Stereoselective synthesis of piperidines

EDITED ABSTRACT. This thesis is divided into two parts. The first part describes the production of a small stereodiverse library of 2-substituted piperidines. Novel chiral titanium alkylidene reagents ii alkylidenated resin-bound esters i to give acid-labile resin-bound enol ethers iii. These were cleaved to give amino ketones iv. The switch in the nature of the resin from acid-stable to acid-labile is key to the purity of the amino ketones iv, as during cleavage only the acid-sensitive enol ethers iii are cleaved, leaving the unreacted esters i on the resin. The amino ketonse iv were cyclized using TMSC1 to give cyclic iminium salts v. Diastereoselective reduction of the iminium salts v with NaBH(OAc)[sub]3 gave piperidines vi which, after cleavage of the chiral protecting group gave the desired enantiomerically-enriched, 2-substituted piperidines vii. [Illustrated] The piperidines vii were produced in good overall yield, high purity, and good to excellent stereochemical purity. By switching the enantiomer of the phenylethylamine chiral protecting group used, either enantiomer of the desired piperidine could be produced at will. The second part of the thesis describes a solution-phase route to 2,6-syn substituted piperidin-4-ones xii inspired by the Petasis-Ferrier rearrangement. Imino esters x derived from [Beta]-amino acids viii were methylenated using the Petasis reagent, dimethyltitanoce, to give imino enol ethers xi containing nucleophilic and electrophilic functionality in the same molecule. The mild microwave conditions used for the methylenation geve the enol ethers xi in minutes. Potentially, the reaction takes advantage of selective heating of the polar Petasis reagent in a non polar solvent system so that the rate determining decomposition of the Petasis reagent is accelerated without affecting any sensitive substrate. Acidic conditions activated the imine and induced cyclization to give the desired 2,6-syn piperidin-4-ones xii in good yield and excellent diastereoselectivity. A small library of piperidinones was produced to demonstrate the method. [Illustrated

The Quasi-Verbal Dispute Between Kripke and 'Frege-Russell'

Traditional descriptivism and Kripkean causalism are standardly interpreted as rival theories on a single topic. I argue that there is no such shared topic, i.e. that there is no question that they can be interpreted as giving rival answers to. The only way to make sense of the commitment to epistemic transparency that characterizes traditional descriptivism is to interpret Russell and Frege as proposing rival accounts of how to characterize a subject’s beliefs about what names refer to. My argument relies on a development of the distinction between speaker’s reference and semantic reference

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity.

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Evaluating the Effects of SARS-CoV-2 Spike Mutation D614G on Transmissibility and Pathogenicity

Global dispersal and increasing frequency of the SARS-CoV-2 spike protein variant D614G are suggestive of a selective advantage but may also be due to a random founder effect. We investigate the hypothesis for positive selection of spike D614G in the United Kingdom using more than 25,000 whole genome SARS-CoV-2 sequences. Despite the availability of a large dataset, well represented by both spike 614 variants, not all approaches showed a conclusive signal of positive selection. Population genetic analysis indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We do not find any indication that patients infected with the spike 614G variant have higher COVID-19 mortality or clinical severity, but 614G is associated with higher viral load and younger age of patients. Significant differences in growth and size of 614G phylogenetic clusters indicate a need for continued study of this variant

Polyurethanes and polyallophanates via sequence-selective copolymerization of epoxides and isocyanates

Aryl isocyanates are introduced as comonomers for ring-opening copolymerization (ROCOP) with epoxides. Informed by studies of reaction kinetics, we show that divergent sequence selectivity for AB- and ABB-type copolymers can be achieved with a single dimagnesium catalyst. The resulting materials respectively constitute a new class of polyurethanes (PUs) and a new class of materials featuring an unprecedented backbone structure, the polyallophanates (PAs). The successful use of isocyanate comonomers in this way marks a new direction for the field of ROCOP while providing distinct opportunities for expansion of PU structural diversity. Specifically, the methodology reported herein delivers PUs featuring fully substituted (tertiary) carbamyl nitrogen atoms, a structural motif that is almost inaccessible via extant polymerization strategies. Thus, in one step from commercially available comonomers, our methodology expands the scope of ROCOP and gives access to diverse materials featuring both privileged (PU) and unexplored (PA) microstructures.Aryl isocyanates are introduced as comonomers for ring-opening copolymerization (ROCOP) with epoxides. Informed by studies of reaction kinetics, we show that divergent sequence selectivity for AB- and ABB-type copolymers can be achieved with a single dimagnesium catalyst. The resulting materials respectively constitute a new class of polyurethanes (PUs) and a new class of materials featuring an unprecedented backbone structure, the polyallophanates (PAs). The successful use of isocyanate comonomers in this way marks a new direction for the field of ROCOP while providing distinct opportunities for expansion of PU structural diversity. Specifically, the methodology reported herein delivers PUs featuring fully substituted (tertiary) carbamyl nitrogen atoms, a structural motif that is almost inaccessible via extant polymerization strategies. Thus, in one step from commercially available comonomers, our methodology expands the scope of ROCOP and gives access to diverse materials featuring both privileged (PU) and unexplored (PA) microstructures

