Enantioselective Syntheses of Strychnos and Chelidonium Alkaloids through Regio- and Stereocontrolled Cooperative Catalysis.

We describe enantioselective syntheses of strychnos and chelidonium alkaloids. In the first case, indole acetic acid esters were established as excellent partner nucleophiles for enantioselective cooperative isothiourea/Pd catalyzed α-alkylation. This provides products containing indole-bearing stereocenters in high yield and with excellent levels of enantioinduction in a manner that is notably independent of the N-substituent. This led to concise syntheses of (-)-akuammicine and (-)-strychnine. In the second case, the poor performance of ortho-substituted cinnamyl electrophiles in the enantioselective cooperative isothiourea/Ir catalyzed α-alkylation was overcome by appropriate substituent choice, leading to enantioselective syntheses of (+)-chelidonine, (+)-norchelidonine, and (+)-chelamine.

Total Synthesis of Strychnine.

The total synthesis of the flagship Strychnos indole alkaloid, strychnine, has been accomplished. The developed synthetic sequence features a novel vinylogous 1,4-addition, a challenging iodinium salt mediated silyl enol ether arylation, a palladium-catalyzed Heck reaction, and a streamlined late-stage conversion to strychnine. Furthermore, an application of asymmetric counterion-directed catalysis (ACDC) in the context of target-oriented organic synthesis has been rendered access to an optically active material. The synthetic sequence described herein represents the most concise entry to optically active strychnine to date.

Oxime Ethers of (E)-11-Isonitrosostrychnine as Highly Potent Glycine Receptor Antagonists.

A series of (E)-11-isonitrosostrychnine oxime ethers, 2-aminostrychnine, (strychnine-2-yl)propionamide, 18-oxostrychnine, and N-propylstrychnine bromide were synthesized and evaluated pharmacologically at human α1 and α1ß glycine receptors in a functional fluorescence-based and a whole-cell patch-clamp assay and in [3H]strychnine binding studies. 2-Aminostrychnine and the methyl, allyl, and propargyl oxime ethers were the most potent α1 and α1ß antagonists in the series, displaying IC50 values similar to those of strychnine at the two receptors. Docking experiments to the strychnine binding site of the crystal structure of the α3 glycine receptor indicated the same orientation of the strychnine core for all analogues. For the most potent oxime ethers, the ether substituent was accommodated in a lipophilic receptor binding pocket. The findings identify the oxime hydroxy group as a suitable attachment point for linking two strychnine pharmacophores by a polymethylene spacer and are, therefore, important for the design of bivalent ligands targeting glycine receptors.

Highly Efficient Formal [2+2+2] Strategy for the Rapid Construction of Polycyclic Spiroindolines: A Concise Synthesis of 11-Demethoxy-16-epi-myrtoidine.

A novel formal [2+2+2] strategy for the stereoselective elaboration of polycyclic indole alkaloids is described. Upon treatment with the catalyst InCl3 (5 mol %), tryptamine-derived enamides reacted readily with methylene malonate, thus enabling rapid and gram-scale access to versatile tetracyclic spiroindolines with excellent diastereoselectivity (21 examples, up to 95 % yield, up to d.r.>95:5). This strategy provides a concise approach to alkaloids isolated from Strychnos myrtoides, as demonstrated by a short synthesis of 11-demethoxy-16-epi-myrtoidine.

Concise Syntheses of bis-Strychnos Alkaloids (-)-Sungucine, (-)-Isosungucine, and (-)-Strychnogucine†B from (-)-Strychnine.

The first chemical syntheses of complex, bis-Strychnos alkaloids (-)-sungucine (1), (-)-isosungucine (2), and (-)-strychnogucine B (3) from (-)-strychnine (4) is reported. Key steps included (1) the Polonovski-Potier activation of strychnine N-oxide; (2) a biomimetic Mannich coupling to forge the signature C23-C5' bond that joins two monoterpene indole monomers; and (3) a sequential HBr/NaBH3 CN-mediated reduction to fashion the ethylidene moieties in 1-3. DFT calculations were employed to rationalize the regiochemical course of reactions involving strychnine congeners.

