Six electron-poor tetrasubstituted olefins were reacted with electron-rich comonomers. Of these, three {dimethyl dicyanofumarate (DDCF), dimethyl 1,1-dicyanoethylene-2,2-dicarboxylate (DDED), and dicarbomethoxymaleic anhydride (DCMA)} were found to polymerize with styrenes and vinyl ethers to form 1:1 alternating copolymers of low molecular weight. All polymerizations with vinyl ethers and DCMA required initiation, while the copolymerizations of DDED and DDCF with styrenes were spontaneous. Tetramethyl ethylenetetracarboxylate, diisopropylidene ethylenetetracarboxylate, and trimethyl cyanoethylenetricarboxylate failed to copolymerize under any conditions. The spontaneous reactions of these tetrasubstituted olefins can best be explained as proceeding via tetramethylene intermediates, resonance hybrids of biradicals and zwitterions. Spontaneous copolymerizations occur from biradical intermediates; cycloadduct formation occurs from both. Tetramethylene formation is electronically controlled during the reaction of DDED and electron-rich comonomers, as reflected by the structure of the isolated cyclobutanes. The orientation of this monomer is the copolymer with styrene is sterically controlled, as suggested by ('13)C NMR. Methyl 3,3-dicyanoacrylate, a new tetrasubstituted olefin, was found to spontaneously copolymerize with styrenes, and to form cyclobutanes with vinyl ethers. It could be copolymerized with vinyl ethers with radical initiation.

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The thesis is concerned with approaches to substituted 2-phenyl- 1,3-oxathiolans and their cycloreversion to olefins. 2-(α-Methoxybenzylthio)acetophenone (l) was prepared by <u>in situ</u> alkylation of the thiolate generated by aminolysis of 0-ethyl-S-phenacyldithiocarbonate with α-chlorobenzyl methyl ether. Reduction of (l) with lithium aluminium hydride gave 2-(α-methoxybenzylthio)—1— phenylethanol which cyclised in the presence of <u>p</u>-toluenesulphonic acid to give 2,5-diphenyl-l,3-oxathiolan. α-(α'-Methoxybenzylthio)acetone (2), was prepared by a similar route to that used for (l). Compounds (1) and (2) and various other a-thiosubstituted ketones were investigated as potential starting materials for the synthesis of substituted β—(α-methoxybenzylthio)alcohols but the transformations attempted were unsuccessful. A reasonably flexible synthesis of substituted oxathiolans and hence the corresponding olefins was developed starting from α—(benzylthio)ketones. The olefins prepared were 2-methyl—3—phenyl—2— butene, 1,2-dimethylcyclohexene and the Z-(3) and E-(4) 3,4—dimethylhex— 3—enes. Alkylation of the a-(benzylthio)ketones proceeded regio— specifically α- to the thio and keto groups. Subsequent reaction with organometallic reagents gave β-benzylthioalcohols. Generally alkyllithiums gave the best yields and higher stereoselectivities in these additions. The benzylthio group was cleaved with sodium/ ammonia to give β-mercaptoalcohols which were condensed with benzaldehyde to give 2-phenyl-l,3-oxathiolans. Treatment of the oxathiolans with lithium diisopropylamide resulted in cycloreversion to olefins in high yields (75-100%). Stereochemical integrity was maintained throughout the reactions used to convert the β-benzylthioalcohols into olefins and consequently the stereoselectivity was determined at the β-benzylthioalcohol forming step. Thus the ratio found for (3) to (4) synthesised from a 3-benzylthioalcohol prepared by reaction of methyllithium with 3-benzylthio-3- methyl-4—hexanone was 3:7, whereas when the β-benzylthioalcohol was prepared from 3-benzylthio-3-methyl-2-pentanone by an ethyllithium reaction the ratio of (3) to (4) subsequently obtained was 6:4.