Quantification of Nitrate−π Interactions and Selective Transport of Nitrate Using Calix[4]pyrroles with Two Aromatic Walls

Herein we disclose the results of our investigations regarding the interactions between the biologically relevant nitrate oxoanion and several “two-wall” aryl-extended calix[4]pyrroles. There exists a clear relationship between the electronic nature of the aromatic walls of the calix[4]pyrroles and the stability of the nitratecalix[4]pyrrole complex. This suggests that NO3––π interactions have an important electrostatic component. We provide energetic estimates for the interaction of nitrate with several phenyl derivatives. Additionally, we report solid-state evidence for a preferred binding geometry of the nitrate anion included in the calix[4]pyrroles. Finally, the “two-wall” aryl-extended calix[4]pyrroles show excellent activity in ion transport through lipid-based lamellar membranes. Notably the best anion transporters are highly selective for transport of nitrate over other anions

One-Pot Conversion of Benzyl Alcohols to N-Protected Anilines and Alkyl Alcohols to Carbamoyl Azides

One-pot, scalable procedures converting benzylic or aliphatic alcohols to various N-functionalized amines are reported in 38-83% overall yields. These multi-step conversions are relatively economic and involve the oxidative formation of acid chloride intermediates and the Curtius rearrangement of acyl azides. Notable aspects of economy include: (1) the use of a relatively green solvent (chlorobenzene) that tolerates both ionic and radical reactions, without the need for rigorously dry or O2-free conditions; (2) the use of minimal amounts of trichloroisocyanuric acid (TCCA) as a cheap and green chlorinating agent to oxidize the alcohol starting materials and then transform the aldehyde intermediates to acid chlorides under photoirradiation for azide addition; (3) the efficient capture of isocyanate intermediates by alcohol or azide nucleophiles providing N-protected anilines or N-protected alkylamines, respectively, the latter of which was employed in the synthesis of an anti-dementia drug, memantine hydrochloride, over two purification steps

Bio-and air-tolerant carbon-carbon bond formations via organometallic ruthenium catalysis

Selected 2+2+2 cycloadditions, alkene-alkyne coupling and fusion of enyne with diazo compound, all triggered by an artificial organometallic ruthenium catalyst are demonstrated to proceed under ambient aerobic aqueous conditions in presence of bodily fluids or cell lysate. To the best of our knowledge, these are the first examples of bio-and air-tolerant C-C bond formation catalyzed by an artificial organometallic compound. © 2009 Institute of Organic Chemistry and Biochemistry

Thermodynamic characterization of halide−π interactions in solution using “two-wall” aryl extended calix[4]pyrroles as model system

Herein, we report our latest experimental investigations of halide−π interactions in solution. We base this research on the thermodynamic characterization of a series of 1:1 complexes formed between halides (Cl–, Br–, and I–) and several α,α-isomers of “two-wall” calix[4]pyrrole receptors bearing two six-membered aromatic rings in opposed meso positions. The installed aromatic systems feature a broad range of electron density as indicated by the calculated values for their electrostatic surface potentials at the center of the rings. We show that a correlation exists between the electronic nature of the aromatic walls and the thermodynamic stability of the X–⊂receptor complexes. We give evidence for the existence of both repulsive and attractive interactions between π systems and halide anions in solution (between 1 and −1 kcal/mol). We dissect the measured free energies of binding for chloride and bromide with the receptor series into their enthalpic and entropic thermodynamic quantities. In acetonitrile solution, the binding enthalpy values remain almost constant throughout the receptor series, and the differences in free energies are provoked exclusively by changes in the entropic term of the binding processes. Most likely, this unexpected behavior is owed to strong solvation effects that make up important components of the measured magnitudes for the enthalpies and entropies of binding. The use of chloroform, a much less polar solvent, limits the impact of solvation effects revealing the expected existence of a parallel trend between free energies and enthalpies of binding. This result indicates that halide−π interactions in organic solvents are mainly driven by enthalpy. However, the typical paradigm of enthalpy–entropy compensation is still not observed in this less polar solvent

CCDC 1002696: Experimental Crystal Structure Determination

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures