Chemical Emulation of the Biosynthetic Route to Anthrasteroids: Synthesis of Asperfloketal A.

The anthrasteroid rearrangement has been discussed for the formation of the eponymous substance class since its discovery. We here report its chemical emulation from a plausible biogenetic precursor and show how it accounts for the formation of asperfloketals A and B through a mechanistic bifurcation event. As a result, these natural products arise from double Wagner-Meerwein rearrangements and, thus, are 1(10→5),1(5→6)- and 1(10→5),4(5→6)diabeo-14,15-secosteroids, respectively. To establish an efficient route to a bioinspired precursor, we devised a sequence of orchestrated oxidative activation and rearrangement from ergosterol.

Biogenesis-Inspired, Divergent Synthesis of Spirochensilide A, Spirochensilide B, and Abifarine B Employing a Radical-Polar Crossover Rearrangement Strategy.

Triterpenoids and related abeo-steroids are of interest to the scientific community for their potent and varied biological activities as well as their unique structures. Within this large and diverse family of natural products, the fir metabolites (-)-spirochensilide A and B are particularly noteworthy for their controversial biogenesis. We herein report the chemical synthesis of the spirochensilides, which involves a concerted sequence of bioinspired rearrangements contributing to its resolution. Points of divergence after each rearrangement step also allow for an approach to the abifarine family of natural products with abifarine B as a synthetic target. Key to this strategy is a radical-polar crossover event to initiate the first rearrangement without the need for a sacrificial functionality to be introduced beforehand.

Synthesis of odorants in flow and their applications in perfumery.

Continuous flow technology is a key technology for sustainable manufacturing with numerous applications for the synthesis of fine chemicals. In recent years, the preparation of odorants utilizing the advantages of flow reactors received growing attention. In this review, we give an overview of selected methods for the synthesis of odorants in flow, including heterogeneously catalyzed reactions, gas reactions, and photochemical C-H functionalization processes. After a brief introduction on types of odorants, the presented odorant syntheses are ordered according to the main odor families "fruity", "green", "marine", "floral", "spicy", "woody", "ambery", and "musky" and their use and importance for perfumery is briefly discussed.

Synthetic strategies for the ibophyllidine alkaloids.

Covering: 1975-2020The ibophyllidine alkaloids are unique pyrroloindole alkaloids exhibiting a five-membered D-ring in contrast to the six-membered D-ring of the more common Aspidosperma and Strychnos alkaloids. This structural feature has made them sought-after targets for organic chemists as well as for the elucidation of their biosynthesis. Beginning with the first and eponymous member ibophyllidine, isolation and structure determination is discussed. The main focus of this review are the diverse chemical approaches towards the ibophyllidines in context with their respective biosynthesis. The often employed Diels-Alder reaction strategy, two other named reaction-based strategies and the most recent enantioselective strategies are presented and compared.

Synthesis of Swinhoeisterol A, Dankasterone A and B, and Periconiastone A by Radical Framework Reconstruction.

A switchable radical framework reconstruction approach to structurally unique 13(14 → 8),14(8 → 7)diabeo-steroid swinhoeisterol A was developed. The conversion of an ergostane skeleton proceeded through the intermediacy of a 13(14 → 8)abeo-framework as present in the dankasterone and periconiastone family of natural products and features a ß scission of a 14-alkoxy radical with concomitant generation of the C8-C13 bond. From this intermediate, and dependent on the conditions employed, the cascade continues with a Dowd-Beckwith rearrangement and leads to the formation of the 13(14 → 8),14(8 → 7)diabeo-framework of the swinhoeisterol class of natural products. The synthesis of these frameworks then allowed for efficient access to swinhoeisterol A (1), dankasterone A (Δ4-2), dankasterone B (2), and periconiastone A (3).

Discoveries and Challenges en Route to Swinhoeisterol†A.

