Thesis advisor: Marc L. Snapper / Tandem processes can have several advantages over multiple single step processes. Non-metathesis transformations of ruthenium alkylidenes were studied and applied to tandem processes. Ruthenium catalyzed tandem RCM/hydroacylation that allows access to tricyclic ring systems from readily available substrates was developed. Mechanistic investigations indicated that this reaction may proceed through a mechanism involving [Ru]-H species. A Ru-catalyzed tandem RCM/olefin isomerization/C-H activation sequence that provides significant advantages in terms of rapid elaboration of simple reaction partners to more complex entities was developed. / Thesis (PhD) — Boston College, 2013. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Thesis advisor: Amir H. Hoveyda / Chapter 1: Efficient Z-Selective Cross-Metathesis of Secondary Allylic Ethers Efficient Z-selective cross-metathesis of secondary allylic ethers were catalyzed by monoaryloxide monopyrrolide molybdenum complexes. Reactions involving both silyl and benzyl protected ethers were demonstrated, as well as ethers containing alkyl, aryl and alkynyl substituents. Mechanistic studies were performed, and the reactions were applied to the total synthesis of several ene-diyne natural products. Chapter 2. Stereoselective Total Synthesis of Disorazole C1 The stereoselective total synthesis of disorazole C1 is reported. The synthesis was completed in 12 longest linear steps. Our synthesis demonstrates the utility of Z-selective cross-metathesis to form both alkenyl borons and alkenyl halides. Another key transformation was a one-pot Suzuki-dimerization reaction to form a symmetric 30 membered ring in relatively high yield. Chapter 3. Stereoselective Cross-Metathesis to Form Trisubstituted Alkenes Initial studies into the stereoselective formation of trisubstituted olefins through molybdenum catalyzed cross-metathesis have been performed. Our mechanistic understanding of the reaction lead us to focus on the synthesis of alkenyl halides, which can be obtained in up 90% yield and 75:25 E:Z selectivity. Chapter 4: Ring-Closing Metathesis in the Synthesis of Natural Products Development of highly efficient and selective ring-closing metathesis reactions have enabled collaborators to successfully implement routes in total synthesis endeavors. A diastereoselective seven-membered ring-closing metathesis enabled the successful synthesis of (±)-tetrapetalone A methyl-aglycon. An enantioselective ring-closing metathesis to form a six membered ring has provided access to enantioenriched aspidosperma alkaloids. / Thesis (PhD) — Boston College, 2016. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Chemistry.

Hepatitis C is a blood-borne disease affecting 130-170 million people worldwide. The causative agent, hepatitis C virus (HCV), infects the liver and is the major reason for chronic liver disease worldwide. The HCV NS3 protease, a key enzyme in the virus replication cycle, has been confirmed to be an important target for drug development. With the recent release of two HCV NS3 protease inhibitors onto the market and an arsenal of inhibitors in clinical trials, there are now hopes of finally combating the disease. However, the success of treatment relies heavily on the ability to overcome the emergence of drug-resistant forms of the protease. The main focus of this thesis was on designing and synthesizing novel inhibitors of the NS3 protease with a unique resistance profile. Efforts were also made to decrease the peptide character of the compounds, with the long-term goal of making them into more drug-like compounds. Special attention was devoted to developing inhibitors based on a phenylglycine in the P2 position, instead of the highly optimized and commonly used P2 proline. Around ninety acyclic and macrocyclic inhibitors have been synthesized and biochemically evaluated. P2 pyrimidinyloxy phenylglycine was successfully combined with an aromatic P1 moiety and alkenylic P1´ elongations, yielding a distinct class of HCV NS3 protease inhibitors. Macrocyclization was performed in several directions of the inhibitors via ring-closing metathesis. Only the macrocyclization between the P3-P1´ residues was successful in terms of inhibitory potency, which suggests that the elongated P1-P1´ residue is oriented towards the P3 side chain. The metathesis reaction was found to be significantly more dependent on the substrate than on the reaction conditions. It was also found that the P3 truncated inhibitors were able to retain good inhibitory potency, which initiated the synthesis and evaluation of a series of P2-P1´ inhibitors. The potential of the P3-P1´cyclized inhibitor and the smaller, acyclic P2-P1´ as new potential drug leads remains to be determined through pharmacokinetic profiling. Gratifyingly, all the inhibitors evaluated on A156T and D168V substituted enzyme variants were able to retain inhibitory potency towards these as compared to wild-type inhibition.

