Date of Award
5-2014
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Legacy Department
Chemistry
Committee Chair/Advisor
Dr. R. Karl Dieter,
Committee Member
Dr. Bill Pennington
Committee Member
Dr. Dev Priya Arya
Committee Member
Dr. Rhett C. Smith
Committee Member
Dr. Daniel C. Whitehead
Abstract
The research discussed in this dissertation is focused on developing new synthetic methodologies for the construction of carbon-carbon and carbon-heteroatom bonds present in several natural products and synthetic intermediates employing organometallic reagents and/or organocatalytic procedure. The presence of rich functionality in the reactive synthons under study provides opportunities for studying a variety of reactions. Effecting a reaction in a regio- and stereoselective fashion is highly attractive as the resulting synthons can be used for the syntheses of larger molecules. We have explored unprecedented variation of Michael Initiated Ring Closure (MIRC) reactions for the syntheses of 1,2,3-trisubstituted cyclopropane derivatives, owing to their numerous applications in several fields involving synthesis of natural products, agrochemicals, pharmaceuticals and flavor/fragrance additives via the reaction of ã,ä-epoxy Michael substrates (e.g., epoxyenoates, epoxyenones, epoxyensulfones and epoxyenamides) with organozincate reagents under the conditions catalytic or stoichiometric in the zinc(II) salts. The diastereoselectivity of a cyclopropanation reaction is dependent upon the solvent employed for alkyl Grignard reagents reacting with epoxyenoates, ensulfones, and enamides but solvent independent for reaction with enones. Excellent diastereoselectivity can be achieved for the epoxy enoates, enones, and ensulfones while the enamides afford modest diastereoselectivity even under optimal conditions. The MIRC adduct can be achieved with phenylmagnesium bromide under the specific reaction conditions designed to minimize the biphenyl formation. The newly developed protocol can also be extended for the diastereoselective cyclopropanation reaction of organozincate reagents with ã-haloenoates. The next application of our new methodologies is to seek a regioselective 1,4-conjugate addition reaction of Grignard reagents to nitrodienes in the presence of Zn(II) salts. The fine-tuning of reaction conditions and employment of a wide range of ligands such as alkyl, aryl, heteroaryl, allyl, vinyl, 1-alkynyl, alcohols and alkyl thiols gave regioselective 1,4-conjuagte addition products in excellent yields. The newly discovered methodology can also be used for the regioselective 1,4-conjugate addition reaction to 2,4-hexadienethiolate. In addition, we made progress in developing new synthetic methodologies for halofunctionalization of alkenes promoted by chiral organocatalyst. Several amidines and Schiff bases effectively catalyze the N-bromosuccinimide (NBS) or N-iodosuccinimide (NIS) promoted haloacetoxylation or haloetherification of alkenes and halolactonization of unsaturated acids in high yield (56-97%) and high diastereoselectivity (95:5-100:0 dr). Our investigation confirmed that the carbon nitrogen double bonds of amidines or Schiff bases acted as efficient catalyst for the transfer of halonium (usually bromonium or iodonium) ion from halogen sources to alkene. Several nucleophilic species such as anions of alcohols, alkyl thiol, benzyl thiol and methane sufonic acid were successfully employed for the bromofunctionalization reaction. Our continued effort in exploring new organocatalysts, imidazolium salts, chiral phosporamidite and chiral diphenylprolinol silyl ether were explored as new entries for the stereoselective halofunctionalization reactions. The piperidine ring is an important structural subunit of many naturally occurring alkaloids and pharmaceutical products. In pursuit of a catalytic asymmetric approach to substituted piperidines or piperidinones, the conjugate addition reaction of Grignard reagents to 4-pyridones using chlorotrimethylsilane or borontrifluoride-diethylether as additive was explored. Copper catalysis was not required for the reaction and mechanistic rationalization suggest the conjugate addition of Grignard reagents to 4-pyridones. This new protocol can be used for the diasteromeric synthesis of trans-2,6-disubstituted tetrahydropyridones selectively, while cuprates give both cis or trans disastereomers or mixtures. The assignment of stereochemistry of these diastereomers is often problematic. The 1D and 2D NMR spectra of the 2,6-disubstituted tetrahydropyridones and corresponding piperidinols was investigated.
Recommended Citation
Dhakal, Ramesh, "New Synthetic Methodologies for Chemo-, Stereo-, and Regioselective 1,4-Conjugate Additions of Organometallic Reagents to Michael and Extended Michael Substrates and Alkene Halofunctionalization Reactions" (2014). All Dissertations. 1353.
https://open.clemson.edu/all_dissertations/1353