In this work, a full account of the authors' synthetic studies is reported that culminated in the first synthesis of 13(14→8),14(8→7)diabeo-steroid swinhoeisterol A as well as the related dankasterones A and B, 13(14→8)abeo-steroids, and periconiastone A, a 13(14→8)abeo-4,14-cyclo-steroid. Experiments are described in detail that provided further insight into the mechanism of the switchable radical framework reconstruction approach. By discussing failed strategies and tactics towards swinhoeisterol A, the successful route that also allowed an access to structurally closely related analogues, such as Δ22 -24-epi-swinhoeisterol A, is eventually presented.

Taxane Meets Propellane: First Chemical Synthesis of Highly Complex Diterpene Canataxpropellane.

The features of two iconic chemical classes are united in the structure of the highly complex diterpene canataxpropellane and set a daunting challenge that has been met by the Gaich group. Their daring strategy and its benefit to the field of terpene chemistry is presented and discussed in this Highlight.

Translation of a Polar Biogenesis Proposal into a Radical Synthetic Approach: Synthesis of Pleurocin A/Matsutakone and Pleurocin B.

A synthetic approach to recently reported and structurally unique 11(9→7) abeo-steroids pleurocin A/matsutakone (1) and pleurocin B (2) was developed by reconsidering the originally suggested polar transformations of their biogenesis. An intricate radical cyclization of a late stage intermediate followed by an oxidative quench was used instead and forged the abeo-framework, while the 9,11-seco-motif was obtained by conversion of ergosterol into a 9,11-secoenol ether employing a mercury-free desaturation of the Treibs type, an oxidative bond scission preluding a dioxa-[4+2]-cycloaddition of an aldehyde to an enone and a combined transacetalization/elimination followed by an ionic hydrogenation.

Rearranged ergostane-type natural products: chemistry, biology, and medicinal aspects.

Classical steroids are long-known privileged leads in drug discovery. Their rearranged counterparts, though, have so far received less attention, although recent isolation and biological testing programmes have revealed a plethora of molecular entities that are both structurally intriguing, as well as biologically relevant. This review will highlight those natural products, and focus on ergostane-derived seco- and abeo-steroids. Their isolation, structure elucidation, and biological properties are reported. A special emphasis of this review lies in their respective (and typically proposed) biosyntheses, to help guide future bio-inspired synthetic attempts.

Form Follows Function: Designer Chemistry at the 52nd Bürgenstock Conference.

The 52nd Bürgenstock Conference on Stereochemistry took place from April 30-May 4, 2017, and showed how chemistry and design go hand-in-hand (as reflected in the image of the Bauhausarchiv in Berlin). In this Conference Report, Philipp Heretsch outlines the program.

Synthesis and Biological Investigation of Δ(12)-Prostaglandin J3 (Δ(12)-PGJ3) Analogues and Related Compounds.

A series of Δ(12)-prostaglandin J3 (Δ(12)-PGJ3) analogues and derivatives were synthesized employing an array of synthetic strategies developed specifically to render them readily available for biological investigations. The synthesized compounds were evaluated for their cytotoxicity against a number of cancer cell lines, revealing nanomolar potencies for a number of them against certain cancer cell lines. Four analogues (2, 11, 21, and 27) demonstrated inhibition of nuclear export through a covalent addition at Cys528 of the export receptor Crm1. One of these compounds (i.e., 11) is currently under evaluation as a potential drug candidate for the treatment of certain types of cancer. These studies culminated in useful and path-pointing structure-activity relationships (SARs) that provide guidance for further improvements in the biological/pharmacological profiles of compounds within this class.

Total Synthesis of Δ(12) -Prostaglandin J3 : Evolution of Synthetic Strategies to a Streamlined Process.

