Site- and Enantioselective C-C and C-B Bond Forming Reactions Catalyzed by Cu-, Mg-, Zn-, or Al-based N-Heterocyclic Carbene Complexes

Thesis advisor: Amir H. HoveydaChapter 1. In this chapter, the ability of chiral bidentate N-heterocyclic carbenes (NHCs) to activate alkylmetal reagents directly in order to promote C&#8210;C bond forming reactions in the absence of a Cu salt is presented. Highly regio- and enantioselective Cu-free allylic alkylation reactions of di- and trisubstituted allylic substrates with organomagnesium, organozinc, and organoaluminum reagents are demonstrated. Chiral bidentate sulfonate-bearing NHC-Zn and NHC-Al complexes are isolated and fully characterized. Based on crystal structures of these catalytic complexes, mechanistic details regarding Cu-free allylic alkylations with alkylmetal reagents are proposed. Chapter 2. New methods for efficient and highly enantioselective Cu-catalyzed allylic alkylation reactions of a variety of trisubstituted allylic substrates with alkylmagnesium and alkyl-, aryl-, 2-furyl-, and 2-thiophenylaluminum reagents are presented. Transformations are promoted by a chiral NHC complex in the presence of commercially available, inexpensive and air stable CuCl2*H2O. Enantiomerically enriched compounds containing difficult-to-access all-carbon quaternary stereogenic centers are obtained. Chapter 3. New methods for highly site- and enantioselective Cu-catalyzed allylic alkylation reactions of allylic phosphates with vinylaluminum reagents are presented. The requisite vinylaluminums are prepared by reaction of readily accessible terminal alkynes with DIBAL-H and used directly without further purification. Vinyl additions are promoted in the presence of a chiral bidentate sulfonate-based NHC complex and a Cu salt. The desired SN2' products are obtained in >98% E selectivities, >98% SN2' selectivities, >98% group selectivities (<2% i-Bu addition) and high enantioselectivities. The enantioselective total synthesis of the natural product bakuchiol highlights the versatility of the one-pot hydroalumination/Cu-catalyzed enantioselective allylic vinylation process. Chapter 4. Efficient and highly site-selective Cu-catalyzed hydroboration reactions of 1,2-disubstituted aryl olefins with bis(pinacolato)diboron (B2(pin)2) are presented. Transformations are promoted by an NHC-Cu complex in the presence of MeOH, affording only secondary &#946;-boronate isomers. A Cu-catalyzed method for the synthesis of enantiomerically enriched secondary alkylboronates promoted by chiral NHC complexes is disclosed. Chapter 5. A new method for efficient and site-selective tandem Cu-catalyzed copper-boron additions to terminal alkynes with B2(pin)2 in the presence of an NHC-Cu complex is demonstrated. In a one-pot process, Cu-catalyzed hydroboration of alkynes provides vinylboronates in situ, which undergo a second site-selective hydroboration to afford vicinal diboronates. Highly Enantiomerically enriched diboronates obtained through Cu-catalyzed enantioselective dihydroboration in the presence of chiral bidentate sulfonate-based NHC-Cu complex are obtained. The control of site selectivity in the first-stage hydroboration of alkynes is critical for efficient and highly enantioselective reactions in the tandem dihydroboration. Functionalizations of the vicinal diboronates described herein underline the significance of the current method.Thesis (PhD) — Boston College, 2010.Submitted to: Boston College. Graduate School of Arts and Sciences.Discipline: Chemistry

Thiourea-Catalyzed Enantioselective Iso-Pictet-Spengler Reactions

A one-pot condensation of isotryptamines and aldehydes that affords enantiomerically enriched 4-substituted tetrahydro-$\gamma$-carbolines is reported. The reaction is induced by a chiral thiourea/benzoic acid dual catalyst system. Purification of the N-Boc-protected products by trituration or crystallization provides the optically pure tetrahydro-$\gamma$-carboline derivatives in a scalable and highly practical procedure.Chemistry and Chemical Biolog

Enantioselective Nucleophile-Catalyzed Synthesis of Tertiary Alkyl Fluorides via the α‑Fluorination of Ketenes: Synthetic and Mechanistic Studies

