A novel iminium ion cascade reaction has been developed that allows for the stereoselective synthesis of a variety of substituted aza-fused bicycles. The combination of amino allylsilanes and aldehydes (or ketones) was used to synthesize a number of quinolizidines and indolizidines in an one-pot reaction sequence. This technology has been used to effect the facile syntheses of several indolizidine and quinolizidine natural products including, (±)-epilupinine, (±)-tashiromine, and (−)-epimyrtine. Substrate scope has been examined varying the type of amino allylsilanes (primary, secondary and conjugated) and carbonyl compounds (aldehydes and ketones) to give a variety of fused ring structures. Varying the components chosen allows for the inclusion of synthetically useful functional groups at different positions on the core structure. The methodology has been used to construct the tricyclic core structures present in the cylindricine family and halichlorine.
Several novel cascade processes have been designed and developed that involve sequential reactions of imines and iminium ions to form substituted quinolizidine ring systems in a single step from simple and readily available starting materials. The utility and promise of these cascade reactions is evident from their application to extraordinarily concise syntheses of the representative quinolizidine alkaloids (+/-)-epilupinine and (-)-epimyrtine.
The addition of research-focused experiences to undergraduate chemistry laboratory courses has been shown to bolster student learning, enhance student retention in STEM, and improve student self-identity as scientists. In the area of synthetic organic chemistry, the preparation of libraries of compounds with novel optical and electronic properties can provide a natural motivational goal for research-focused exercises that can be undertaken by individual students or collectively as a class. However, integrating such experiences into a community college teaching laboratory setting can face challenges imposed by the cost of supplies, limited laboratory space, and access to characterization facilities. To address these challenges, we have devised a sequence of inquiry-driven, research-focused laboratory exercises that can be readily integrated into an organic chemistry laboratory course with minimal cost. This sequence consists of a multistep synthesis of perylenediimide dyes that introduces students to advanced synthetic techniques, such as organometallic coupling reactions, column purification, and reactions performed under inert atmosphere. This high-yield, three-part synthesis can be easily varied by individual students or small groups within a class to form a broad library of compounds with potential utility for applications in light harvesting, molecular electronics, catalysis, and medicine. We describe the design of low-cost workstations for chemical synthesis under inert atmosphere and provide auxiliary lesson plans that can be used to expand the scope of a laboratory course beyond synthetic organic chemistry by introducing students to concepts in molecular spectroscopy.
EXPERIMENTAL PROCEDURESGeneral. Unless otherwise indicated, all starting materials and solvents were obtained from commercial suppliers and used without further purification. Tetrahydofuran (THF) and diethyl ether (Et 2 O) were dried by passage through two columns of activated neutral alumina, acetonitrile (CH 3 CN) was dried by passage through two columns of activated molecular sieves, and methylene chloride (CH 2 Cl 2 ) was distilled from calcium hydride. All solvents contained less than 50 ppm H 2 O by Karl Fisher coulometric moisture analysis. Reactions involving air-or moisture-sensitive reagents or intermediates were performed in flame-dried glassware under an atmosphere of dry nitrogen or argon. Flash chromatography was performed following the Still 1 protocol with ICN Biomedical ICN-SILITech 32-63d silica gel with the indicated solvents. Proton ( 1 H) and carbon ( 13 C) NMR spectra were obtained using a Varian Unity Plus (400 MHZ) or Varian Unity Plus (500MHz) spectrometer as solutions in CD 3 CN unless otherwise noted. Chemical shifts are reported as parts per million (ppm, δ) and referenced to the residual protic solvent unless otherwise noted. Coupling constants are reported in hertz (Hz).
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