Halogenated alkenes are a group of commercially important chemicals. For example tetrafluoroethylene is the monomer used for the production of poly- tetrafluoroethylene, hexachloro-1:3-butadiene is a by-product from the manufacture of chlorinated solvents and perchloroethylene is widely used as a dry cleaning agent. Due to possible exposure to haloalkenes and the nephrotoxicity observed in animal studies, concern has been expressed for the potential of these compounds to cause toxicity to man. Animal studies have shown that these compounds undergo inter-organ metabolism and are bioactivated by enzymes of glutathione processing. The metabolites are delivered to the kidney where they cause proximal tubular cell necrosis. This site-specific toxicity is due to accumulation of the metabolites via specific transport mechanisms and bioactivation via the enzyme C-S lyase present in high amounts in the proximal tubules. The aim of this research was to investigate the mechanisms of toxicity of haloalkene S'-conjugates in vitro using cultures of rat and human proximal tubular cells. This study demonstrates that human proximal tubular cells are sensitive to haloalkene. -conjugate toxicity, particularly DC VC. Human exposuredata has shown that workers exposed to trichloroethylene (Bimer et al, 1993) and perchloroethylene (Mutti et al, 1992) excrete nephrotoxic metabolites and markers of renal damage respectively. In the light of these findings and the toxicity of DCVC in HPT cells, exposure to halogenated alkenes should be controlled and those exposed monitored.

by Eric Kwok Wai Tam. / Thesis (Ph.D.)--Chinese University of Hong Kong, 1996. / Includes bibliographical references. / Table of Contents --- p.i / Acknowledgement --- p.iv / Abstract --- p.v / Abbreviation --- p.vii / Part A / Enantiospecific Syntheses of Cyclohexane Oxides from (-)-Quinic Acid / Chapter 1. --- Synthetic Application of (-)-Quinic Acid --- p.1 / Chapter 1.1 --- Introduction --- p.1 / Chapter 1.2 --- Syntheses of Cyclohexane Derivatives --- p.2 / Chapter 1.2.1 --- Syntheses of Shikimic Acid (2) and its Derivatives --- p.2 / Chapter 1.2.2 --- "Syntheses of D-myo-Inositol 1,4,5-Trisphosphate (52) & its analog" --- p.15 / Chapter 1.2.3 --- Syntheses of Mycosporins --- p.17 / Chapter 1.2.4 --- Synthesis of (+)-Palitantin (76) --- p.19 / Chapter 1.2.5 --- "Synthesis of 2-Crotonyloxy-(4R,5R,6R)-4,5,6-trihydroxy- cyclohex-2-enone (COTC) (82)" --- p.20 / Chapter 1.2.6 --- Syntheses of Cyclophellitol (83) and its Diastereomers --- p.21 / Chapter 1.2.7 --- Syntheses of Pseudo-sugars and its Derivatives --- p.24 / Chapter 1.2.8 --- Syntheses of Aminocyclitol Antibiotics --- p.34 / Chapter 1.2.9 --- Syntheses of A-ring Precursor of Daunomycin --- p.36 / Chapter 1.2.10 --- "Synthesis of 19-nor-lα,25-Dihydroxyvitamin D3" --- p.38 / Chapter 1.2.11 --- Synthesis of Isoquinuclidines --- p.41 / Chapter 1.2.12 --- Synthesis of Cyclohexenyl Iodide: Taxol CD-ring Precursor --- p.44 / Chapter 1.2.13 --- Synthesis of C-20 to C-34 Segment of FK-506 --- p.46 / Chapter 1.2.14 --- Synthesis of the Hexahydrobenzofuran Subunit of Avermectins --- p.49 / Chapter 1.2.15 --- Synthesis of Bicyclic Core of Enediyne --- p.50 / Chapter 1.2.16 --- Syntheses of Two Enantiopure Derivatives of 4-Hydroxy-2-cyclohexone --- p.53 / Chapter 1.3 --- Synthesis of Homochiral Linear Molecules --- p.57 / Chapter 1.3.1 --- Syntheses of (3S)-Mevalonolactone and its Derivatives --- p.57 / Chapter 1.3.2 --- Synthesis of the Subunit in Maytansinoids --- p.58 / Chapter 1.3.3 --- Synthesis of (+)-Negamycin --- p.59 / Chapter 1.3.4 --- Syntheses of Hepoxilins B3 and its Stereoisomers --- p.61 / Chapter 1.3.5 --- Synthesis