthesis of sceptrin and ageliferin are reported by programming the fragmentation of an oxaquadricyclane. A hallmark of our approach to this family of alkaloids is the minimal use of protecting groups despite the presence of 10 nitrogen atoms in the target compounds. Thus, the fundamental chemistry of the 2-aminoimidazole heterocycle was explored without masking its innate reactivity. Insights gained during these explorations led to total syntheses of oxysceptrin and nakamuric acid and a successful construction of the carbon skeleton of axinellamine.     

The Enchanting Alkaloids of Yuzuriha

The oriental plant Yuzuriha (Daphniphyllum macropodum) elaborates a fascinating family of polycyclic, squalene-derived alkaloids that provide a test for state-of-the-art methods of organic synthesis. The intriguing structures of these natural products have inspired us to design and explore two rather different approaches for their laboratory synthesis. This article recounts and contrasts these two different syntheses. The first approach was based on a method of synthetic design that emphasizes efficient construction of the polycyclic skeleton of the molecule (Corey's “network analysis”). A strategic bond was identified and the synthesis planned around the late formation of this bond. The synthesis that was designed by this approach proceeded smoothly until the point where it was necessary to remove functional groups that had been incorporated solely for the purpose of forming the strategic bond. Although the problems were eventually overcome, the resulting synthesis was too long and did not control the configuration of one of the stereocenters. The second approach was based on a possible biosynthesis of one of the alkaloids and provided surprisingly easy access to the simpler members of the family. The success of this synthesis led to a concrete proposal about the biosynthesis of the alkaloids and to the discovery of the astonishing transformation depicted in Scheme 27. In this marvelous reaction, an acyclic squalene derivative is converted by successive treatment with ordinary commodity chemicals into a pentacyclic alkaloid. The transformation involves the formation of four carbon–carbon bonds, two carbon-nitrogen bonds, and one carbon-hydrogen bond!     

Stereodivergent total syntheses of precoccinelline, hippodamine, coccinelline, and convergine

[structure: see text] A stereodivergent approach toward total syntheses of Coccinellidae defensive alkaloids is described. These syntheses feature a highly diastereoselective intramolecular aza-[3 + 3] annulation strategy, which represents a de novo approach to this family of natural products.     

Recent Advances on the Total Syntheses of Communesin Alkaloids and Perophoramidine

The communesin alkaloids are a diverse family of Penicillium‐derived alkaloids. Their caged‐polycyclic structure and intriguing biological profiles have made these natural products attractive targets for total synthesis. Similarly, the ascidian‐derived alkaloid, perophoramidine, is structurally related to the communesins and has also become a popular target for total synthesis. This review serves to summarize the many elegant approaches that have been developed to access the communesin alkaloids and perophoramidine. Likewise, strategies to access the communesin ring system are reviewed.     

Intramolecular Biaryl Oxidative Coupling of Stilbene Substrates by Vanadium Oxytrichloride (VOCl3): Facile Synthesis of Substituted Phenanthrene Derivatives

The biaryl unit is extensively presented in many classes of natural products, such as polyketides, terpenes, lignanes,coumarins, flavonoids, tannins, and many alkaloids.[1] It has long been recognized that an intramolecular oxidative phenolic or nonphenolic coupling reaction serves as the key step in the biosynthesis of these natural products, and the non-enzymic analogue of this transformation can lead the elegantly simple syntheses of these compounds.[2] During the last decade, a large number of oxidative coupling reagents, such as ferric chloride (FeCl3), phenyliodine(Ⅲ)bis(trifluoroacetate) (PIFA), lead(Ⅳ) tetraacetate [Pb(OAc)4], thallium(Ⅲ) triflouroacetate (TTFA), as well as vanadium oxytrifluoride (VOF3),[3,4] have been developed for this target. However, extensive application of this synthetic potential has been limited by low yields and unexpected side reactions usually encountered.     

