4,5-Disubstituted N -Methylimidazoles as Versatile Building Blocks for Defined Side-Chain Introduction

Modulation of voltage-gated Na+ and K+ channels by pumiliotoxin 251D: A “joint venture” alkaloid from arthropods and amphibians

Abstract Certain amphibians provide themselves with a chemical defense by accumulating lipophilic alkaloids into skin glands from dietary arthropods. Examples of such alkaloids are pumiliotoxins (PTXs). In general, PTXs are known as positive modulators of voltage-gated sodium channels (VGSCs). Unlike other PTXs, PTX 251D does not share this characteristic. However, mice and insect studies showed that PTX 251D is highly toxic and to date the basis of its toxicity remains unknown. In this work, we searched for the possible target of PTX 251D . The toxin was therefore made synthetically and tested on four VGSCs (mammalian rNa v 1.2/β 1 , rNa v 1.4/β 1 , hNa v 1.5/β 1 and insect Para/tipE ) and…

Synthesis and Oxidant Properties of Phase 1 Benzepine N-Oxides of Common Antipsychotic Drugs

There is increasing evidence that cell constituents are oxidized by widely used antipsychotic drugs but until now the underlying chemistry has remained unclear. It is well known that such drugs readily undergo N-oxidation as a first key metabolic step. To gain insight into the problem, the tertiary phase 1 N-oxides of clozapine, olanzapine, quetiapine, and zotepine were synthesized, together with the N,S-dioxides of quetiapine and zotepine. These N-oxides were then subjected to well-established chemical transformations to test their oxidant properties in group VIII transition-metal­-catalyzed reactions. In the osmium tetroxide catalyzed dihydroxylation of styrene or cinnamyl alcohol and in …

Synthesis of Optically Active Hydroxyalkyl Cycloheptatrienes: A Key Step in the Total Synthesis of 6,11-Methylene-LXB4

AbstractStarting from methyl cycloheptatrienyl-1-carboxylate, 6-acylation was successfully achieved employing glutaryl chloride in the presence of AlCl3 under controlled reaction conditions to furnish keto carboxylic acid product. After protection of this keto carboxylic acid as tert-butyl ester, reagent-controlled enantioselective reductions delivered configuration-defined methyl-6-hydroxylalkyl cycloheptatriene-1-carboxylates with up to 80% ee. Whereas simple NaBH4 reduction of the keto carboxylic acid and subsequent lactonization afforded a methyl-6-tetrahydropyranonyl cycloheptatriene-1-carboxylate. Resolution using chiral HPLC delivered the product enantiomers with up to >99% ee Fin…

Synthesis of Enantiopure ω-(4-Fluorophenyl)-6,11-Methylene Lipoxin B4 Methyl Ester

AbstractThe synthesis of Lipoxin B4 analogues (LXB4) to gain access to stabilized inflammation-resolving compounds is an active field of research. Focusing on variation and stabilization of the conjugated E,Z,E,E C6–C13 tetraene moiety of natural LXB4, a methylene bridge introduced between C6 and C11 suppresses any Z/E isomerization of the C8–C9 olefin. Furthermore, rapid ω-oxidation (C20) should be avoided by replacing the C18–C20 segment by an aromatic moiety. Optically active C1–C12 building blocks were accessed from methyl cycloheptatriene-1-carboxylate (C6–C11, C21) and glutaryl chloride (C1–C5) as described earlier. The ω-segment was generated via a five-step sequence starting from 4-…

Zwitterionic Aza-Claisen Rearrangements Controlled by Pyrrolidine Auxiliaries - Useful Key Steps in Convergent Enantioselective Syntheses

Chiral pyrrolidine substituents served as efficient auxiliaries in diastereoselective zwitterionic ketene aza-Claisen rearrangements. Palladium-catalysed N-allylation starting from optically active proline and prolinol derivatives, as well as from (2S,5S)-2,5-dimethoxymethylpyrrolidine, gave various allylamines bearing trisubstituted olefin moieties. Treatment with complex carboxylic acid fluorides in the presence of trimethylaluminium induced activated ketene addition to the nitrogen and subsequent [3,3] sigmatropic rearrangement to give γ,δ-unsaturated amides with excellent simple diastereoselectivities and up to 11:1 auxiliary-induced diastereomeric ratios. Cleavage of the pyrrolidine am…

ChemInform Abstract: Flexible Synthesis of Planar Chiral Azoninones and Optically Active Indolizidinones.

