Synthesis of Bench-Stable N-Quaternized Ketene N,O-Acetals and Preliminary Evaluation as Reagents in Organic Synthesis.

N-Quaternized ketene N,O-acetals are typically an unstable, transient class of compounds most commonly observed as reactive intermediates. In this report, we describe a general synthetic approach to a variety of bench-stable N-quaternized ketene N,O-acetals via treatment of pyridine or aniline bases with acetylenic ethers and an appropriate Brønsted or Lewis acid (triflic acid, triflimide, or scandium(III) triflate). The resulting pyridinium and anilinium salts can be used as reagents or synthetic intermediates in multiple reaction types. For example, N-(1-ethoxyvinyl)pyridinium or anilinium salts can thermally release highly reactive O-ethyl ketenium ions for use in acid catalyst-free electrophilic aromatic substitutions. N-(1-Ethoxyvinyl)-2-halopyridinium salts can be employed in peptide couplings as a derivative of Mukaiyama reagents or react with amines in nucleophilic aromatic substitutions under mild conditions. These preliminary reactions illustrate the broad potential of these currently understudied compounds in organic synthesis.

Synthesis, Characterization, and Computational Modeling of N-(1-Ethoxyvinyl)pyridinium Triflates, an Unusual Class of Pyridinium Salts.

N-Substituted pyridinium salts constitute one of the most valuable reagent classes in organic synthesis, due to their versatility and ease of use. Herein we report a preliminary synthesis and detailed structural analysis of several N-(1-ethoxyvinyl)pyridinium triflates, an unusual class of pyridinium salts with potentially broad use as a reagent in organic synthesis. Treatment of pyridines with trifluoromethane sulfonic acid and ethoxyacetylene generates stable, isolable adducts which have been extensively characterized, due to their novelty. Three-dimensional structural stability is perpetuated by an array of C-H•••O hydrogen bonds involving oxygen atoms from the -SO3 groups of the triflate anion, and hydrogen atoms from the aromatic ring and vinyl group of the pyridinium cation. Predictions from density functional theory calculations of the energy landscape for rotation about the exocyclic C-N bond of 2-chloro-1-(1-ethoxyvinyl)pyridine-1-ium trifluoromethanesulfonate (7) and 1-(1-ethoxyvinyl)pyridine-1-ium trifluoromethanesulfonate (16) are also reported. Notably, the predicted global energy minimum of 7 was nearly identical to that found within the crystal structure.

Total syntheses of the monoterpene indole alkaloids (±)-alstilobanine A and E and (±)-angustilodine.

A synthetic strategy has been developed culminating in stereoselective total syntheses of the small class of unusual monoterpenoid indole alkaloids exemplified by alstilobanines A (3) and E (2) and angustilodine (1). A pivotal step includes a novel intermolecular Michael-type addition of an indole ester dianion to a piperidine-derived nitrosoalkene to form the C15, C16 bond of the alkaloids. In addition, an application of the Romo protocol for effecting a stereoselective intramolecular nucleophile-assisted aldol-lactonization was employed, leading to a ß-lactone incorporating the requisite cis-fused 2-azadecalin moiety and also setting the C15, C19, C20 relative stereochemistry of the metabolites. It was then possible to stereoselectively effect an aldolization of a dianion derived from this indole ester ß-lactone intermediate with formaldehyde to introduce the requisite C16 hydroxymethyl group. Further manipulations of the system ultimately led to the three alkaloids in racemic form.

Synthesis and crystal structure of a bench-stable pyridinium ketene hemiaminal: 1-(1-eth-oxy-ethen-yl)-2-[meth-yl(phen-yl)amino]-pyridin-1-ium tri-fluoro-methane-sulfonate.

The novel bench-stable N-quaternized ketene N,O-acetal, C16H19N2O+·CF3O3S-, was synthesized and its structure determined. The title compound is a rare example of a pyridinium ketene hemiaminal for which a crystal structure has been determined, joining the 2-chloro-1-(1-ethyoxyethen-yl)pyridin-1-ium tri-fluoro-methane-sulfonate salt from which it was synthesized. The cationic species of the title compound can be defined by three individually planar fragments assembling into a non-coplanar cation. The phenyl substituent extending from the amino nitro-gen atom and the ethyoxyvinyl substituent extending from the pyridine N atom are oriented on the same side of the mol-ecule and maintain the closest coplanar relationship of the three fragments. Supra-molecular inter-actions are dominated by C-H⋯O inter-actions from the cation to the SO3 side of the tri-fluoro-methane-sulfonate anion, forming a two-dimensional substructure.