Oxazine ring construction: methods and applications to natural product synthesis

Although natural products containing a 1,2-oxazine ring are rare, more examples in this family of natural products have been discovered since trichodermamides A and B were reported in 2003. In addition to their structural novelty, these natural products possess very interesting bioactivities that are strongly dependent on their structures, making them attractive targets for investigating structure-activity relationships (SAR). In this feature article, we summarized the methodologies developed in recent years for constructing the 1,2-oxazine rings. Racemic and enantioselective total syntheses of trichodermamides A and B, based on these methodologies, are reviewed in detail.     

Cascade Reactions: A Driving Force in Akuammiline Alkaloid Total Synthesis

The akuammiline alkaloids are a family of intricate natural products which have received considerable attention from scientists worldwide. Despite the fact that many members of this alkaloid class were discovered over 50 years ago, synthetic chemistry has been unable to address their architectures until recently. This minireview provides a brief overview of the rich history of the akuammiline alkaloids, including their isolation, structural features, biological activity, and proposed biosyntheses. Furthermore, several recently completed total syntheses are discussed in detail. These examples not only serve to highlight modern achievements in alkaloid total synthesis, but also demonstrate how the molecular scaffolds of the akuammilines have provided inspiration for the discovery and implementation of innovative cascade reactions for the rapid assembly of complex structures.     

Efficient Enantioselective Syntheses of Chiral Natural Products Facilitated by Ligand Design

The employment of enantioselective transition‐metal‐catalyzed transformations as key steps in asymmetric natural product syntheses have attracted considerable attention in recent years owing to their versatile synthetic utilities, mild conditions and high efficiency in chirality generation. The chiral catalysts or supporting ligands are believed to be crucial for the requisite reactivity and enantioselectivity. Therefore, the rational design of chiral ligands is at the heart of developing new asymmetric transition‐metal catalyzed reactions and provides an avenue to the asymmetric synthesis of natural products. Our group has been engaged in the development of transition‐metal‐catalyzed enantioselective cross‐coupling, cyclization and other related reactions and the application of these methodologies to natural product syntheses. In this account, we summarized our recent synthetic efforts towards the efficient total syntheses of several different types of natural products including terpenes, alkaloids and polyketides facilitated by the design of a series of versatile P‐chiral phosphorous ligands.     

Biosynthesis and Chemical Synthesis of Presilphiperfolanol Natural Products

Presilphiperfolanols constitute a family of biosynthetically important sesquiterpenes which can rearrange to diverse sesquiterpenoid skeletons. While the origin of these natural products can be traced to simple linear terpene precursors, the details of the enzymatic cyclization mechanism that forms the stereochemically dense tricyclic skeleton has required extensive biochemical, computational, and synthetic investigation. Parallel efforts to prepare the unique and intriguing structures of these compounds by total synthesis have also inspired novel strategies, thus resulting in four synthetic approaches and two completed syntheses. While the biosynthesis and chemical synthesis studies performed to date have provided much insight into the role and properties of these molecules, emerging questions regarding the biosynthesis of newer members of the family and subtle details of rearrangement mechanisms have yet to be explored.     

Recent developments in the synthesis of zoanthamine alkaloids

This review provides a compilation of the most recent synthetic approaches and total syntheses of zoanthamine alkaloids, which are structurally unique heptacyclic marine natural products that display a range of interesting biological activities. This review is focused on synthetic methodologies for the construction of the three adjacent quaternary asymmetric carbon atoms on the cyclohexane ring (C-ring) of these compounds. The literature covered in this review dates from 2008 to the end of 2013.     

Progress on the total synthesis of natural products in China: From 2006 to 2010

This paper summarizes the progress on the total syntheses of natural products accomplished in mainland China during the period from 2006 to 2010.The overview focuses on the first total synthesis of natural products of contemporary interest including alkaloids,cyclopeptides and cyclic depsipeptides,macrolides,terpenoids and steroids,saponins and glycosides.The development of novel synthetic strategies and methodologies,and application of new selective synthetic methods in the total syntheses of natural products are included as well.     