First Synthesis of Medium-Sized Ring Allenyl Lactams

Medium-sized lactams bearing an axially chiral allene unit have been synthesized by using an aza-ketene Claisen rearrangement. Starting from 2-alkynylpiperidines or 2-alkynylazepines, ring enlargement enabled the highly diastereoselective formation of 10- or 11-membered lactams with a 4,5-allene subunit. X-ray analysis of the allenylacezinone showed the presence of a strained cumulated olefin system with a defined arrangement of the functional groups. The cyclic allenes were found to be stable upon heating up to 50 °C.

Nitrated Fatty Acids Modulate the Physical Properties of Model Membranes and the Structure of Transmembrane Proteins

Nitrated fatty acids (NO2 -FAs) act as anti-inflammatory signal mediators, albeit the molecular mechanisms behind NO2 -FAs' influence on diverse metabolic and signaling pathways in inflamed tissues are essentially elusive. Here, we combine fluorescence measurements with surface-specific sum frequency generation vibrational spectroscopy and coarse-grained computer simulations to demonstrate that NO2 -FAs alter lipid organization by accumulation at the membrane-water interface. As the function of membrane proteins strongly depends on both, protein structure as well as membrane properties, we consecutively follow the structural dynamics of an integral membrane protein in presence of NO2 -FAs. …

New Optically Active 4-Alkoxyprolinol Ethers Derived from trans-4-Hydroxy-L-proline

(2S,4R)-trans-4-Hydroxy-L-proline has been used as thechiral-pool source in the efficient syntheses of optically active protected 4-hydroxyprolinols. After N-acyl protection andester formation, the first ether moiety was introduced maintaining the chiral centre adjacent to the ester. Then, reduction of the ester delivered the corresponding carbinol, which had to be alkylated selectively to avoid side reactions with the N-protecting group. Finally, the N-acyl function was removed to generate the target methyl and tert-butyl ethers displaying defined substitution patterns. The so-formed optically active 4-alkoxyprolinol ethers can be used as core fragments in biologically active compounds or …

Synthesis of Optically Active N-(4-Hydroxynon-2-enyl)pyrrolidines: Key Building Blocks in the Total Synthesis of Streptomyces coelicolor Butanolide 5 (SCB-5) and Virginiae Butanolide A (VB-A)

AbstractStarting from 5-methylhexanal and (S)-configured N-propargylprolinol ethers, coupling delivered N-(4-hydroxynon-2-ynyl)prolinol derivatives as mixtures of C4 diastereomers. Resolution of the epimers succeeded after introduction of an (R)-mandelic ester derivative and subsequent HPLC separation. Alternatively, suitable oxidation gave the corresponding alkynyl ketone. Midland reagent controlled diastereoselective reduction afforded a defined configured propargyl alcohol with high selectivity. LiAlH4 reduction and Mosher analyses of the allyl alcohols enabled structure elucidation. The suitably protected products are used as key intermediates in enantioselective Streptomyces γ-butyrola…

Synthesis of (+) and (‐)‐Streptomyces coelicolor Butanolide 5 (SCB‐5)

Synthesis of 1-Palmitoyl-2-((E)-9- and (E)-10-nitrooleoyl)-sn-glycero-3-phosphatidylcholines

Extensive investigation of nitrated phospholipids in connection with various biologically important processes requires reliable access to suitable material. A selective chemical synthesis introducing a defined nitrofatty acid at the sn-2 position of a 2-lyso sn-glycero-3-phosphatidylcholine was developed. Given that the nitroalkene moiety of both reactant nitrofatty acid derivative and the product esters is characterised by particular sensitivity to nucleophile addition and, depending on the intermediate, subsequent olefin isomerisation and retro-Henry-type reaction, a reliable two-step ester formation was introduced. The activation of the nitrofatty acid succeeded after reaction with trich…

Total Synthesis of (-)-C/D-cis-De­hydro-3-O-methyl-estradiols

A convergent synthesis of (–)-dehydro-3-O-methyl-C/D-cis-estradiol started from stereochemically defined substituted optically active 3-(2-arylethyl)-γ-butyrolactones. Regioselective bromination of the anisyl moiety, reductive ring opening of the iodolactone, and protecting-group changes led to a Weinreb amide. This then underwent an intramolecular Grignard reaction closing the B-ring to give a tetralone with defined configuration. Introduction of C-11 through an allyl Grignard addition and subsequent ring-closing metathesis gave a tetrahydro phenanthrene derivative. Oxidation of the side-chain alcohol resulted in the key aldehyde group, and a final samarium-diiodide-mediated reductive D-ri…

Aza-Claisen Rearrangement

ChemInform Abstract: First Synthesis of Medium-Sized Ring Allenyl Lactams.