The total synthesis of Δ(12) -prostaglandin J3 (Δ(12) -PGJ3 , 1), a reported leukemia stem cell ablator, through a number of strategies and tactics is described. The signature cross-conjugated dienone structural motif of 1 was forged by an aldol reaction/dehydration sequence from key building blocks enone 13 and aldehyde 14, whose lone stereocenters were generated by an asymmetric Tsuji-Trost reaction and an asymmetric Mukaiyama aldol reaction, respectively. During this program, a substituent-governed regioselectivity pattern for the Rh-catalyzed C-H functionalization of cyclopentenes and related olefins was discovered. The evolution of the synthesis of 1 from the original strategy to the final streamlined process proceeded through improvements in the construction of both fragments 13 and 14, exploration of the chemistry of the hitherto underutilized chiral lactone synthon 57, and a diastereoselective alkylation of a cyclopentenone intermediate. The described chemistry sets the stage for large-scale production of Δ(12) -PGJ3 and designed analogues for further biological and pharmacological studies.

Synthesis of Strophasterol†A Guided by a Proposed Biosynthesis and Innate Reactivity.

The synthesis of strophasterol A, a moderator of endoplasmatic reticulum (ER) stress in Alzheimer's disease, and the first member of a structurally unprecedented class of secosterols, was achieved through the implementation of a key step of its proposed biosynthesis and two C-H oxidations. Analysis of the innate reactivity of the intermediates enabled the identification of a novel way to prepare an α-chloro-γ-hydroxy-δ-keto enone, as well as its vinylogous α-ketol rearrangement to a δ-keto carboxylic acid.

Total synthesis of trioxacarcin DC-45-A2.

An enantioselective total synthesis of trioxacarcin DC-45-A2 (1) featuring a novel Lewis acid-induced cascade rearrangement of epoxyketone 6 to forge the polyoxygenated 2,7-dioxabicyclo[2.2.1]heptane core of the molecule is described.

Synthesis and biological evaluation of QRSTUVWXYZA' domains of maitotoxin.

The synthesis of QRSTUVWXYZA' domains 7, 8, and 9 of the highly potent marine neurotoxin maitotoxin (1), the largest secondary metabolite isolated to date, is described. The devised synthetic strategy entailed a cascade Takai-Utimoto ester olefination/ring closing metathesis to construct ring Y, a hydroxydithioketal cyclization/methylation sequence to cast ring X, a Horner-Wadsworth-Emmons coupling of WXYZA' ketophosphonate 11 with QRSTU aldehyde 12 to form enone 10, and a reductive hydroxyketone ring closure to forge ring V. 2D NMR spectroscopic analysis and comparison of (13)C chemical shifts with those of the corresponding carbons of maitotoxin revealed close similarities supporting the originally assigned structure of this region of the natural product. Biological evaluations of various synthesized domains of maitotoxin in this and previous studies from these laboratories led to fragment structure-activity relationships regarding their ability to inhibit maitotoxin-elicited Ca(2+) influx in rat C6 glioma cells.

Total synthesis of Δ¹²-prostaglandin J3, a highly potent and selective antileukemic agent.

A catalytic asymmetric total synthesis of the potent and selective antileukemic Δ(12)-prostaglandin J3 (Δ(12)-PGJ3) is described. The convergent synthesis proceeded through intermediates 2 and 3, formed enantioselectively from readily available starting materials and coupled through an aldol reaction followed by dehydration to afford stereoselectively the cyclopentenone alkylidene structural motif of the molecule.

C-H-Functionalization logic guides the synthesis of a carbacyclopamine analog.

The chemical synthesis of carbacyclopamine analog 2, a cyclopamine analog with an all-carbon E-ring, is reported. The use of C-H-functionalization logic and further metal-catalyzed transformations allows for a concise entry to this new class of acid-stable cyclopamine analogs.

Synthesis and antioxidant evaluation of (S,S)- and (R,R)-secoisolariciresinol diglucosides (SDGs).

