Direct dehydrative N-Pyridinylation of amides, the interrupted Bischler-Napieralski reaction, and the enantioselective total synthesis and arylative dimerization of aspidosperma alkaloids

Thesis (Ph. D. in Organic Chemistry)--Massachusetts Institute of Technology, Dept. of Chemistry, 2013.Cataloged from PDF version of thesis. Vita.Includes bibliographical references.I. Direct Dehydrative N-Pyridinylation of Amides A method for the single-step N-pyridinylation of secondary amides is described. The process involves electrophilic activation of secondary amides with trifluoromethanesulfonic anhydride in the presence of 2-fluoropyridine followed by introduction of a pyridine N-oxide derivative and warming to afford the corresponding N-pyridinyl tertiary amide derivatives. The structure of activated amide intermediates is probed through in situ monitoring, and a mechanism supported by in situ monitoring and deuterium labeling experiments is discussed. II. Synthesis of Spirocyclic Indolines by Interruption of the Bischler-Napieralski Reaction The development of a versatile method for the synthesis of spirocyclic pyrrolidinoindolines is described. Treatment of N-acyltryptamines with trifluoromethanesulfonic anhydride-2-chloropyridine reagent combination affords highly persistent spiroindoleninium ions, which are selectively trapped intra- and intermolecularly by various nucleophiles. III. A Concise and Versatile Double-Cyclization Strategy for the Highly Stereoselective Synthesis and Novel Arylative Dimerization of Aspidosperma Alkaloids A strategy for the concise, stereoselective synthesis of aspidosperma alkaloids and related structures via a common putative diiminium ion intermediate is described. The approach enables the dimerization of aspidosperma-type structures at the sterically hindered C2-position. The diiminium intermediate is prepared in situ from an enantioenriched [alpha]-quaternary 2- chlorotryptamine lactam through a stereoselective electrophilic double-cyclization cascade. The key C5-quaternary stereocenter is secured via successive diastereoselective [alpha]-alkylations of pseudoephenamine crotonamide.by Jonathan William Medley.Ph.D.in Organic Chemistr

Introductory programming: a systematic literature review

As computing becomes a mainstream discipline embedded in the school curriculum and acts as an enabler for an increasing range of academic disciplines in higher education, the literature on introductory programming is growing. Although there have been several reviews that focus on specific aspects of introductory programming, there has been no broad overview of the literature exploring recent trends across the breadth of introductory programming. This paper is the report of an ITiCSE working group that conducted a systematic review in order to gain an overview of the introductory programming literature. Partitioning the literature into papers addressing the student, teaching, the curriculum, and assessment, we explore trends, highlight advances in knowledge over the past 15 years, and indicate possible directions for future research

Biomass production of herbaceous energy crops in the United States: field trial results and yield potential maps from the multiyear regional feedstock partnership

Current knowledge of yield potential and best agronomic management practices for perennial bioenergy grasses is primarily derived from small-scale and short-term studies, yet these studies inform policy at the national scale. In an effort to learn more about how bioenergy grasses perform across multiple locations and years, the U.S. Department of Energy (US DOE)/Sun Grant Initiative Regional Feedstock Partnership was initiated in 2008. The objectives of the Feedstock Partnership were to (1) provide a wide range of information for feedstock selection (species choice) and management practice options for a variety of regions and (2) develop national maps of potential feedstock yield for each of the herbaceous species evaluated. The Feedstock Partnership expands our previous understanding of the bioenergy potential of switchgrass, Miscanthus, sorghum, energycane, and prairie mixtures on Conservation Reserve Program land by conducting long-term, replicated trials of each species at diverse environments in the U.S. Trials were initiated between 2008 and 2010 and completed between 2012 and 2015 depending on species. Field-scale plots were utilized for switchgrass and Conservation Reserve Program trials to use traditional agricultural machinery. This is important as we know that the smaller scale studies often overestimated yield potential of some of these species. Insufficient vegetative propagules of energycane and Miscanthus prohibited farm-scale trials of these species. The Feedstock Partnership studies also confirmed that environmental differences across years and across sites had a large impact on biomass production. Nitrogen application had variable effects across feedstocks, but some nitrogen fertilizer generally had a positive effect. National yield potential maps were developed using PRISM-ELM for each species in the Feedstock Partnership. This manuscript, with the accompanying supplemental data, will be useful in making decisions about feedstock selection as well as agronomic practices across a wide region of the country

