Part 3. A Novel Stereocontrolled, In Situ, Solution- and Solid-Phase, Aza Michael Approach for High-Throughput Generation of Tetrahydroaminoquinoline-Derived Natural-Product-like Architectures

With the goal of rapidly accessing tetrahydroquinoline-based natural-product-like polycyclic architectures, herein, we report an unprecedented, in situ, stereocontrolled Aza Michael approach in solution and on the solid phase. The mild reaction conditions required to reach the desired target are highly attractive for the use of this method in library generation. To our knowledge, this approach has not been used before, and it opens a novel route leading to a wide variety of tetrahydroquinoline-derived bridged tricyclic derivatives.NRC publication: Ye

Part 1. Modular Approach to Obtaining Diverse Tetrahydroquinoline-Derived Polycyclic Skeletons for Use in High-Throughput Generation of Natural-Product-like Chemical Probes

A practical synthesis of a tetrahydroaminoquinoline scaffold (12) was developed that used a stereocontrolled aza Michael as the key reaction. Three tetrahydroquinoline alkaloid-like, tricyclic derivatives 16, 18, and 19 with different medium to macrocyclic ring skeletons were obtained, using this scaffold as the starting material, in a modular manner. The macrocyclic compounds with an isolated olefin and an electron-deficient olefin were obtained by ring-closing metathesis approaches. Compounds 16 and 18 are unique and contain bridged 10- and 12-membered functionalized rings. The NMR studies of these compounds revealed interesting information on the conformation of the bicyclic scaffolds that was dependent on the nature and the size of the macrocyclic rings. Finally, this modular methodology, using compound 21 anchored onto the solid support, successfully led to the generation of different macrocyclic derivatives, 23, 25, and 27 in solid-phase synthesis. The solid-phase synthesis approach outlined in this article has the potential to generate tetrahydroquinolinebased tricyclic compounds containing different medium to macrocyclic architectures.NRC publication: Ye

Identifying Tightly Regulated and Variably Expressed Networks by Differential Rank Conservation (DIRAC)

A powerful way to separate signal from noise in biology is to convert the molecular data from individual genes or proteins into an analysis of comparative biological network behaviors. One of the limitations of previous network analyses is that they do not take into account the combinatorial nature of gene interactions within the network. We report here a new technique, Differential Rank Conservation (DIRAC), which permits one to assess these combinatorial interactions to quantify various biological pathways or networks in a comparative sense, and to determine how they change in different individuals experiencing the same disease process. This approach is based on the relative expression values of participating genes—i.e., the ordering of expression within network profiles. DIRAC provides quantitative measures of how network rankings differ either among networks for a selected phenotype or among phenotypes for a selected network. We examined disease phenotypes including cancer subtypes and neurological disorders and identified networks that are tightly regulated, as defined by high conservation of transcript ordering. Interestingly, we observed a strong trend to looser network regulation in more malignant phenotypes and later stages of disease. At a sample level, DIRAC can detect a change in ranking between phenotypes for any selected network. Variably expressed networks represent statistically robust differences between disease states and serve as signatures for accurate molecular classification, validating the information about expression patterns captured by DIRAC. Importantly, DIRAC can be applied not only to transcriptomic data, but to any ordinal data type

Structural investigation of bacterial capsular polysaccharides

Eighty strains of Klebsiella bacteria have been isolated and serotyped according to their capsular polysaccharide antigens (K antigens). A number of research groups have taken part in an extensive program to determine the chemical structures of these polysaccharide antigens. As part of this continuing program, this thesis includes a structural investigation of the capsular polysaccharide of Klebsiella κ39 An acidic capsular polysaccharide was isolated from Klebsiella κ39 and a partial hydrolysis study was conducted. An acidic pentasaccharide was isolated from the hydrolysate and studied by ¹H- and ¹³C-n.m.r., mass spectrometry and methylation analyses. This oligosaccharide was assigned the following structure: [See thesis for equation]. The relationship of this oligosaccharide to the polysaccharide will be discussed with reference to n.m.r. and methylation analysis studies. Similar studies are being conducted to determine the structures of the E.coli capsular polysaccharide antigens. This thesis includes a preliminary study of E.coli κ26.Science, Faculty ofChemistry, Department ofGraduat

