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Mechanistic and Stereochemical Studies of Photoinduced Electron Transfer Cyclization Reactions: the Role of Nitrogen

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Mechanistic and Stereochemical Studies of Photoinduced Electron Transfer Cyclization Reactions: the Role of Nitrogen MECHANISTIC AND STEREOCHEMICAL STUDIES OF PHOTOINDUCED ELECTRON TRANSFER CYCLIZATION REACTIONS: THE ROLE OF NITROGEN. THE AQUEOUS PRINS REACTION AND EFFORTS TOWARDS THE TOTAL SYNTHESIS OF (+)-DACTYLOLIDE by Danielle L. Aubele B.S., Allegheny College, 1999 M.S., University of Pittsburgh, 2002 Submitted to the Graduate Faculty of Arts and Sciences in partial fulfillment of the requirements for the degree of Doctor of Chemistry University of Pittsburgh 2004 UNIVERSITY OF PITTSBURGH FACULTY OF ARTS AND SCIENCES This dissertation was presented by Danielle L. Aubele It was defended on Wednesday, August 18th, 2004 and approved by Dennis P. Curran Kay Brummond Billy Day Paul E. Floreancig Dissertation Director ii Copyright by Danielle L. Aubele, 2004 iii Paul E. Floreancig MECHANISTIC AND STEREOCHEMICAL STUDIES OF PHOTOINDUCED ELECTRON TRANSFER CYCLIZATION REACTIONS: THE ROLE OF NITROGEN. THE AQUEOUS PRINS REACTION AND EFFORTS TOWARDS THE TOTAL SYNTHESIS OF (+)-DACTYLOLIDE Danielle L. Aubele, PhD University of Pittsburgh, 2004 A novel method for catalytic electron transfer initiated cyclization reaction for the formation of cyclic acyl aminals through a unique method of carbon-carbon σ-bond activation has been developed. This new cyclization strategy employs a potent electrophile, generated by a photoinitiated single electron oxidation of a homobenzylic amide or t-butyl carbamate, which reacts with an appended nucleophile allowing for the formation of cyclic acyl aminals. OH NMQPF6, hν , NaOAc O HN R Na2S2O3, O2, DCE, Tol. R N O H O The Lewis acid-surfactant-combined catalyst (LASC) was employed in a novel method for effecting intramolecular Prins cyclization reactions in water. Acetals of 1,2 and 1,3 di- and tri- substituted alcohols with a tethered allyl silane have been converted to 2,6-syn- tetrahydropyrans. The LASCs are generated in situ by the addition of cerium nitrate to a solution of sodium dodecylsulfate and acetal in water. A heterogeneous reaction environment is created in which the acetal is trapped within the hydrophobic core of the immediately generated micelle. Intarmolecular Prins cyclization is catalyzed upon interaction of the acetal with Lewis acidic cerium cations located at the surface of the micelle. LASC mediated intramolecular Prins cyclization reactions are efficient, high yielding, and an environmentally benign method of generating 2,6-cis-tetrahydropyrans. iv R H H R O OH OH O Ce(NO ) 6H O n O 3 3 2 HO SiMe3 n Br n NaO3SOC12H25, H2O R = alkyl, alkenyl n = 1 or 2 A highly convergent route towards the total synthesis of the marine macrolide (+)- dactylolide is currently being pursued. The route involves the condensation of two highly functionalized segments of the molecule, an α,β-unsaturated aldehyde and a 1,3-syn-diol, to form a cyclic α,β-unsaturated acetal. Both enantiopure segments arise from vinylogous aldol reactions, providing the three necessary stereocenters. The key synthetic transformation involves intramolecular Prins cyclization of a cyclic α,β-unsaturated acetal with a pendent allylsilane to provide the 2,6-cis-disubstituted-4-methylenetetrahydropyran core of the molecule efficiently and stereoselectively. Other key transformations include a completely trans selective selenoxide- selenate [2,3] sigmatropic rearrangement and the selective oxidation of a primary allylic alcohol in the presence of a secondary alcohol with Dess-Martin periodinane. OPMB O O H OTBS OHC O O TBSO OPMB + H H SiMe3 O O O OH OH O OBu OTBDPS OTBDPS v TABLE OF CONTENTS PREFACE...................................................................................................................................... xi 1. Mechanistic and stereochemical studies of photoinduced electron transfer initiated cyclization reactions: the role of nitrogen....................................................................................... 1 1.1. Introduction to electron transfer...................................................................................... 1 1.2. Results........................................................................................................................... 20 1.3. Discussion of electron transfer initiated cyclization reactions ..................................... 44 1.4. Conclusion .................................................................................................................... 52 1.5. Experimental................................................................................................................. 54 1.6. References................................................................................................................... 100 2. The aqueous Prins reaction ................................................................................................. 104 2.1. Introduction................................................................................................................. 104 2.2. Results and Discussion............................................................................................... 117 2.3. Conclusion .................................................................................................................. 130 2.4. Experimental............................................................................................................... 132 2.5. References................................................................................................................... 151 3. Efforts towards the total synthesis of (+)-Dactylolide........................................................ 154 3.1. Introduction................................................................................................................. 154 3.2. Results and Discussion............................................................................................... 166 3.3. Conclusion .................................................................................................................. 183 3.4. Experimental............................................................................................................... 184 3.5. References................................................................................................................... 203 APPENDIX A............................................................................................................................. 207 Mechanistic and stereochemical studies of photoinduced electron transfer initiated cyclization reactions: the role of nitrogen (Supporting Information)........................................................ 207 APPENDIX B ............................................................................................................................. 260 The aqueous Prins reaction (Supporting Information)............................................................ 260 APPEDIX C................................................................................................................................ 291 Efforts towards the total synthesis of (+)-Dactylolide (Supporting information)................... 291 vi LIST OF TABLES Table 1.1: Variations of ETIC reaction conditions....................................................................... 28 Table 1.2: Altering aromatic cosolvents....................................................................................... 32 Table 1.3: Substrates tested under catalytic aerobic ETIC conditions.......................................... 35 Table 1.4: Additional homobenzylic stabilizing groups............................................................... 38 Table 1.5: Nitrogen as a nucleophile ............................................................................................ 41 Table 1.6: ETIC conditions with varying base and solvent.......................................................... 76 Table 1.7: ETIC conditions with varyiation in aromatic cosolvent.............................................. 76 Table 1.8: Catalytic aerobic ETIC conditions............................................................................... 77 Table 2.1: Intramolecular Prins cyclization with Lewis/Brønstead acids................................... 120 Table 2.2: Optimal surfactant chain length................................................................................. 124 Table 2.3: Cost/benefit analysis of cerium III salts .................................................................... 125 Table 2.4: Summary of intramolecular Prins cyclization substrates........................................... 131 Table 3.1: Screening of viable Prins cyclization conditions....................................................... 177 vii LIST OF FIGURES Figure 1.1: Electronic transition resulting from photoexcitation.................................................... 3 Figure 1.2: Photochemical pathways ..............................................................................................3 Figure 1.3: IP and EA of both the ground and excited state species .............................................. 4 Figure 1.4: Ground state redox reactions........................................................................................5 Figure 1.5: Photoinitiated electron transfer ....................................................................................6 Figure 1.6: Primary reaction pathways for radical cations ............................................................. 7 Figure 1.7: PET induced mesolytic cleavage of C-C bond............................................................. 9 Figure
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