Biogenetic space-guided synthesis of rearranged terpenoids.

Natural product chemistry is constantly challenged by newly discovered, complex molecules. Elements of complexity arise from unprecedented frameworks, with a large amount of densely packed stereogenic centres and different functional groups along with a generally high oxidation state. As a prime example, rearranged triterpenoids possess all these elements. For their total synthesis, a limit of what is considered sensible in terms of steps and yield is frequently reached. As an alternative, semisynthetic approaches have gained a great amount of attention in recent years. In this featured article, we present our and others' contributions towards the development of efficient and economic syntheses of complex terpenoid natural products and elaborate on the underlying rationale of biogenetic space-guided synthetic analysis.

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.

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.

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.

A Modular, Argon-Driven Flow Platform for Natural Product Synthesis and Late-Stage Transformations.

A modular flow platform for natural product synthesis was designed. To access different reaction setups with a maximum of flexibility, interchangeable 3D-printed components serve as backbone. By switching from liquid- to gas-driven flow, reagent and solvent waste is minimized, which translates into an advantageous sustainability profile. To enable inert conditions, "Schlenk-in-flow" techniques for the safe handling of oxygen- and moisture sensitive reagents were developed. Adopting these techniques, reproducible transformations in natural product synthesis were achieved.

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 Aspidodispermine via Pericyclic Framework Reconstruction.

A divergent approach to the pyrroloquinoline scaffold as present in the class of Aspidosperma alkaloids was developed. As a case study, abundant and renewable nicotinic acid was transformed via pericyclic framework reconstruction into aspidodispermine, a unique member of pyrroloquinoline alkaloids. The sequence comprises a [2 + 2]-photocycloaddition, a Ramberg-Bäcklund contraction, and a strain-promoted formal electrocyclic rearrangement of a bicyclo[2.2.0]hexene and is potentially extendable to pyrroloindole scaffolds as present in the ibophyllidine alkaloids.

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.

Synthesis of the Alleged Structures of Fortisterol and Herbarulide and Structural Revision of Herbarulide.

The alleged structures of 5,6-epoxy-5,6-secosteroids fortisterol and herbarulide differ only in the stereoconfiguration of C24. Applying insights into the hypothetical biosynthesis of this class of natural products, we devised a short synthetic access (four and eight steps, respectively) starting from commercial ergosterol and featuring an alkoxy radical rearrangement. The comparison of nuclear magnetic resonance spectroscopic data revealed herbarulide having the proposed structure of fortisterol, whereas synthesis of another two diastereomers could not conclusively prove the true structure of fortisterol. Along the way, a high-yielding and scalable access to the infamous Burawoy's ketone not requiring chromium(VI) reagents was developed.

Scalable Synthesis of Functionalized Ferrocenyl Azides and Amines Enabled by Flow Chemistry.

A scalable access to functionalized ferrocenyl azides has been realized in flow. By halogen-lithium exchange of ferrocenyl halides and trapping with tosyl azide, a variety of functionalized ferrocenyl azides were obtained in high yields. To allow a scalable preparation of these potentially explosive compounds, a flow protocol was developed accelerating the reaction time to minutes and circumventing accumulation of potentially hazardous intermediates. The corresponding ferrocenyl amines were then prepared by a reliable reduction process.

Five-Step Synthesis of Yaequinolones J1 and J2.

A concise synthesis of yaequinolones J1 and J2 is reported. The route is based on the aryne insertion into the σ-C-N bond of an unsymmetric imide followed by a diastereoselective aldol cyclization of the resulting N-acylated aminobenzophenone. The chromene motif is generated in the first step by an organocatalytic tandem Knoevenagel electrocyclization of citral and 2-bromoresorcinol. The approach adheres to the ideality principle, using almost exclusively strategic bond-forming reactions.

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).

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.

Synthesis of Quinolinone Alkaloids via Aryne Insertions into Unsymmetric Imides in Flow.

A general strategy for the synthesis of 3,4-dioxygenated quinolin-2-one natural products is reported. The key step is a regioselective insertion of arynes into unsymmetric imides. When performed in continuous flow, the reaction proceeds within minutes, while lower yields and longer reaction times are observed in batch. The resulting N-acylated 2-aminobenzophenones were transformed to (±)-peniprequinolone, (±)-aflaquinolones E and F, (±)-6-deoxyaflaquinolone E, (±)-quinolinones A and B, and (±)-aniduquinolone C in 1-3 steps.

Photochemical degradation of trypan blue.

PURPOSE: To investigate the photochemical degradation of trypan blue (TB) and to identify decomposition products. METHODS: Defined solution samples of TB and a mixture with lutein/zeaxanthin were exposed to blue light. Thermal degradation processes were ruled out using controls not subjected to irradiation. All samples were analyzed using optical microscopy, UV/Vis spectroscopy, matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry and nuclear magnetic resonance (NMR) spectrometry. Degradation kinetics were determined based on changes in absorbance; intermediates were identified by analyzing mass differences of characteristic fragment ion peaks within the fragmentation patterns, and assignments were verified by NMR. RESULTS: TB demonstrated a photochemical degradation, which can be triggered by lutein/zeaxanthin. Intermediates vary depending on the presence of lutein/zeaxanthin. The self-sensitized photodegradation of TB occurs under generation of dimethyl sulfate and presumed formation of phenol. In contrast, within the presence of lutein/zeaxanthin the decomposition of TB indicates the formation of methoxyamine and sulfonyl arin. Thermal degradation processes were not observed. CONCLUSIONS: TB demonstrated a photodegradation that may be triggered by lutein/zeaxanthin and results in the formation of cytotoxic decomposition products. Our findings contribute to understand degradation mechanisms of TB and may elucidate previous clinical and experimental observations of cellular toxicity after TB application.

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 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.