Synthesis of the Strychnos Alkaloid (-)-Strychnopivotine and Confirmation of its Absolute Configuration.

The first enantioselective synthesis of (-)-strychnopivotine from a known and inexpensive phenol has been achieved in 15 steps. The strategy is based on a new diastereoselective aza-Michael-enol-ether cascade desymmetrization of a dienone, guided by a removable lactic acid-derived chiral auxiliary. Synthesis involves a phenol dearomatization, a conjugated silicon addition, a stereoselective double reductive amination, and two Heck-type carbopalladations as key steps. The absolute configuration of the natural compound, which, to date, has been uncertain, was confirmed by using circular dichroism (CD) spectroscopy and X-ray analyses.

Preparation of the Core Structure of Aspidosperma and Strychnos Alkaloids from Aryl Azides by a Cascade Radical Cyclization.

A novel approach to prepare the core structure of Aspidosperma and Strychnos alkaloids is described. The strategy is based on a cyclization cascade involving the formation of quaternary carbon center followed by trapping of the radical intermediate by an aryl azide to build the 5-membered ring of the pyrrolocarbazole system. This reaction is run with triethylborane without the need for any hydrogen atom donor such as a tin hydride or tris(trimethylsilyl)silane, and it furnishes the tetracyclic framework as a single diastereomer. The influence of different N-protecting groups on the starting iodoacetamide has been examined.

Strychnine as Target, Samarium Diiodide as Tool: A Personal Story.

Strychnine stands out from the group of classical natural products as one of the first complex compounds to be isolated in pure form and an extreme challenge to be structurally characterized. It has played a central role in natural product total syntheses and the surge in the development of innovative synthetic methods for many decades. Recently, we have accomplished one of the shortest formal total syntheses of strychnine (in ten steps and 14% overall yield or even shorter in eight steps and 10% overall yield). The evolution of a productive synthetic strategy, as well as the synthetic challenges tackled, are described here in detail, including examples of related transformations. The successful synthetic strategy was inspired by the premise that the core structure could be derived from simple aromatic indole precursors by a reductive SmI2 -induced ketyl-aryl coupling. Other key reactions included a diastereoselective reduction and a regioselective elimination protocol. Altogether one of the shortest syntheses of iso-strychnine and hence of strychnine was established.

Isostrychnine synthesis mediated by hypervalent iodine reagent.

Althought there are several reported synthetic routes to strychnine, one of the most widely recognized alkaloids, we report an unexplored route with an oxidative dearomatizing process mediated by hypervalent iodine as the key step. The new syntheses of isostrychnine and strychnine have been achieved from an readily available phenol in nine and ten steps. In addition to the key step, these syntheses involve an aza Michael-ether-enol tandem transformation, two heck type cyclizations, a reductive isomerization, and a double reductive amination in cascade leading to the alkaloid main core.

Evolution of a short route to strychnine by using the samarium-diiodide-induced cascade cyclization as a key step.

This comprehensive report accounts the development of a highly diastereoselective samarium diiodide-induced cascade reaction of substituted indolyl ketones. The complexity-generating transformation with SmI2 allows the diastereoselective generation of three stereogenic centers including one quaternary center in one step. The obtained tetra- or pentacyclic dihydroindole derivatives are structural motifs of many monoterpene indole alkaloids, and their subsequent transformations gave way to one of the shortest approaches towards strychnine (14 % overall yield in ten steps, or 10 % overall yield in eight steps). During the course of this report we discuss the influence of substituents on the cyclization step, plausible mechanistic scenarios for the SmI2 -induced cascade reaction, diastereoselective reductive amination, and regioselective dehydratization protocols towards the pentacyclic core structure of strychnos alkaloids.

Reaction schemes visualized in network form: the syntheses of strychnine as an example.