Secoisolariciresinol diglucosides (SDGs) (S,S)-SDG-1 (major isomer in flaxseed) and (R,R)-SDG-2 (minor isomer in flaxseed) were synthesized from vanillin via secoisolariciresinol (6) and glucosyl donor 7 through a concise route that involved chromatographic separation of diastereomeric diglucoside derivatives (S,S)-8 and (R,R)-9. Synthetic (S,S)-SDG-1 and (R,R)-SDG-2 exhibited potent antioxidant properties (EC50=292.17±27.71 µM and 331.94±21.21 µM, respectively), which compared well with that of natural (S,S)-SDG-1 (EC50=275.24±13.15 µM). These values are significantly lower than those of ascorbic acid (EC50=1129.32±88.79 µM) and α-tocopherol (EC50=944.62±148.00 µM). Compounds (S,S)-SDG-1 and (R,R)-SDG-2 also demonstrated powerful scavenging activities against hydroxyl [natural (S,S)-SDG-1: 3.68±0.27; synthetic (S,S)-SDG-1: 2.09±0.16; synthetic (R,R)-SDG-2: 1.96±0.27], peroxyl [natural (S,S)-SDG-1: 2.55±0.11; synthetic (S,S)-SDG-1: 2.20±0.10; synthetic (R,R)-SDG-2: 3.03±0.04] and DPPH [natural (S,S)-SDG-1: EC50=83.94±2.80 µM; synthetic (S,S)-SDG-1: EC50=157.54±21.30 µM; synthetic (R,R)-SDG-2: EC50=123.63±8.67 µM] radicals. These results confirm previous studies with naturally occurring (S,S)-SDG-1 and establish both (S,S)-SDG-1 and (R,R)-SDG-2 as potent antioxidants and free radical scavengers for potential in vivo use.

Microbiologically produced carboxylic acids used as building blocks in organic synthesis.

Oxo- and hydroxy-carboxylic acids are of special interest in organic synthesis. However, their introduction by chemical reactions tends to be troublesome especially with regard to stereoselectivity. We describe herein the biotechnological preparation of selected oxo- and hydroxycarboxylic acids under "green" conditions and their use as promising new building blocks. Thereby, our biotechnological goal was the development of process fundamentals regarding the variable use of renewable raw materials, the development of a multi purpose bioreactor and application of a pilot plant with standard equipment for organic acid production to minimize the technological effort. Furthermore the development of new product isolation procedures, with the aim of direct product recovery, capture of products or single step operation, was necessary. The application of robust and approved microorganisms, also genetically modified, capable of using a wide range of substrates as well as producing a large spectrum of products, was of special importance. Microbiologically produced acids, like 2-oxo-glutaric acid and 2-oxo-D-gluconic acid, are useful educts for the chemical synthesis of hydrophilic triazines, spiro-connected heterocycles, benzotriazines, and pyranoic amino acids. The chiral intermediate of the tricarboxylic acid cycle, (2R,3S)-isocitric acid, is another promising compound. For the first time our process provides large quantities of enantiopure trimethyl (2R,3S)-isocitrate which was used in subsequent chemical transformations to provide new chiral entities for further usage in total synthesis and pharmaceutical research.Oxo- and hydroxy-carboxylic acids are of special interest in organic synthesis. However, their introduction by chemical reactions tends to be troublesome especially with regard to stereoselectivity. We describe herein the biotechnological preparation of selected oxo- and hydroxycarboxylic acids under "green" conditions and their use as promising new building blocks. Thereby, our biotechnological goal was the development of process fundamentals regarding the variable use of renewable raw materials, the development of a multi purpose bioreactor and application of a pilot plant with standard equipment for organic acid production to minimize the technological effort. Furthermore the development of new product isolation procedures, with the aim of direct product recovery, capture of products or single step operation, was necessary. The application of robust and approved microorganisms, also genetically modified, capable of using a wide range of substrates as well as producing a large spectrum of products, was of special importance. Microbiologically produced acids, like 2-oxo-glutaric acid and 2-oxo-D-gluconic acid, are useful educts for the chemical synthesis of hydrophilic triazines, spiro-connected heterocycles, benzotriazines, and pyranoic amino acids. The chiral intermediate of the tricarboxylic acid cycle, (2R,3S)-isocitric acid, is another promising compound. For the first time our process provides large quantities of enantiopure trimethyl (2R,3S)-isocitrate which was used in subsequent chemical transformations to provide new chiral entities for further usage in total synthesis and pharmaceutical research.