Thesis advisor: Amir H. Hoveyda / We have synthesized Ru-carbene isocyanide complexes that promote both ring-opening metathesis polymerization of norbornene as well as cycloisomerization of diethyl diallylmalonate. We have also synthesized a N-heterocyclic carbene complex bearing a biphenylthiol moiety, and we installed this ligand on a Ru-carbene to produce a racemic chiral bidentate Ru-thiolate complex. Although the Ru-thiolate was found to initiate more slowly than the corresponding biphenoxide catalyst, both perform ring-opening/cross-metathesis (ROCM) with similar efficiency. Several other bidentate Ru-complexes were synthesized where the anionic ligand was varied (tosylate, pivalate, and phenylthiolate), as well as a new Re-alkylidene bis-pyrrolide. We have expanded the scope of Ru-catalyzed enantioselective ROCM of cyclopropenes utilizing a variety of ester, ketone, ether, and aliphatic olefin cross-partners. The utility of this method was demonstrated in the enantioselective total synthesis of the marine natural product (+)-sporochnol, which was synthesized in 8% overall yield across eleven linear steps. Additionally, we have developed an enantio- and Z-selective ROCM of enol ethers and oxabicycles; we propose the origin of Z-selectivity to arise from a lower barrier to ruthancyclobutane cleavage/formation for the cis-substituted ruthenacyclobutane vs the trans-substituted ruthenacyclobutane (which is favored for ROCM of oxabicycles and styrene). We also have found that stereogenic-at-Ru complexes are capable of undergoing non-metathesis isomerization through polytopal rearrangements. This observation may explain why cyclopropene ROCM suffers from low enantioselectivity for many substrates. We have developed a diasteroselective ROCM reaction, which utilizes commercially available ruthenium dichloride catalysts in the presence of chiral allylic alcohols and cyclopropenes. Our investigation revealed that the presence of a hydroxyl group dramatically accelerates the rate of ROCM vs the corresponding methyl ether and delivered products in high yield and diastereoselectivity. Furthermore, we found that the methyl ether delivered the opposite diastereomer vs the allylic alcohol; this led us to propose that intramolecular H-bonding between the hydroxyl proton and a chloride ligand controls the diastereoselectivity and enhances the rate of the ROCM. Protic additives have also been found to promote polytopal rearrangements in stereogenic-at-Ru complexes; H-bonding may facilitate olefin metathesis in a similar fashion to polytopal rearrangement by reducing the trans effect during the transition state to ruthenacyclobutane formation. A number of synthetically useful allylic alcohols and strained olefin substrates efficiently provide products in high diastereoselectivity and with good E:Z selectivity (89:11-97:3 dr, 4:1-11:1 E:Z). We have developed a Mo-catalyzed Z-selective cross-metathesis (CM) reaction. A wide range of olefin cross partners were found to be effective for both enol ether and allylic amide substrates (51-97% yield, 81 to 98% Z). We applied our Z-selective CM method to the synthesis of KRN7000, a potent immunostimulant (the Z-allylic amide was obtained in 85% yield and 96% Z). We also utilized Z-selective CM in the formal synthesis of an enol ether plasmalogen C18 (plasm)-16:0 (PC), a lipid membrane component found in mammalian brain tissue (the enol ether was obtained in >98:2 Z selectivity). Z-selective cross-metathesis is therefore a new tool for synthetic chemists to access important building blocks for the synthesis of biologically active molecules. We have developed a Z-selective cross-metathesis of vinyl and allyl boronates. Reactions of both substrate classes proceed to between 50-95% conv and deliver Z-vinylboronate and Z-crotylboronate products in 85-93% Z selectivity. Allylboronate CM provides Z-crotylboronates which can be used for diastereoselective crotylation. The utility of Z-selective vinylboronate CM was demonstrated in the synthesis of a dienyl boronate (obtained in 83% yield and >98% Z) that will be utilized in the total synthesis of the potent anti-cancer agent disorazole C1. / Thesis (PhD) — Boston College, 2012. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.
| Identifer | oai:union.ndltd.org:BOSTON/oai:dlib.bc.edu:bc-ir_101828 |
| Date | January 2012 |
| Creators | O'Brien, Robert Vincent |
| Publisher | Boston College |
| Source Sets | Boston College |
| Language | English |
| Detected Language | English |
| Type | Text, thesis |
| Format | electronic, application/pdf |
| Rights | Copyright is held by the author, with all rights reserved, unless otherwise noted. |
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