Enantioselective total syntheses of (-)-palau'amine, (-)-axinellamines, and (-)-massadines

Dimeric pyrrole-imidazole alkaloids represent a rich and topologically unique class of marine natural products. This full account will follow the progression of efforts that culminated in the enantioselective total syntheses of the most structurally ornate members of this family: the axinellamines, the massadines, and palau'amine. A bio-inspired approach capitalizing on the pseudo-symmetry of the members of this class is recounted, delivering a deschloro derivative of the natural product core. Next, the enantioselective synthesis of the chlorocyclopentane core featuring a scalable, catalytic, enantioselective Diels-Alder reaction of a 1-siloxydiene is outlined in detail. Finally, the successful divergent conversion of this core to each of the aforementioned natural products, and the ensuing methodological developments, are described.     

Natural guanidine derivatives

The chemistry (isolation, biosynthesis and synthesis) and biological activities of natural products bearing a guanidine function are reviewed, including macrocyclic derivatives from terrestrial microbes, peptides from cyanobacteria and guanidine alkaloids from marine invertebrates. The review contains 258 references.     

抗癌天然产物苦马豆素的合成研究进展

在过去十多年中, 多羟基吲哚兹定生物碱因其结构和多样性的生物活性(抗病毒、抗肿瘤、免疫调节活性)而引起了极大的关注. 其中最著名的成员是苦马豆素, 一种从灰苦马豆等植物中提取出来的化合物, 被证明具有治疗恶性肿瘤的作用并因此进行了大量合成研究. 到目前为止文献报道的合成方法都是基于碳水化合物原料或非碳水化合物底物和不对称反应. 尽管有些合成路线有效并且有实用价值, 但进一步开发制备天然或非天然吲哚兹定生物碱的通用和实用方法仍然非常重要. 总结了苦马毒素的合成研究进展, 以便为它的规模化生产提供思路和方法.     

番荔枝内酯————明日抗癌之星

本文介绍一类近年来被发现于番荔枝科(Annonaceae)植物中的强抗肿瘤活性化合物----番荔枝内酯(annonaceousacetogenin) , 从这类化合物的结构特点, 生理活性, 生源假说, 化学合成等几个方面综述了在该领域的氧基状况 .     

Short total syntheses of the avenaciolide family of natural products

The avenaciolide family of natural products are small α-methylene bis-γ-lactones that exhibit a wide variety of biological activities. Herein we report concise syntheses of five members of this family of natural products along with the synthesis of one non-natural analogue. The syntheses proceed in five or six steps from simple, commercially available compounds and feature a key oxidative cyclization/lactonization reaction that likely occurs via a radical mechanism.     

Michael addition-based cyclization strategy in the total synthesis of Lycopodium alkaloids

Lycopodium alkaloids, a unique family of biologically important natural products isolated and characterized from various species of Lycopodium (sensu lato), have attracted extensive attention from chemists and pharmacists in the past three decades. Michael addition-based cyclization has been successfully employed as an elegant and efficient ring-construction protocol of constructing key cyclohexanone intermediates in the total synthesis of Lycopodium alkaloids. This mini-review chooses and summarizes several representative total syntheses of various Lycopodium alkaloids in which intramolecular Michael addition severed as the key methodology.     

Unified route to the palmarumycin and preussomerin natural products. Enantioselective synthesis of (-)-preussomerin G

The total syntheses of eight members of the palmarumycin family have been achieved, with identification of the absolute stereochemistry for three of these natural products. In addition, the ras-farnesyl transferase inhibitor (-)-preussomerin G has been synthesized, achieving the first enantioselective route for accessing this family of natural products. Highlights of the synthetic work include an asymmetric epoxidation of a cyclic enone in excellent yield and enantiomeric excess and a potentially biomimetic oxidative spirocyclization for the introduction of the bis-spiroketal array unique to the preussomerin natural products.     

Beta-phenylethylamines and the isoquinoline alkaloids

This review covers beta-phenylethylamines and isoquinoline alkaloids that are derived from them, including further products of oxidation, condensation with formaldehyde and rearrangement, some of which do not contain an isoquinoline system, together with naphthylisoquinoline alkaloids, which have a different biogenetic origin. The occurrence of the alkaloids, with the structures of new bases, together with their reactions, syntheses and biological activities are reported. The literature from July 2000 to June 2001 is reviewed, with 495 references cited.