The catalytic asymmetric synthesis of alkyl fluorides, particularly α-fluorocarbonyl compounds, has been the focus of substantial effort in recent years. While significant progress has been described in the formation of enantioenriched secondary alkyl fluorides, advances in the generation of tertiary alkyl fluorides have been more limited. Here, we describe a method for the catalytic asymmetric coupling of aryl alkyl ketenes with commercially available N-fluorodibenzenesulfonimide (NFSI) and C_6F_5ONa to furnish tertiary α-fluoroesters. Mechanistic studies are consistent with the hypothesis that the addition of an external nucleophile (C_6F_5ONa) is critical for turnover, releasing the catalyst (PPY*) from an N-acylated intermediate. The available data can be explained by a reaction pathway wherein the enantioselectivity is determined in the turnover-limiting transfer of fluorine from NFSI to a chiral enolate derived from the addition of PPY* to the ketene. The structure and the reactivity of the product of this proposed elementary step, an α-fluoro-N-acylpyridinium salt, have been examined

Association between registered nurse staffing levels and in-hospital mortality in craniotomy patients using Korean National Health Insurance data

The level of registered nurse (RN) staffing is a fundamental factor influencing patient safety. Craniotomy patients need intensive care after surgery, the majority of which is provided by RNs. This study was conducted to investigate the relationship of the RN staffing level of general wards and intensive care units (ICUs) with in-hospital mortality after craniotomy using Korean National Health Insurance claim data. The RN staffing level was categorized based on the bed-to-RN ratio. The in-hospital mortality rate of craniotomy patients was elevated at hospitals with a high bed-to-RN ratio in general wards, ICUs, and hospitals overall. It was determined that in-hospital mortality of craniotomy patients could be decreased by more than 50% by reducing the bed-to-RN ratio from 4.5 or more to less than 3.5 in general wards, from 1.25 or more to less than 0.88 in ICUs, and from 2.5 or more to less than 1.67 in hospitals overall. Since the RN staffing level is related to the in-hospital mortality rate of craniotomy patients, a sufficient staffing level of RNs should be ensured to reduce the mortality of craniotomy patients.This study was supported by the Basic Science Research Program through National Research Foundation of Korea (NRF) funded by the Ministry of Education in 2017 (grant number: 2017R1D1A1B03033771). The funder was not involved in conducting this study and did not play any role in the design of the study, the collection, analysis, and writing of the manuscript

Phosphine-Catalyzed Enantioselective Intramolecular [3+2] Annulations To Generate Fused Ring Systems

Substantial progress has been described in the development of asymmetric variants of the phosphine-catalyzed intermolecular [3+2] annulation of allenes with alkenes; however, there have not been corresponding advances for the intramolecular process, which can generate a higher level of complexity (an additional ring and stereocenter(s)). In this study, we describe the application of chiral phosphepine catalysts to address this challenge, thereby providing access to useful scaffolds that are found in bioactive compounds, including diquinane and quinolin-2-one derivatives, with very good stereoselectivity. The products of the [3+2] annulation can be readily transformed into structures that are even more stereochemically rich. Mechanistic studies are consistent with β addition of the phosphepine to the allene being the turnover-limiting step of the catalytic cycle, followed by a concerted [3+2] cycloaddition to the pendant olefin

Nonenzymatic Dynamic Kinetic Resolution of Secondary Alcohols via Enantioselective Acylation: Synthetic and Mechanistic Studies

Because of the ubiquity of the secondary carbinol subunit, the development of new methods for its enantioselective synthesis remains an important ongoing challenge. In this report, we describe the first nonenzymatic method for the dynamic kinetic resolution (DKR) of secondary alcohols (specifically, aryl alkyl carbinols) through enantioselective acylation, and we substantially expand the scope of this approach, vis-à-vis enzymatic reactions. Simply combining an effective process for the kinetic resolution of alcohols with an active catalyst for the racemization of alcohols did not lead to DKR, due to the incompatibility of the ruthenium-based racemization catalyst with the acylating agent (Ac_2O) used in the kinetic resolution. A mechanistic investigation revealed that the ruthenium catalyst is deactivated through the formation of a stable ruthenium–acetate complex; this deleterious pathway was circumvented through the appropriate choice of acylating agent (an acyl carbonate). Mechanistic studies of this new process point to reversible N-acylation of the nucleophilic catalyst, acyl transfer from the catalyst to the alcohol as the rate-determining step, and carbonate anion serving as the Brønsted base in that acyl-transfer step