of C-21 to C-25 Fragment of FK-506 --- p.62 / Chapter 1.4 --- Synthesis of Cyclopentane Derivatives --- p.63 / Chapter 1.4.1 --- Synthesis of 11 α-Hydroxy-13-oxaprostanoic Acid --- p.65 / Chapter 1.4.2 --- Synthesis of (-)-Pentenomycin I --- p.66 / Chapter 1.4.3 --- Syntheses of Carbovir and its Derivatives --- p.66 / Chapter 1.5 --- Synthesis of Cycloheptane Derivatives --- p.68 / Chapter 1.6 --- Conclusion --- p.70 / References --- p.71 / Chapter 2. --- Introduction of Cyclohexane Oxides --- p.81 / Chapter 2.1 --- General Background --- p.81 / Chapter 2.2 --- Previous Syntheses of Cyclohexane Oxides --- p.86 / Chapter 2.2.1 --- Racemic Syntheses of Crotepoxide --- p.86 / Chapter 2.2.2 --- Racemic Syntheses of Senepoxide --- p.89 / Chapter 2.2.3 --- A Racemic Synthesis of Pipoxide --- p.92 / Chapter 2.2.4 --- Syntheses of Enantiopure Cyclohexane Oxides --- p.93 / References --- p.96 / Chapter 3. --- Retrosynthetic Analysis and Strategy --- p.99 / Chapter 3.1 --- Antithetic Analysis of Cyclohexane Oxides --- p.99 / Chapter 3.2 --- Problems Encounter in the Conversion of Diene into Cyclohexane Oxides --- p.100 / Chapter 3.3 --- Photo-oxygenation Approach to Cyclohexane Oxides --- p.102 / Chapter 3.4 --- Reasons for Choosing the Silyl Ether as Blocking Group --- p.104 / Chapter 3.5 --- Strategy for Synthesis of Diene 373 from Quinic acid --- p.105 / References --- p.106 / Chapter 4. --- Results and discussion --- p.108 / Chapter 4.1 --- Synthesis of Silyl Benzoate381 --- p.108 / Chapter 4.2 --- Synthesis of Alkene373 --- p.111 / Chapter 4.3 --- Syntheses of (+)-Crotepoxide (289)，(+)-Bosenepoxide (290) and (-)-iso-Crotepoxide (304) --- p.115 / Chapter 4.4 --- "Syntheses of the (+)-β-Senepoxide (295)，(+)-Pipoxide Acetate (365), (-) Tintanoxide (294) and (-)-Senepoxide (291)" --- p.121 / References --- p.124 / Chapter 5. --- Conclusion --- p.126 / Chapter 6. --- Experimental Section --- p.128 / References --- p.142 / Part B / Ruthenium Catalyzed cis-Dihydroxylation of Alkene / Chapter 1. --- Introduction --- p.143 / Chapter 1.1 --- Background --- p.143 / Chapter 1.2 --- General cis-Dihydroxylation Methods --- p.144 / Chapter 1.2.1 --- Potassium Permanganate (KMnO4) --- p.144 / Chapter 1.2.2 --- Osmium Tetraoxide (OsO4) --- p.146 / Chapter 1.3 --- Ruthenium Tetraoxide Oxidations --- p.148 / Chapter 1.4 --- Previous Reports of Using Ruthenium Tetraoxide (RuO4) Mediated syn-Dihydroxylation of Olefins --- p.149 / Chapter 1.4.1 --- The Snatzke and Fehlhaber Work --- p.149 / Chapter 1.4.2 --- The Sharpless and Akashi Work --- p.150 / Chapter 1.4.3 --- The Sica and Co-workers Work --- p.150 / References --- p.152 / Chapter 2. --- Ruthenium-Catalyzed cis-Dihydroxylation of Alkenes --- p.155 / Chapter 2.1 --- """Flash"" Dihydroxylation" --- p.155 / Chapter 2.2 --- "Stereochemical Outcome of ""Flash"" Dihydroxylation" --- p.155 / References --- p.157 / Chapter 3. --- Results and Discussion --- p.158 / Chapter 3.1 --- "Scope and Limitations of ""Flash"" Dihydroxylation" --- p.158 / Chapter 3.2 --- "Study of the Diastereoselectivity of ""Flash"" Dihydroxylation" --- p.168 / Chapter 3.3 --- "Study of Co-oxidants for ""Flash"" Dihydroxylation" --- p.170 / Chapter 3.4 --- "Solvent Effect for ""Flash"" Dihydroxylation" --- p.171 / Chapter 3.5 --- "Synthetic Application of ""Flash"" Dihydroxylation" --- p.173 / References --- p.175 / Chapter 4. --- Conclusion --- p.176 / Chapter 5. --- Experimental Section --- p.177 / References --- p.185 / Appendix --- p.186

Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1980. / MICROFICHE COPY AVAILABLE IN ARCHIVES AND SCIENCE. / Vita. / Includes bibliographical references. / by Christopher Reiser. / Ph.D.

