Substituent effects in the transannular cyclizations of germacranes. Synthesis of 6-epi-costunolide and five natural steiractinolides

The occurrence and orientation of substituents in the 10-membered ring characteristic of germacranes is determinant in the stereochemical outcome of the acid-promoted transannular cyclization of these metabolites. An explanation of the synthesis of eudesmanolides and guaianolides produced by the Umbelliferae family of plants is advanced. The syntheses of the natural products 6-epi-costunolide and five steiractinolides are reported.     

Total syntheses of lindenane-type sesquiterpenoids: (±)-chloranthalactones A, B, F, (±)-9-hydroxy heterogorgiolide, and (±)-shizukanolide E

Chloranthalactones A, B, F, 9-hydroxy heterogorgiolide, and shizukanolide E are a family of natural lindenane-type sesquiterpenoids isolated mainly from chloranthaceae. A general synthetic strategy was accomplished by us for the racemic total syntheses of the five natural products. The key steps included substrate-controlled Matteson epoxidation of ketone and highly diastereoselective intramolecular Hodgson cyclopropanation to construct the challenging cis, trans-3/5/6 tricyclic skeleton, along with a methodology developed for the γ-alkylidenebutenolide ring formation.     

Syntheses of Fumagillin and Ovalicin

This review focuses on the synthetic strategies used for the construction of fumagillin, ovalicin, and other natural products of this family that are known angiogenesis inhibitors. These compounds are comprised of a cyclohexane framework, two epoxides, and five or six contiguous stereogenic centers. The first total syntheses of fumagillin and ovalicin were reported by Corey in 1972 and 1985, respectively. There were numerous studies directed at these natural products in the decades that followed with many reports appearing in the year 2000 or later. Despite the relatively small size of these molecules, their syntheses highlight the efficient construction of stereogenic centers in organic synthesis.     

Total syntheses of (R)-argentilactone and (R)-goniothalamin via catalytic enantioselective allylation of aldehydes

The total syntheses of (R)-argentilactone (five steps, 25% overall yield) and (R)-goniothalamin (three steps, 61% overall yield) have been described through the enantioselective catalytic allylation of aldehydes (including a propargylic aldehyde) which provided a rapid access to these natural products that display very interesting biological activities.     

Total synthesis and biosynthesis of the paraherquamides: an intriguing story of the biological Diels-Alder construction

The syntheses and biosyntheses of the paraherquamide and brevianamide families of prenylated indole-derived alkaloids are reviewed. It has been proposed that the unique bicyclo[2.2.2]diazaoctan ring system that is common to this family of natural products, arises by a biological intramolecular Diels-Alder cycloaddition reaction. Both synthetic approaches and total syntheses of several members of this family of natural products are reviewed. The biosynthesis of these alkaloids has also constituted an active area of research and the current state of knowledge on the biosynthesis of these natural products are reviewed.     

Total syntheses of (+)-spiculoic acid A and (+)-zyggomphic acid, new marine natural products of polyketide origin

The total syntheses of both natural (+)-spiculoic acid A and (+)-zyggomphic acid, new cytotoxic marine natural products of polyketide origin, have been accomplished for the first time. These syntheses were achieved by the highly stereoselective and high-yielding intramolecular Diels-Alder reaction of a functionalized (E,E,E)-2,7,9-dodecanal derivative to construct the core tetrahydroindan-2-one skeleton. A stereocongener of (+)-spiculoic acid A, i.e., the (2R,5S,6R)-isomer, was also synthesized. The details of these total syntheses are described.     

A comparative analysis of the total syntheses of the amphidinolide T natural products

In this article we compare and contrast the strategies and tactics used in the syntheses of the amphidinolide T family of natural products that have been reported by Fürstner, Ghosh and ourselves. Similar approaches to the trisubstituted THF ring present in the targets are utilized in all of the syntheses, but each strategy showcases a different means of macrocyclization.     

Total synthesis of two naturally occurring polyacetylenic glucosides (−)-bidensyneoside A1 and B,and an analogue of (−)-bidensyneoside C

The total syntheses of two novel polyacetylenic natural products bidensyneoside A1 and B, as well as an analogue of bidensyneoside C are described. These syntheses are based on our recently developed strategy. A new preparation of the required starting material (E)-3-penten-1-yne was developed. The preparation of the analogue of (−)-bidensyneoside C further confirms the side chain configuration of the natural product as (R).     

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.     

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.     

Total synthesis of infectopyrone,aplysiopsenes A–C,ent-aplysiopsene D,phomapyrones A and D, 8,9-dehydroxylarone,and nectriapyrone

The total synthesis of the 2-pyrone natural products nectriapyrone, aplysiopsenes A–C, ent-aplysiopsene D, phomapyrones A and D, and of 8,9-dehydroxylarone were achieved by Wittig olefination starting with vermopyrone. Infectopyrone was synthesized by Horner–Wadsworth–Emmons reaction starting with phomapyrone D. Racemic phomapyrone C methyl ether was obtained by hydrogenation of nectriapyrone. The total syntheses were achieved starting from commercially available 3,5-heptanedione and led to the desired natural products in 18–46% over 5–6 steps, whereupon all five-step syntheses were carried out with a single chromatographic workup. The total synthesis of infectopyrone, aplysiopsenes A–D, of phomapyrones A and D, and of 8,9-dehydroxylarone were achieved for the first time, giving unambiguous proof for the proposed structures of these natural products.     

