Structural Basis and Enzymatic Mechanism of the Biosynthesis of C9‐ from C10‐Monoterpenoid Indole Alkaloids

Cutting carbons : The three‐dimensional structure of polyneuridine aldehyde esterase (PNAE) gives insight into the enzymatic mechanism of the biosynthesis of C₉‐ from C₁₀‐monoterpenoid indole alkaloids (see scheme). PNAE is a very substrate‐specific serine esterase. It harbors the catalytic triad S87‐D216‐H244, and is a new member of the α/β‐fold hydrolase superfamily. Its novel function leads to the diversification of alkaloid structures.

     

Biosynthesis of Monoterpenoid Indole Alkaloid Ajmaline Catalyzed by Novel Reductases

Introduction OneofthemajorrootalkaloidsoftheIndianme dicinalplantRauvolfiaserpenlinaBenth.exKurzis namedajmaline.Theenzymaticbiosynthesisofthisal kaloidhasbeenstudiedforalongtimebyourgroup[1].Asaresult,abiosyntheticpathwayhasbeenestab lished,inwhichabout1…     

Designing Fluorinated Cinchona Alkaloids for Enantioselective Catalysis: Controlling Internal Rotation by a Fluorine‐Ammonium Ion gauche Effect (φNCCF)

The C9 position of cinchona alkaloids functions as a molecular hinge, with internal rotations around the C8? C9 (τ₁) and C9? C4′ (τ₂) bonds giving rise to four low energy conformers ( 1 ; anti‐closed, anti‐open, syn‐closed, and syn‐open). By substituting the C9 carbinol centre by a configurationally defined fluorine substituent, a fluorine‐ammonium ion gauche effect (σ_C?H→σ_C?F*; F^δ????N⁺) encodes for two out of the four possible conformers ( 2 ). This constitutes a partial solution to the long‐standing problem of governing internal rotations in cinchonium‐based catalysts relying solely on a fluorine conformational effect.     

Enantiospecific Total Syntheses and Assignment of Absolute Configuration of Cannabinol‐Skeletal Carbazole Alkaloids Murrayamines‐O and ‐P

First enantiospecific total syntheses of the cannabinol‐skeletal carbazole alkaloids murrayamines‐O and ‐P isolated from root barks of Murraya euchrestifoli, have been accomplished by highly diastereoselective, Lewis acid catalyzed coupling reactions of commercially available monoterpenes with carbazole derivative, which in addition to confirming the structure also established the absolute configuration of the natural products. Synthesis of both natural products and their enantiomers was achieved with high atom economy, in a protecting‐group free manner and in six steps longest linear sequence from commercially available aniline derivative and verbenol.     

Conformational Analysis,Thermal Rearrangement,and EI‐MS Fragmentation Mechanism of (1(10)E,4E,6S,7R)‐Germacradien‐6‐ol by 13C‐Labeling Experiments

An uncharacterized terpene cyclase from Streptomyces pratensis was identified as (+)‐(1(10)E,4E,6S,7R)‐germacradien‐6‐ol synthase. The enzyme product exists as two interconvertible conformers, resulting in complex NMR spectra. For the complete assignment of NMR data, all fifteen (¹³C₁)FPP isotopomers (FPP=farnesyl diphosphate) and (¹³C₁₅)FPP were synthesized and enzymatically converted. The products were analyzed using various NMR techniques, including ¹³C, ¹³C COSY experiments. The (¹³C)FPP isotopomers were also used to investigate the thermal rearrangement and EI fragmentation of the enzyme product.     

Towards the Core Structure of Strychnos Alkaloids Using Samarium Diiodide‐Induced Reactions of Indole Derivatives

This report describes the development of a first and second generation approach towards the synthesis of the ABCEG pentacyclic core structure of Strychnos alkaloids. First, we discuss a sequential approach applying a series of functional group transformations to prepare suitable precursors for cyclization reactions. These include attempts of samarium diiodide‐induced cyclizations or a Barbier‐type reaction of a transient lithium organyl, which successfully led to a tetracyclic key building block earlier used for the synthesis of strychnine. Secondly, we account our first steps towards the development of an atom‐economical samarium diiodide‐induced cascade reaction using “dimeric” indolyl ketones as cyclization precursors. In this context, we discuss plausible mechanisms for the samarium diiodide‐induced cascade reaction as well as transformations of the obtained tetracyclic dihydroindoline derivatives.     

Palladium‐Catalyzed One‐Pot Three‐ or Four‐Component Coupling of Aryl Iodides,Alkynes, and Amines through CN Bond Cleavage: Efficient Synthesis of Indole Derivatives

An efficient synthesis of N‐substituted indole derivatives was realized by combining the Pd‐catalyzed one‐pot multicomponent coupling approach with cleavage of the C(sp³)?N bonds. Three or four components of aryl iodides, alkynes, and amines were involved in this coupling process. The cyclopentadiene–phosphine ligand showed high efficiency. A variety of aryl iodides, including cyclic and acyclic tertiary amino aryl iodides, and substituted 1‐bromo‐2‐iodobenzene derivatives could be used. Both symmetric and unsymmetric alkynes substituted with alkyl, aryl, or trimethylsilyl groups could be applied. Cyclic secondary amines such as piperidine, morpholine, 4‐methylpiperidine, 1‐methylpiperazine, 2‐methylpiperidine, and acyclic amines including secondary and primary amines all showed good reactivity. Further application of the resulting indole derivatives was demonstrated by the synthesis of benzosilolo[2,3‐b]indole.     

Alkaloids from Arundo donax. XVII. Structure of the Dimeric Indole Alkaloid Arundaphine

The newdimeric alkaloid arundaphine, a tryptamine-tryptamine base, was isolated from roots and rhizomes of Arundo donax (Poaceae). Spectral data and an x-ray structure analysis established its structure as 1-[3-(2-dimethylaminoethyl)-5-hydroxy-1H-4-indolyl]-3-hydroxy-3-(2-methylaminoethyl)-2-indolinone.     

Structures and Biosynthesis of Corvol Ethers—Sesquiterpenes from the Actinomycete Kitasatospora setae

Here we present the functional characterization of a sesquiterpene cyclase from Kitasatospora setae. The enzyme converts the sesquiterpene precursor farnesyl diphosphate (FPP) into two previously unknown and unstable sesquiterpene ethers for which we propose the trivial names corvol ethers A and B. Both compounds were purified and their structures were determined by one‐ and two‐dimensional NMR spectroscopy. A biosynthetic mechanism for the FPP cyclization by the corvol ether synthase was proposed. The results from the incubation experiments of the corvol ether synthase with isotopically labeled precursors were in line with this mechanism, while alternative mechanisms could clearly be ruled out.     

InCl3‐Mediated Addition of Indole to Isatogens: An Expeditious Synthesis of 13‐deoxy‐Isatisine A

A strategy directed towards the total synthesis of isatisine A that involves several late‐stage metal‐catalyzed transformations that address the key carbon–carbon and carbon–heteroatom bond formations has been developed. As a part of this strategy, methods for the addition of indoles to isatogens that lead selectively to either 2,2‐disubstituted N‐hydroxyindolin‐3‐one or 2,2‐disubstituted indolin‐3‐one compounds have been developed by employing InCl₃ as a catalyst or as the reagent. The present methods provide the first examples of the additions of indoles to the isatogen nucleus. To demonstrate its viability, the synthesis of 13‐deoxy‐isatisine A has been completed in ten steps from a known and easily available lactone.     

Regio‐ and Chemoselective N‐1 Acylation of Indoles: Pd‐Catalyzed Domino Cyclization to Afford 1,2‐Fused Tricyclic Indole Scaffolds

A concise method for the synthesis of 1,2‐fused tricyclic indole scaffolds by domino cyclization involving a Pd‐catalyzed Sonogashira coupling, indole cyclization, regio‐ and chemoselective N‐1 acylation, and 1,4‐Michael addition is reported. This method provides straightforward access to tetrahydro[1,4]diazepino[1,2‐a]indole and hexahydro[1,5]diazocino[1,2‐a]indole scaffolds.