A vast number of halogenated natural products have been isolated to date that contain unique structural and electronic characteristics due to the installed halogen. These properties not only aid in their bioactivity, but also put into question nature's biosynthesis of these complex molecules. Nature's ability to install halogens in a direct and concise manner has inspired our group to seek out chemical transformations that accomplish the same efficiency in the context of synthesizing complex natural products. Specifically, our group has targeted challenges in the areas of halonium-induced polyene cyclization, asymmetric halonium addition to alkenes, and medium-sized bromoether formation, as having access to such transformations would further facilitate total syntheses of these halogenated isolates. Only a few electrophilic iodonium reagents have proven capable of inducing polyene cyclization of linear terpene precursors, though, to date, these only include substrates with electron rich functional groups. Due to this, we targeted development of a new iodonium reagent, IDSI. This easily synthesized, isolable solid has promoted cyclization of both electron rich and poor linear polyene precursors in good yields and diastereoselectivities. The produced iodinated cores allow for further diversification as demonstrated in the formal synthesis of loliolide, stemodin, and K-76. In general, the use of IDSI in previous routes decreases step count, increases overall yields, and avoids the use of stoichiometric amounts of toxic metals. In addition, the chloronium variant, CDSC, completed the first polyene cyclization ever to be initiated by a chloronium electrophile. With the development of our halonium reagents, BDSB (the bromonium variant), IDSI, and CDSC, we next varied the synthesis of each reagent to include an asymmetric component. While their use in polyene cyclization only produced racemic materials, the iodohydroxylation of simple alkenes provided up to 63% ee with only a select substrate. Yet, this chiral IDSI reagent is one of only a handful of strategies capable of transferring an iodonium electrophile with moderate enantioselectivity (above 50% ee). By analyzing the hypothesized biosynthesis of the Laurencia natural isolates, we realized the proposed direct 8-membered bromoetherification from a linear precursor was most likely an unfavorable event, leading us to investigate an alternative idea. Discovery of a unique bromonium-induced ring expansion method generated 8-membered bromoethers diastereoselectively in a single step in good yields. From easily prepared tetrahydrofuran precursors, a variety of diastereomers of 8-endo and 8-exo bromoethers were generated selectively, modeling the cores of over half of the medium-sized isolates. This method was then expanded to include diastereoselective synthesis of 9-membered bromoethers, also found in the Laurencia family. The BDSB-induced ring expansion strategy was then used as the key step in the completed formal total synthesis of laurefucin, an 8-endo bromoether in the Laurencia natural products. By utilizing this method, we have developed the shortest synthesis of any 8-membered bromoether isolate in the family to date. Due to the breadth of products this transformation has generated, we believe this bromonium-induced ring expansion may have biosynthetic relevance. Our proposed biosynthesis could account for generation of not only the 8-membered bromoethers, but also additional 5-, 7- and 9-membered ethers found in the family. Additional experiments were completed to support this pathway, including mimicking enzymatic conditions as well as intercepting the proposed intermediates.