A practical synthesis of (all-Z)-eicosa-3,6,9,12-tetraene, a pheromone component isolated from emerald moths

A short and practical synthesis of (all-Z)-eicosa-3,6,9,12-tetraene, a component of the emerald moth pheromone is reported. Two different methodologies are used both starting with the natural polyunsaturated fatty acid (all-Z)-eicosa-5,8,11,14,17-pentaenoic acid (EPA). The methodology can be used for the syntheses of a homologous series of analogues of the pheromone that may be practical for analytical purposes of similar natural products.     

A Morita-Baylis-Hillman adduct allows the diastereoselective synthesis of styryl lactones

We disclosed herein a diastereoselective approach for the total syntheses of (±)-Leiocarpin A and (±)-Goniodiol. These biologically active styryl lactones were obtained from a common intermediate, prepared in five steps and 40% overall yield, using a simple synthetic sequence starting from a Morita-Baylis-Hillman adduct. The total syntheses of these styryl lactones were accomplished in nine steps. This is the first report on the total synthesis of this class of natural products starting from Morita-Baylis-Hillman adduct.     

Total syntheses of (±)-cis- and (±)-trans-neocnidilides

Total syntheses of two antimicrobial natural products (±)-cis-neocnidilide and (±)-trans-neocnidilide starting from a readily preparable cyclohexa[b]-fused 5-oxabicyclo[2.1.1]hexane derivative are presented. The diastereomeric tetrahydrofuran tricarboxylate epimers obtained from a BF₃·OEt₂ promoted Grob-type fragmentation of the oxa-bicycle derivative were converted into title natural products by employing pyridinium dichromate/acetic anhydride mediated bis-oxidative cleavage reaction.     

Concise syntheses of 5,6-dibromotryptamine and 5,6-dibromo-N,N-dimethyltryptamine en route to the antibiotic alternatamide D

Concise syntheses of the natural products 5,6-dibromotryptamine, 5,6-dibromo-N,N-dimethyltryptamine and the bromotryptamine antibiotic alternatamide D have been accomplished starting from the common intermediate, 5,6-dibromoindole-3-carbaldehyde.     

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.     

Total Syntheses of Sarcandrolide J and Shizukaol D: Lindenane Sesquiterpenoid [4+2] Dimers

The syntheses of members of a family of lindenane sesquiterpenoid [4+2] dimers led to the total syntheses of sarcandrolide J and shizukaol D. Inspired by a modified biosynthetic pathway, a cascade featuring furan formation/alkene isomerization/Diels–Alder cycloaddition was devised to construct the congested polycyclic architecture of the target molecules with the correct stereochemistry. This study presents a pioneering synthetic entry to this family of natural products and paves the way for fully exploring their biological functions.     

Ladderane Natural Products: From the Ground Up

The ladderane family of natural products are well known for their linearly concatenated cyclobutane skeletal structure. Owing to their unique carbocyclic framework, several chemical syntheses have been reported since their discovery in 2002. The focus of this review is to showcase the novel tactics that have been used to generate the ladderane core and the challenges that are associated with the synthesis of these unusual and complex natural products.     

Total synthesis of bidensyneosides A2 and C: remarkable protecting group effects in glycosylation

Bidensyneosides are a group of five recently identified polyacetylenic glucosides from Bidens parviflora WILLD, a traditional Chinese medicinal plant that contains rich bioactive natural products. It was shown that bidensyneosides inhibited both histamine release and nitric oxide production. The synthesis of bidensyneoside A2 (2) and C (4) as well as 3-deoxybidensyneoside C (5) are described. These syntheses establish a synthetic entry to the bidensyneosides and confirm the stereochemistry at C3. Furthermore, a remarkable protecting group effect on orthoester formation was observed during the glycosylation reaction.     

Cascade reactions leading to the mechanism of action of vinaxanthone and xanthofulvin,natural products that drive nerve repair

The natural products vinaxanthone and xanthofulvin promote regeneration in animal models of spinal cord injury and corneal transplant. However, inhibition of the initially described biological target of these compounds, semaphorin 3A, does not fully account for the recovery demonstrated in vivo following administration of the natural products. Through chemical synthesis substantial quantities of both natural products have been accessed with early reaction development paving the way for synthesizing both compounds. The success of a model system, first disclosed herein, translated to the syntheses of both natural products. Following from this we also report for the first time the discovery of a new target of the natural products, the succinate receptor 1 (SUCNR1). Both natural products function as positive allosteric modulators of SUCNR1. As the first known allosteric modulators of SUCNR1, the compounds represent powerful new tools to understand the pharmacology of SUCNR1 and its control of growth and cellular defense.