Physicochemical factors that affect electroporation of lung cancer and normal cell lines

Electroporation is used for cancer therapy to efficiently destroy cancer tissues by transferring anticancer drugs into cancer cells or by irreversible tumor ablation without resealing pores. There is growing interest in the electroporation method for the treatment of lung cancer, which has the highest mortality rate among cancers. Improving the cancer cell selectivity has the potential to expand its use. However, the factors that influence the cell selectivity of electroporation are debatable. We aimed to identify the important factors that influence the efficiency of electroporation in lung cells. The electropermeabilization of lung cancer cells (H460, A549, and HCC1588) and normal lung cells (MRCS, WI26 and L132) was evaluated by the transfer of fluorescence dyes. We found that membrane permeabilization increased as cell size, membrane stiffness, resting transmembrane potential, and lipid cholesterol ratio increased. Among them, lipid composition was found to be the most relevant factor in the electroporation of lung cells. Our results provide insight into the differences between lung cancer cells and normal lung cells and provide a basis for enhancing the sensitivity of lung cancers cells to electroporation. (C) 2019 Elsevier Inc. All rights reserved.N

4-Isopropyl-2,6-bis(1-phenylethyl)aniline 1, an Analogue of KTH-13 Isolated from Cordyceps bassiana

The Cordyceps species has been a good source of compounds with anticancer and anti-inflammatory activities. Recently, we reported a novel compound (4-isopropyl-2,6-bis(1-phenylethyl)phenol, KTH-13) with anticancer activity isolated from Cordyceps bassiana and created several derivatives to increase its pharmacological activity. In this study, we tested one of the KTH-013 derivatives, 4-isopropyl-2,6-bis(1-phenylethyl)aniline 1 (KTH-13-AD1), with regard to anti-inflammatory activity under macrophage-mediated inflammatory conditions. KTH-13-AD1 clearly suppressed the production of nitric oxide (NO) and reactive oxygen species (ROS) in lipopolysaccharide (LPS) and sodium nitroprusside- (SNP-) treated macrophage-like cells (RAW264.7 cells). Similarly, this compound also reduced mRNA expression of inducible NO synthase (iNOS) and tumor necrosis factor-α (TNF-α), as analyzed by RT-PCR and real-time PCR. Interestingly, KTH-13-AD1 strongly diminished NF-κB-mediated luciferase activities and nuclear translocation of NF-κB family proteins. In accordance, KTH-13-AD1 suppressed the upstream signaling pathway of NF-κB activation, including IκBα, IKKα/β, AKT, p85/PI3K, and Src in a time- and dose-dependent manner. The autophosphorylation of Src and NF-κB observed during the overexpression of Src was also suppressed by KTH-13-AD1. These results strongly suggest that KTH-13-AD1 has strong anti-inflammatory features mediated by suppression of the Src/NF-κB regulatory loop

Asymmetric nucleophilic catalysis with planar-chiral DMAP derivatives and chiral phosphines : synthetic and mechanistic studies

Thesis: Ph. D. in Organic Chemistry, Massachusetts Institute of Technology, Department of Chemistry, 2014.Cataloged from PDF version of thesis. Vita.Includes bibliographical references.Chapter 1 describes the development and detailed mechanistic investigation of the first non-enzymatic method for the dynamic kinetic resolution of secondary alcohols via enantioselective acylation, with acetyl isopropyl carbonate, through the use of a planar-chiral DMAP derivative (an acylation catalyst) in combination with a ruthenium complex (an alcohol-racemization catalyst). Chapter 2 describes the development and detailed mechanistic investigation of the enantioselective synthesis of tertiary alkyl fluorides via the [alpha]-fluorination of ketenes catalyzed by a planar-chiral nucleophile with N-fluorodibenzenesulfonimide in the presence of sodium pentafluorophenoxide. Chapter 3 describes the development and preliminary mechanistic study of the first asymmetric, phosphine-catalyzed intramolecular [3 + 2] cycloadditions of allenes with alkenes that furnish an array of diastereomerically pure bicyclic compounds bearing two or three contiguous tertiary! quaternary stereocenters.by Sarah Yunmi Lee.Ph. D. in Organic Chemistr