John K. Snyder

Asymmetric oxidation of olefins to vicinal diols with osmium tetroxide

Abstract High levels of asymmetry can be achieved in the osmium tetroxide cis-hydroxylation of olefins by employing (−)-(R,R)-N,N,N′,N′-tetramethylcyclohexane-1,2- trans -diamine as a chiral ligand for the osmium.

Remodelling of the natural product fumagillol employing a reaction discovery approach

In the search for new biologically active molecules, diversity-oriented synthetic strategies break through the limitation of traditional library synthesis by sampling new chemical space. Many natural products can be regarded as intriguing starting points for diversity-oriented synthesis, wherein stereochemically rich core structures may be reorganized into chemotypes that are distinctly different from the parent structure. Ideally, to be suited to library applications, such transformations should be general and involve few steps. With this objective in mind, the highly oxygenated natural product fumagillol has been successfully remodelled in several ways using a reaction-discovery-based approach. In reactions with amines, excellent regiocontrol in a bis-epoxide opening/cyclization sequence can be obtained by size-dependent interaction of an appropriate catalyst with the parent molecule, forming either perhydroisoindole or perhydroisoquinoline products. Perhydroisoindoles can be further remodelled by cascade processes to afford either morpholinone or bridged 4,1-benzoxazepine-containing structures. The natural product fumagillol has been exploited as a stereochemically rich scaffold for the synthesis of a structurally unique, chemically diverse library with chemotypes distinctly different from the parent structure. Thus, fumagillol has been remodelled into a diverse array of isoindoles, isoquinolines, furans, mopholinones and benzoxazepines.

Intramolecular Inverse Electron Demand Diels–Alder Reactions of Tryptamine with Tethered Heteroaromatic Azadienes

Abstract 1,2,4,5-Tetrazines and 1,2,4-triazines tethered to tryptamine via the ethylamine side chain undergo intramolecular inverse electron demand cycloadditions to produce adducts with the [ABazaCE]-ring skeleton of the Aspidosperma alkaloids.

Dienophilicity of imidazole in inverse electron demand Diels–Alder reactions: cycloadditions with 1,2,4,5-tetrazines and the structure of zarzissine

Abstract The inverse electron demand cycloadditions of 2-substituted imidazoles with dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate produced imidazo[4,5-d]pyridazines in good yields. This chemistry was applied to the synthesis of 2-amino-1H-imidazo[4,5-d]pyridazine (1), the structure reported for zarzissine, a cytotoxic marine alkaloid. Differences in the 1H- and 13C NMR spectra of 1 with those reported for zarzissine necessitated a structural revision, and zarzissine was then considered to be the corresponding 2-amino-1H-imidazo[4,5-b]pyrazine (2), which was subsequently synthesized from the parent heterocycle.

Optically pure chiral sulfoxides using ephedrine as a chiral auxiliary

Abstract Optically pure chiral sulfoxides can be formed in good to excellent yields by sequential displacement reactions of organometallic reagents on the 1,2,3-oxathiazolidine-S-oxide formed from ephedrine and thionyl chloride, a modification of the Wudl and Lee procedure.

Chapter 6.2 Six-membered ring systems: Diazines and benzo derivatives

Publisher Summary This chapter provides information on six-membered ring systems, including diazines and benzo derivatives. Diazines and their derivatives are extremely important to the field of chemistry and the general population, because of their invaluable biological activities. The chapter presents a discussion on the preparation and reaction of (1) pyrimidines, (2) quinazolines, (3) pyridazines, (4) cinnolines, (5) phthalazines, (6) pyrazines, (7) phenazines, and (8) quinoxalines. A common method for the preparation of the fully aromatized pyrimidine skeleton is the condensation of amidine-containing substrates with suitable carbonyl compounds. Among these protocols, α, β-unsaturated carbonyl and 1,3-dicarbonyl compounds are used. Aromatic nucleophilic substitution reactions (SNAr) are commonly applied in the transformations of pyrimidines. Quinazolines, the benzo derivatives of pyrimidines, were prepared in a variety of ways from methods analogous to those used to synthesize pyrimidines to vastly different condensation schemes. A long-established method to prepare pyridazines is the condensation of 1,4-dicarbonyl compounds with hydrazine. Cinnolines, one of the two benzo derivatives of pyridazines, received considerable attention, because of the pharmacological activities exhibited by these heterocycles. The most common way to construct the pyrazine ring is the condensation of 1,2-diamines with 1,2-dicarbonyl compounds followed by the aromatization.

Discovery of new antimalarial chemotypes through chemical methodology and library development.

In an effort to expand the stereochemical and structural complexity of chemical libraries used in drug discovery, the Center for Chemical Methodology and Library Development at Boston University has established an infrastructure to translate methodologies accessing diverse chemotypes into arrayed libraries for biological evaluation. In a collaborative effort, the NIH Chemical Genomics Center determined IC50’s for Plasmodium falciparum viability for each of 2,070 members of the CMLD-BU compound collection using quantitative high-throughput screening across five parasite lines of distinct geographic origin. Three compound classes displaying either differential or comprehensive antimalarial activity across the lines were identified, and the nascent structure activity relationships (SAR) from this experiment used to initiate optimization of these chemotypes for further development.

Cycloadditions of chiral anthracenes: effect of the trifluoromethyl group ☆

Abstract Chiral anthracene template, 10-methyl-9-(1-methoxy-2,2,2-trifluoroethyl)anthracene undergoes highly diastereoselective cycloadditions with maleic anhydride and 5-acetoxy-2(5 H )-furanone. Subsequent regioselective and stereoselective manipulations demonstrate the synthetic utility in conversions to enantioenriched butenolides, and elucidate the origin of diastereoselection.

Selective oxidation of canthines to canthin-6-ones with triethylbenzylammonium permanganate

Abstract Oxidation of canthines, prepared from intramolecular inverse electron demand Diels-Alder reactions of indole with tethered triazines, produced the corresponding canthin-6-ones regiospecifically, with no detected canthin-4-ones.

A facile preparation of pyrrolo[3,4-b]indoles

Abstract Reductive ring contraction of dimethyl 5 H -pyridazino[4,5-b]indole-1,4-dicarboxylate produced dimethyl 2,4-dihydropyrrolo[3,4-b]indole-1,3-dicarboxylate.