The use of polymer supports for transition metal catalysts are very important and useful in synthetic organic chemistry as they make possible the separation and isolation of catalysts and products quite easy. These polymer-bound ligands/catalysts/reagents can, often, be recovered and recycled numerous times and typically yield products in high purity, negating the need for further purification steps (i.e. column chromatography). Because of this, interest in these systems has garnered international attention in the scientific community as being “Green”. Historically, insoluble, polymer-supports (i.e. Merrifield resin) were used to develop recoverable catalysts. This has the advantage of easy separation and isolation from products after a reaction; because of their insolubility, such supported catalysts can be easily removed by gravity filtration. However, these catalysts often have relatively poor reactivity and selectivity when compared to homogeneous catalysts. Because of this disadvantage, our lab has had interest in the development of soluble polymer-supports for transition metal catalysts. We have developed several separation methods for these soluble polymer-bound catalysts. These include thermomorphic liquid/liquid and solid/liquid as well as latent biphasic liquid/liquid separation techniques. This dissertation describes the use of both, latent biphasic liquid/liquid separation systems and thermomorphic solid/liquid separation systems. In order to perform a latent biphasic iii liquid/liquid separation, a polymer-bound catalyst must have a very high selectivity for one liquid phase over the other. Our lab has pioneered the use of polyisobutylene (PIB) oligomers as supports for transition metal catalysts. Previous work has shown that these oligomers are > 99.96 % phase selectively soluble in nonpolar solvents. This has allowed us to prepare PIB-supported salen Cr(III) complexes that can be used in a latent biphasic liquid/liquid solvent system. The synthesis of these complexes is quite straightforward and such species can be characterized using solution state 1H and 13C NMR spectroscopy. Also, these complexes can be used to catalyze the ring opening of meso epoxides with azidotrimethylsilane (TMS-N3) and can be recovered and recycled up to 6 times, with no loss in catalytic activity. To perform a thermomorphic solid/liquid separation, a polymer-bound catalyst that is completely insoluble at room temperature but soluble upon heating must be used. Our lab has pioneered the use of polyethylene oligomers (PEOlig) as supports for transition metal catalysts. Such PEOlig-supported catalysts are able perform homogeneous catalytic reactions at elevated temperatures (ca. 65 ○C), but, upon cooling, precipitate out of solution as solids while the products stay in solution. This process allows for the easy separation of a solid catalyst from the product solution. Described herein, is the development of PEOlig-supported salen-Cr(III) complexes and PEOlig-supported NHC-Ru complexes. The preparation of these complexes is also straightforward and such species can be characterized using solution state variable temperature (VT) 1H and 13C NMR spectroscopy. In the case of the PEOlig-supported salen-Cr(III) complex, it was found to be a recoverable/recyclable catalyst for the ring opening of epoxides with TMS-N3 and could be reused 6 times with no loss in activity. The PE-supported NHC-Ru complex was able to be used as a recyclable ring closing metathesis (RCM) catalyst and could be used up to 10 times.

Reaction of 3-sulfonyl acetamides with various substituted methyl acrylate derivatives furnished pyroglutamate and glutarimidess via [3+2] and [3+3] cycloaddition respectively. The results were applied to the synthesis of pyrrolizidine skeleton, tylophorine, cryptopleurine and fused bicyclic glutarimides.

Chapter 1: Reaction of benzoaldehyde with wittig agents or isophone to build up conjugate carbon chain, then combined with electron acceptor to furnished the chromophores. The charge-transfer chromophores, which have the first molecular hyperpolarizability

We use stepwise [3+3] annulation to prepare the asymmetric glutarimides, and then establish a new approach to isoquinolone skeleton starting from glutarimides via regioselective nucleophilic addition and ring-closing metathesis reaction. Finally, we applied this method to the synthetic studies toward (¡Ó)-Xylopinine.

The thesis subject is mainly involved in Green Chemistry approach. Thiophene, furan and pyridine carboxaldehydes were chosen as starting compounds and vinylation and allylation with Grignard reaction afforded the corresponding racemic heteroaryl substituted allylic and homoallylic alcohols. Subsequent resolution with enzymes (PS-Amano II, Lipozym and Novazym 435) gave enantiomerically enriched alcohols with the e.e. values varied between 65 and 99%. The absolute configurations of all substrates are known. As a result of O-allylation with the common procedure formed the feasible carbon backbone for the ring closing metathesis reaction. All ring closing metathesis reactions were performed by Grubbs&rsquo / catalyst with just 5% catalyst loading. The absolute configurations of dihydrofuran and dihydropyran derivatives are known, since the chiral center configurations of all substrates are preserved throughout all the applied processes.

The main subject of this thesis is synthesis of chiral diene systems via Ring Closing Enyne Metathesis (RCEM). Furan and thiophene carbaldehydes were chosen as starting compounds. As a result of allylation and propargylation reaction of these aldehydes targeting racemic heteroaryl substituted homoallylic and homopropargylic alcohols were synthesized. Enantiomerically enriched alcohols were obtained by enzymatic resolution method with different enzymes (PS-II, Lipozyme) with the high enantiomeric excess values. Absolute configurations of all alcohols are known. O-allylation and O-propargylation reactions of enantiomerically pure alcohols, afforded feasible enyne units for RCEM were synthesized successfully. All RCEM reactions were performed by using Grubbs&amp / #8223 / 1st generation catalyst. The absolute configuration of all chiral diene systems were known since during the course of the all reactions, configurations were preserved. As a last step, Diels-Alder reactions were applied to some of these chiral diene systems to get bicyclic compounds and comment on the stereoselectivity. Only one diastereomeric cycloadduct was observed as a result of Diels-Alder applications.

The major subject of this thesis is the synthesis of enantiomerically enriched gamma and delta lactones via Ring Closing Metathesis (RCM). Furan and thiophene substituted aldehydes were transformed to the corresponding heteroaryl substituted allylic and homoallylic alcohols by using vinyl and allylmagnesium bromide, respectively and then resultant racemic alcohols were resolved by hydrolase type enzymes (PSC-II, Lipozyme, CAL-B) with high enantiomeric excess values. Since the absolute configuration of alcohols were known, it was possible to determine the configuration of the synthesized compounds. After the enantiomeric enrichment of the alcohols, subsequent acylation with acryloyl and methacryloyl chloride afforded feasible diene system that was subjected to ring closing metathesis reaction 1st and 2nd generation Grubbs&rsquo / catalysts were used. These lactones were used to test their biological activities.