Representation of synthesis sequences in a network form provides an effective method for the comparison of multiple reaction schemes and an opportunity to emphasize features such as reaction scale that are often relegated to experimental sections. An example of data formatting that allows construction of network maps in Cytoscape is presented, along with maps that illustrate the comparison of multiple reaction sequences, comparison of scaffold changes within sequences, and consolidation to highlight common key intermediates used across sequences. The 17 different synthetic routes reported for strychnine are used as an example basis set. The reaction maps presented required a significant data extraction and curation, and a standardized tabular format for reporting reaction information, if applied in a consistent way, could allow the automated combination of reaction information across different sources.

Is there no end to the total syntheses of strychnine? Lessons learned in strategy and tactics in total synthesis.

From the 19th century to the present, the complex indole alkaloid strychnine has engaged the chemical community. In this Review, we examine why strychnine has been and remains today an important target for directed synthesis efforts. A selection of the diverse syntheses of strychnine is discussed with the aim of identifying their influence on the evolution of the strategy and tactics of organic synthesis.

Syntheses of strychnine, norfluorocurarine, dehydrodesacetylretuline, and valparicine enabled by intramolecular cycloadditions of Zincke aldehydes.

A full account of the development of the base-mediated intramolecular Diels-Alder cycloadditions of tryptamine-derived Zincke aldehydes is described. This important complexity-generating transformation provides the tetracyclic core of many indole monoterpene alkaloids in only three steps from commercially available starting materials and played a key role in short syntheses of norfluorocurarine (five steps), dehydrodesacetylretuline (six steps), valparicine (seven steps), and strychnine (six steps). Reasonable mechanistic possibilities for this reaction, a surprisingly facile dimerization of the products, and an unexpected cycloreversion to regenerate Zincke aldehydes under specific conditions are also discussed.

Collective synthesis of natural products by means of organocascade catalysis.

Organic chemists are now able to synthesize small quantities of almost any known natural product, given sufficient time, resources and effort. However, translation of the academic successes in total synthesis to the large-scale construction of complex natural products and the development of large collections of biologically relevant molecules present significant challenges to synthetic chemists. Here we show that the application of two nature-inspired techniques, namely organocascade catalysis and collective natural product synthesis, can facilitate the preparation of useful quantities of a range of structurally diverse natural products from a common molecular scaffold. The power of this concept has been demonstrated through the expedient, asymmetric total syntheses of six well-known alkaloid natural products: strychnine, aspidospermidine, vincadifformine, akuammicine, kopsanone and kopsinine.

Samarium diiodide induced ketyl-(het)arene cyclisations towards novel N-heterocycles.

In this tutorial review we discuss recent advances in the field of ketyl-(het)arene cyclisations promoted by samarium diiodide and related processes. Couplings of samarium ketyls with carbon-carbon multiple bonds are perhaps the most useful reactions to create carbocycles and heterocycles of various ring sizes. They have also successfully been exploited for the synthesis of biologically active compounds or natural products. In this article we intend to summarise our diversity orientated approaches towards nitrogen heterocycles and emphasize other approaches with SmI(2) as well as electrochemical cyclisation methods providing similar N-heterocycles. We also briefly discuss our recently published formal total synthesis of strychnine employing a new samarium diiodide induced cascade reaction as key step. All these examples demonstrate the high synthetic potential of samarium ketyl-(het)arene cyclisations for the preparation of various types of important heterocyclic compounds.

Concise total syntheses of (+/-)-strychnine and (+/-)-akuammicine.

Concise total syntheses of Strychnos alkaloids strychnine (1) and akuammicine (2) have been realized in 13 and 6 operations, respectively. Key steps include (1) the vinylogous Mannich reaction; (2) a novel, sequential one-pot spirocyclization/intramolecular aza-Baylis-Hillman reaction; and (3) a Heck cyclization. The synthesis of 1 proceeds via the Wieland-Gumlich aldehyde (26).

Total synthesis of (+/-)-strychnine via a [4 + 2]-cycloaddition/rearrangement cascade.

A new strategy for the synthesis of the Strychnos alkaloid (+/-)-strychnine has been developed and is based on an intramolecular [4 + 2]-cycloaddition/rearrangement cascade of an indolyl-substituted amidofuran. The critical D-ring was assembled by an intramolecular palladium-catalyzed enolate-driven cross-coupling of an N-tethered vinyl iodide. [reaction: see text].