Synthesis of Spirocyclic Indolines by Interruption of the Bischler–Napieralski Reaction

The development of a versatile method for the synthesis of spirocyclic pyrrolidinoindolines is discussed. Treatment of N-acyltryptamines with trifluoromethanesulfonic anhydride–2-chloropyridine reagent combination affords highly persistent spiroindoleninium ions that are subject to intra- and intermolecular addition at C2 by nucleophiles.National Institute of General Medical Sciences (U.S.) (GM074825)Camille & Henry Dreyfus Foundation. Teacher-Scholar Awards ProgramUnited States. Dept. of Defense (National Defense Science and Engineering Graduate (NDSEG) Fellowships

Concise and Enantioselective Total Synthesis of (−)-Mehranine, (−)-Methylenebismehranine, and Related

We report an efficient and highly stereoselective strategy for the synthesis of Aspidosperma alkaloids based on the transannular cyclization of a chiral lactam precursor. Three new stereocenters are formed in this key step with excellent diastereoselectivity due to the conformational bias of the cyclization precursor, leading to a versatile pentacyclic intermediate. A subsequent stereoselective epoxidation followed by a mild formamide reduction enabled the first total synthesis of the Aspidosperma alkaloids (−)-mehranine and (+)-(6S,7S)-dihydroxy-N-methylaspidospermidine. A late-stage dimerization of (−)-mehranine mediated by scandium trifluoromethanesulfonate completed the first total synthesis of (−)-methylenebismehranine.National Institute of General Medical Sciences (U.S.) (GM074825

Direct Synthesis of Azaheterocycles from N-Aryl/Vinyl Amides. Synthesis of 4-(Methylthio)-2-phenylquinazoline and 4-(4-Methoxyphenyl)-2-phenylquinoline

A flame-dried, 300-mL three-necked round-bottomed flask equipped with a 3.0 cm footballshaped stir bar, rubber septum, and low temperature thermometer is charged with benzanilide (1) (Note 1) (6.02 g, 30.5 mmol, 1 equiv), sealed under an argon atmosphere, and fitted with an argon inlet. Anhydrous dichloromethane (Note 2) (60 mL) followed by 2-chloropyridine (Note 3) (5.76 mL, 6.97 g, 61.4 mmol, 2.01 equiv) is added via syringe, and the heterogeneous mixture is vigorously stirred and cooled to <−70 °C (dry-ice–acetone bath, internal temperature). After 10 min, trifluoromethanesulfonic anhydride (Note 4) (Tf[subscript 2]O, 5.60 mL, 9.39 g, 33.3 mmol, 1.09 equiv) is added via syringe over 5 min at <−65 °C (internal temperature). After 15 min, the reaction flask is warmed to 0 °C (ice–water bath). After 5 min, the deep red solution becomes homogeneous and a solution of thiocyanic acid methyl ester (2) (Note 1) (2.52 mL, 2.67 g, 36.5 mmol, 1.20 equiv) in anhydrous dichloromethane (40 mL) is added via cannula over 5 min at 5–6 °C (Note 5). After 10 min, the cold bath is removed, and the reaction mixture is allowed to warm to 23 °C. After 2.5 h, triethylamine (Note 2) (10.0 mL, 7.26 g, 71.7 mmol, 2.35 equiv) is added via syringe over one min. The resulting mixture is concentrated with a rotary evaporator (20 mmHg, 30 °C). The remaining deep red oil is purified by flash column chromatography (Note 6) to afford quinazoline 3 (6.15 g, 80%) as an off-white solid (Note 7).National Institute of General Medical Sciences (U.S.

Catalytic, Diastereoselective 1,2-Difluorination of Alkenes

We describe a direct, catalytic approach to the 1,2-difluorination of alkenes. The method utilizes a nucleophilic fluoride source and an oxidant in conjunction with an aryl iodide catalyst and is applicable to alkenes with all types of substitution patterns. In general, the vicinal difluoride products are produced with high diastereoselectivities. The observed sense of stereoinduction implicates anchimeric assistance pathways in reactions of alkenes bearing neighboring Lewis basic functionality