An expedient reductive method for conversion of ketoximes to the corresponding carbonyl compounds.

A wide array of readily prepared pivalates of ketoximes can be converted to the corresponding ketones in good yields by treatment with iron powder in THF containing catalytic amounts of both trimethylsilyl chloride and glacial acetic acid at room temperature for 30 minutes, followed by a brief aqueous workup.

Efficient methodology for alkylation of vinylnitroso compounds with carbon nucleophiles.

A diverse array of nitrosoalkenes derived from both acyclic and cyclic ketones, as well as aldehydes, via the Denmark protocol using alpha-chloro-O-TBS-oximes can be trapped efficiently in situ by a wide variety of potassium ester enolates to afford conjugate addition products in good yields.

A mild, efficient method for the oxidation of alpha-diazo-beta-hydroxyesters to alpha-diazo-beta-ketoesters.

A wide variety of alpha-diazo-beta-ketoesters can be prepared in good overall yields via a two-step sequence involving addition of ethyl lithiodiazoacetate to aliphatic, aromatic and conjugated aldehydes followed by mild oxidation with the Dess-Martin periodinane.

Preparation of N-(2-alkoxyvinyl)sulfonamides from N-tosyl-1,2,3-triazoles and Subsequent Conversion to Substituted Phthalans and Phenethylamines.

Decomposition of N-tosyl-1,2,3-triazoles with rhodium(II) acetate dimer in the presence of alcohols forms synthetically versatile N-(2-alkoxyvinyl)sulfonamides, which react under a variety of conditions to afford useful N- and O-containing compounds. Acid-catalyzed addition of alcohols or thiols to N-(2-alkoxyvinyl)sulfonamide-containing phthalans provides access to ketals and thioketals, respectively. Selective reduction of the vinyl group in N-(2-alkoxyvinyl)sulfonamide-containing phthalans via hydrogenation yields the corresponding phthalan in good yield, whereas reduction with sodium bis(2-methoxyethoxy)aluminumhydride generates a ring-opened phenethylamine analogue. Because the N-(2-alkoxyvinyl)sulfonamide functional group is synthetically versatile, but often hydrolytically unstable, this protocol emphasizes key techniques in preparing, handling, and reacting these pivotal substrates in several useful transformations.

Niche-Based Screening in Multiple Myeloma Identifies a Kinesin-5 Inhibitor with Improved Selectivity over Hematopoietic Progenitors.

Novel therapeutic approaches are urgently required for multiple myeloma (MM). We used a phenotypic screening approach using co-cultures of MM cells with bone marrow stromal cells to identify compounds that overcome stromal resistance. One such compound, BRD9876, displayed selectivity over normal hematopoietic progenitors and was discovered to be an unusual ATP non-competitive kinesin-5 (Eg5) inhibitor. A novel mutation caused resistance, suggesting a binding site distinct from known Eg5 inhibitors, and BRD9876 inhibited only microtubule-bound Eg5. Eg5 phosphorylation, which increases microtubule binding, uniquely enhanced BRD9876 activity. MM cells have greater phosphorylated Eg5 than hematopoietic cells, consistent with increased vulnerability specifically to BRD9876's mode of action. Thus, differences in Eg5-microtubule binding between malignant and normal blood cells may be exploited to treat multiple myeloma. Additional steps are required for further therapeutic development, but our results indicate that unbiased chemical biology approaches can identify therapeutic strategies unanticipated by prior knowledge of protein targets.

A study of the scope and regioselectivity of the ruthenium-catalyzed [3 + 2]-cycloaddition of azides with internal alkynes.

[3 + 2]-Cycloadditions of alkyl azides with various unsymmetrical internal alkynes in the presence of CpRuCl(PPh3)2 as catalyst in refluxing benzene have been examined, leading to 1,4,5-trisubstituted-1,2,3-triazoles. Whereas alkyl phenyl and dialkyl acetylenes undergo cycloadditions to afford mixtures of regioisomeric 1,2,3-triazoles, acyl-substituted internal alkynes react with complete regioselectivity. In addition, propargyl alcohols and propargyl amines were found to react with azides to afford single regioisomeric products.