In-situ observation of nucleation and growth of PbSe magic-sized nanoclusters and regular nanocrystals

In-situ observation of the temporal evolution of the absorption of PbSe nanocrystals (NCs) via a low-temperature noninjection approach is presented. Based on a model reaction of lead oleate (Pb(OA)2) and n-trioctylphosphine selenide (TOPSe) in 1-octadecene at 35\u201380 \ub0C, the use of commercially available TOP (90 or 97%) in affecting the formation of the NCs is explored. TOPSe solutions made from TOP 90% exhibited higher reactivity than those made from TOP 97%. 31P NMR spectroscopy detected no dioctylphosphine selenide (DOPSe) but some DOP in 481.0 M TOPSe/TOP solution (made from TOP 90%), as well as no diphenylphosphine selenide (DPPSe) when DPP was added to the 481.0 M solution. Hence, it is proposed that, for the formation of PbSe monomers, an indirect pathway dominates with the formation of a Pb\u2013P complex/intermediate, which results from the activation of Pb(OA)2 by a phosphine compound (such as DPP, DOP, or TOP) and in turn reacts with TOPSe. With the use of TOP 90% and the addition of secondary phosphine DPP, the formation of PbSe magic-sized nanoclusters (MSNCs) and regular NCs (RNCs) is investigated. With proper tuning of the synthesis conditions, the formation of various PbSe MSNCs versus RNCs is monitored in situ with versus without the addition of DPP, or at different reaction temperatures but otherwise identical synthetic formulation and reaction parameters. Accordingly, the degree of supersaturation (DS) of the PbSe monomer affecting the development of these PbSe MSNCs versus RNCs is proposed; the higher the DS, the more the MSNCs are favored. Also, surface-determined cluster\u2013cluster aggregation is proposed to be the growth mechanism for both the RNCs and MSNCs. For the former, quantized growth is followed by continuous growth. For the latter, the sizes of the magic-sized families are calculated.Peer reviewed: YesNRC publication: Ye

Effect of clathrate hydrate formation and decomposition on NMR parameters in THF\u2013D2O Solution

The NMR spin\u2013lattice relaxation time (T1), spin\u2013spin relaxation time (T2) and the diffusion coefficient D were measured for 1H in a 1:17 mol % solution of tetrahydrofuran (THF) in D2O. The aim of the work was to clarify some earlier points raised regarding the utility of these measurements to convey structural information on hydrate formation and reformation. A number of irregularities in T1 and T2 measurements during hydrate processes reported earlier are explained in terms of the presence of interfaces and possible temperature gradients. We observe that T1 and T2 in solution are exactly the same before and after hydrate formation, thus confirming that the solution is isotropic. This is inconsistent with the presence of memory effects, at least those that may affect the dynamics to which T1 and T2 are sensitive. The measurement of the diffusion coefficient for a number of hours in the subcooled solution before nucleation proved invariant with time, again suggesting that the solution remains isotropic without affecting the guest dynamics and diffusion.Peer reviewed: YesNRC publication: Ye

Stereoselective Diversity-Oriented Solution and Solid-Phase Synthesis of Tetrahydroquinoline-Based Polycyclic Derivatives

A diversity-oriented solution and solid-phase synthesis of tetrahydroquinoline-based tricyclic derivatives has been achieved from enantiomerically pure, natural product-like bicyclic scaffold. The solution synthesis of enantiopure bicyclic scaffold was developed by asymmetric hetero Michael reaction. Our approach for the synthesis of polycyclic derivatives utilized regio- and stereoselective hetero Michael reaction and ringclosing metathesis as key steps in solution and on solid phase.NRC publication: Ye

Part 2: Building Diverse Natural-Product-Like Architectures from a Tetrahydroaminoquinoline Scaffold. Modular Solution- and Solid-Phase Approaches for Use in High-Throughput Generation of Chemical Probes

The solution- and solid-phase synthesis to obtain several natural-product-like, tetrahydroquinoline-based, polycyclic derivatives were developed. In one approach, two derivatives (38 and 41) having an eight-membered unsaturated lactam were successfully obtained both in solution and on solid support.NRC publication: Ye