Medium-sized lactams bearing an axially chiral allene unit have been synthesized by using an aza-ketene Claisen rearrangement. Starting from 2-alkynylpiperidines or 2-alkynylazepines, ring enlargement enabled the highly diastereoselective formation of 10- or 11-membered lactams with a 4,5-allene subunit. X-ray analysis of the allenylacezinone showed the presence of a strained cumulated olefin system with a defined arrangement of the functional groups. The cyclic allenes were found to be stable upon heating up to 50 °C.

Recent Advances in Asymmetric [3,3]-Sigmatropic Rearrangements.

The synthesis of new complex structures is still a challenge in preparative organic chemistry. Focusing on the generation of defined stereogenic centers, the [3,3]-sigmatropic rearrangements are known as reliable reactions. Always, a highly ordered transition state must be passed through, which allows the shift of chiral information from the reactant into the nascent product. Generally, the complete [1,3]- and, frequently, the [1,4]-chirality transfer enables one to predict the configuration of the new centers. This review focuses on Claisen and Cope rearrangements, which adopt the chiral information via a so termed asymmetric induction. This means, that the directing chiral subunit is plac…

Flexible Synthesis of Planar Chiral Azoninones and Optically Active Indolizidinones

The flexible synthesis of defined substituted optically active indolizidinones starting from chiral pool (S)-proline and trans 4-hydroxy-(S)-proline is described. Several defined 2-vinylpyrrolidines were generated in short sequences. The aza-Claisen rearrangement using chloro and phenylketene equivalents delivered nine-membered-ring lactams with up to three stereogenic centres and pS-arranged E olefins. Depending on the substitution pattern, certain azoninones had a flexible conformation and showed pS/pR double-bond flipping. Treatment of the unsaturated lactams with the soft electrophile iodine induced diastereoselective transannular ring contractions. Here, the planar chiral arrangement o…

Synthesis and Derivatization of Substituted (R)- and (S)-C-Allylglycines

Various (R)- and (S)-C-allylglycine derivatives were synthesized by means of an auxiliary controlled diastereoselective aza-Claisen rearrangement. Starting from (S)-configured auxiliaries derived from optically active proline, an aza-Claisen rearrangement enabled us to synthesize α(R)-configured γ,δ-unsaturated amides. Since (R)-allylglycine derivatives could be directly generated by reacting N-allylproline derivatives and various protected glycine fluorides, the corresponding (S)-enantiomers were built-up via an initial α-chloroacetyl chloride rearrangement and a subsequent chloride azide substitution with complete inversion of the configuration. High diastereoselectivities were obtained (…

1,2-Asymmetric Induction in Diastereo­selective Zwitterionic Aza-Claisen Rearrangements: Key Steps in Optically Active Alkaloid Synthesis

The zwitterionic aza-Claisen rearrangement of optically active N-allylpyrrolidines and α-phenoxyacetyl fluorides proceeds with complete simple diastereoselectivity (internal asymmetric induction) and complete 1,2-asymmetric induction to generate a new C–C bond adjacent to a chiral C-N-Boc functionality. The resulting γ,δ-unsaturated amides were cyclised to give the corresponding pyrrolizidinones, which enabled the determination of the relative configuration of the stereotriads. Vinyl group degradation and a final lactam reduction gave an optically active analogue of (+)-petasinine (a pyrrolizidine alkaloid). Furthermore, the stereotriad-containing amides should be useful key intermediates f…

Recent Advances in Charge-Accelerated aza-Claisen Rearrangements

Aza-Claisen rearrangements (3-aza-Cope rearrangements) have gained an in- creasing interest in synthetic organic chemistry. Originally, the exceptionally high reaction temperatures of this hetero variant of the well-known 3,3-sigmatropic reaction limited their applicability to selected molecules. Since about 1970, charge acceleration enabled a signifi- cant reduction of the reaction temperature to be achieved, and cation- and anion-promoted rearrangements found their way into the syntheses of more complex molecules. The first to- tal syntheses of natural products were reported. The development of zwitterionic aza-Claisen rearrangements allowed the reactions to be run at room temperature or …

4,5-Disubstituted 1-Methylimidazoles via Cyclization of Defined α-Aminoketones: Synthesis of Fungerin and Analogues I

A protocol for the chemoselective synthesis of the fungal metabolite fungerin has been developed. First the required N-methyl α-aminoketone was generated starting from sarcosine, propiolic acid, and prenyl bromide. Marckwald thioimidazole cyclization and subsequent sulfur removal delivered the target fungerin as well as an analogue, respectively, displaying defined substitution patterns.

Synthesis of Enantiopure 6,11‐Methylene Lipoxin B4Methyl Ester

Synthesis of Optically Active 15-epi-9,14-Methylene Lipoxin A4

The synthesis of lipoxin A4 and B4 analogues (LXA4, LXB4) to gain access to stabilized inflammation resolving compounds is an important field of research. Starting from known structural requirements of the natural compounds displaying biological activity and a broad investigation of their rapid metabolism, various LXA4 derivatives have been developed and tested. Focusing on variation and stabilization of the conjugated E,E,Z,E C7–C14 tetraene moiety of natural LXA4, a methylene bridge introduced between C9 and C14 might suppress any Z/E isomerization of the C11–C12 olefin. Intending to enable at least known structure variations in connection with the C1–C7 and the C15–C20 fragments, a conve…

Recent Advances in Asymmetric [3,3]-SigmatropicRearrangements

The synthesis of new complex structures is still a challenge in preparative organic chemistry. Focusing on the generation of defined stereogenic centers, the [3,3]-sigmatropic rearrangements are known as reliable reactions. Always, a highly ordered transition state must be passed through, which allows the shift of chiral information from the reactant into the nascent product. Generally, the complete [1,3]- and, frequently, the [1,4]-chirality transfer enables one to predict the configuration of the new centers. This review focuses on Claisen and Cope rearrangements, which adopt the chiral information via a so termed asymmetric induction. This means, that the directing chiral subunit is plac…

CCDC 926977: Experimental Crystal Structure Determination

Related Article: Carolin Heescher, Dieter Schollmeyer and Udo Nubbemeyer|2013|Eur.J.Org.Chem.|2013|4399|doi:10.1002/ejoc.201300389

CCDC 907670: Experimental Crystal Structure Determination

Related Article: Jochen Körber, Stefan Löffler, Dieter Schollmeyer, Udo Nubbemeyer|2013|Synthesis|45|2875|doi:10.1055/s-0033-1338519

CCDC 2077847: Experimental Crystal Structure Determination

Related Article: Lukas Trippe, Analuisa Nava, Andrea Frank, Dieter Schollmeyer, Udo Nubbemeyer|2021|Synthesis|53|3760|doi:10.1055/a-1512-1763

CCDC 2076144: Experimental Crystal Structure Determination

Related Article: Jonas Donges, Sandra Hofmann, Moritz Brüggemann, Andrea Frank, Dieter Schollmeyer, Udo Nubbemeyer|2021|Eur.J.Org.Chem.|2021|3345|doi:10.1002/ejoc.202100497

CCDC 1428732: Experimental Crystal Structure Determination

Related Article: Nora M. Kaluza, Dieter Schollmeyer, Udo Nubbemeyer|2016|Eur.J.Org.Chem.|2016|357|doi:10.1002/ejoc.201501341

CCDC 985005: Experimental Crystal Structure Determination

Related Article: Frank Bohland, Irina Erlin, Lukas Platte, Maike Schröder, Dieter Schollmeyer, Udo Nubbemeyer|2014|Eur.J.Org.Chem.|2014|6272|doi:10.1002/ejoc.201402720

CCDC 985006: Experimental Crystal Structure Determination

Related Article: Frank Bohland, Irina Erlin, Lukas Platte, Maike Schröder, Dieter Schollmeyer, Udo Nubbemeyer|2014|Eur.J.Org.Chem.|2014|6272|doi:10.1002/ejoc.201402720

CCDC 907672: Experimental Crystal Structure Determination

Related Article: Jochen Körber, Stefan Löffler, Dieter Schollmeyer, Udo Nubbemeyer|2013|Synthesis|45|2875|doi:10.1055/s-0033-1338519

CCDC 1428734: Experimental Crystal Structure Determination

Related Article: Nora M. Kaluza, Dieter Schollmeyer, Udo Nubbemeyer|2016|Eur.J.Org.Chem.|2016|357|doi:10.1002/ejoc.201501341

CCDC 2076145: Experimental Crystal Structure Determination

Related Article: Jonas Donges, Sandra Hofmann, Moritz Brüggemann, Andrea Frank, Dieter Schollmeyer, Udo Nubbemeyer|2021|Eur.J.Org.Chem.|2021|3345|doi:10.1002/ejoc.202100497

CCDC 1428733: Experimental Crystal Structure Determination

Related Article: Nora M. Kaluza, Dieter Schollmeyer, Udo Nubbemeyer|2016|Eur.J.Org.Chem.|2016|357|doi:10.1002/ejoc.201501341

CCDC 907671: Experimental Crystal Structure Determination

Related Article: Jochen Körber, Stefan Löffler, Dieter Schollmeyer, Udo Nubbemeyer|2013|Synthesis|45|2875|doi:10.1055/s-0033-1338519

CCDC 926976: Experimental Crystal Structure Determination

Related Article: Carolin Heescher, Dieter Schollmeyer and Udo Nubbemeyer|2013|Eur.J.Org.Chem.|2013|4399|doi:10.1002/ejoc.201300389