Doctor of Philosophy / Department of Chemistry / Duy H. Hua / (+)-Myriceric acid A, [(+)-1.1], is a natural product isolated in 0.01% yield from the southern bayberry, myrica cerifera twigs. It is a specific ETA receptor antagonist because it selectively inhibits the endothelin-1 (ET-1) induced increase in [Ca2+] (IC50 = 11 + 2 nM) and antagonizes the binding of ET-1 (Ki = 66 + 15 nM), in rat aortic smooth muscle cells. ET-1 is a potent vasoconstrictor peptide released by the vascular endothelial cell. Over production of this peptide causes vasospasm, which may lead to heart attack, stroke, pulmonary hypertension, and congestive heart failure. My research involved the development of a total synthesis of (+)-myriceric acid A. This is a triterpenoid compound that has five six-member rings, seven stereo-centers, a carboxylic acid group, and a trans-caffeoyl ester side chain. The synthesis was planned to be accomplished by adding the D and E rings to the known ABC ring compound (4a'S,4b'R,8a'R)-1',1',4a',8a'-tetramethyldecahydro-1'H-spiro[[1,3]dioxolane-2,2'-phenanthren]-8'(3'H)-one [(-)-2.1]. Many model studies, both convergent and linear syntheses, were conducted to determine the best approach to construct the D and E rings. From these studies it was determined that a linear synthesis was best. After the ABCD ring compound (4aR,4bR,6aR,10bR)-1,1,4a,10b-tetramethyl-4,4a,4b,5,6,6a,7,8,10b,11,12,12a-dodecahydro-1H-spiro[chrysene-2,2'-[1,3]dioxolan]-9(3H)-one [(-)-3.41a] was synthesized, several approaches were investigated for the functionalization of the D ring. The best method turned out to be one in which the C14 position of 3.41a was functionalized by a Michael addition of a nitrile group. Conversion of the nitrile to the aldehyde proved to be problematic, but was overcome by the formation of an interesting cyclic hemiiminal which hydrolyzed cleanly to the aldehyde (4aR,4bR,6aR,10aS,10bR,12aR)-1,1,4a,10b-tetramethyl-9-oxohexadecahydro-1H-spiro[chrysene-2,2'-[1,3]dioxolane]-10a-carbaldehyde (4.22) when treated with acid. Herein, the studies that led to the tetra-cyclic aldehyde 4.22, a key intermediate for the synthesis of (+)-myriceric acid A, will be discussed.

Doctor of Philosophy / Department of Chemistry / Duy H. Hua / The first chapter of this dissertation introduces and discusses the syntheses of a series of substituted quinolines as glycogen synthase kinase-3[beta] (GSK-3[beta]) inhibitors. GSK-3[beta] is highly associated with Alzheimer’s disease (AD), and it is suggested that inhibition of this enzyme could alleviate the symptoms of AD. Total 16 novel substituted quinolines were designed and synthesized, and their bio-activities were evaluated on MC65 cell protection assay. Four of the most active compounds were selected to test their enzyme inhibitory activities on GSK-3[beta] and protein kinase C assays. Among these compounds, 4-{[6-methoxy-4-methyl-5-(3-(trifluoromethyl)phenoxy)quinolin-8-ylamino]methyl} phenol (1.5) shows the highest MC65 cell protection and GSK-3[beta] enzyme inhibitory activities and potential enzyme specificity. Structure-activity relationship (SAR) was built as well, and the binding mode was simulated via computational method to interpret the observed SAR. Although additional bio-evaluation is needed, compound 1.5 is a promising lead compound for the development of more active and less toxic drug for the conteraction of AD. The second chapter introduces the progress on the total synthesis of myriceric acid A. Myriceric acid A is a triterpene-type natural product which was isolated from the young twigs of Myrica cerifera. It is a non-peptide endotheline-1 (ET-1) receptor antagonist. The total synthesis of this natural product started from the stereoselective synthesis of bicyclic intermediate (R)-5,8a-dimethyl-3,4,8,8a-tetrahydronaphthalene-1,6(2H,7H)-dione [(-)-2.28]. Then a new method was developed to enatioselectively synthesize the tricyclic intermediate (4aR,8R,8aR)-8-(tertbutyldimethylsilyloxy)-1,4a,8a-trimethyl-4,4a,4b,5,6,7,8,8a,9,10-decahydro phenanthren-2(3H)-one [(+)-2.72] which used the synthesized optically-pure (4aR,5R)-5-(tertbutyldimethylsilyloxy)-1,4a-dimethyl-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one [(-)-2.53] derived from (-)-2.28 and [alpha]-trimethylsilylvinyl ethyl ketone via a cascade reductive Michael addition – aldol condensation reaction. After functional group inter-conversion, the desired tricyclic intermediate (4a'S,8a'R)-1',1',4a',8a'-tetramethyldecahydro-1'H-spiro[[1,3]dioxolane-2,2'-phenanthren]-8'(3'H)-one [(-)-2.33] was synthesized. An intramolecular cascade Michael addition-aldol condensation reaction was designed to construct the triterpene-skeleton of myriceric acid A, and the desired starting material for this reaction was prepared with the trimethyl{(4a'R,8a'R)-1',1',4a',8a'-tetramethyl-3',4',4a',4b',5',6',8a',9',10',10a'-decahydro-1'Hspiro[(1,3)dioxolane-2,2'-phenanthrene]-8'-yloxy}silane [(-)-2.81] and 3,3-dimethyl-7-oxooctanal (2.46) via Mukaiyama aldol condensation reaction. The resulting pentacyclic compound was further transformed to the desired ester (6a'R,8a'R,12a'S,12b'R,14b'R)-ethyl 4',4',6a',11',11',14b'-hexamethyl-8'-oxo-2',4',4a',5',6',6a',8',8a',9',10',11',12',12a',12b',13',14',14a',14b'-octadecahydro-1'H-spiro[(1,3) dioxolane - 2, 3 '- picene]-8a'-carboxylate (-)-2.106. The further investigation on total synthesis of myriceric acid A will be pursued in future.

Master of Science / Department of Chemistry / Duy H. Hua / (+)-myriceric acid A is known as a non-peptide ETA receptor antagonist. It is isolated from the natural plant Myrica cerfera with 0.01% yield which is very low. The total synthesis of (+)-myriceric acid A is being pursued in Hua’s lab. (+)-myriceric acid A specifically blocks the vasoconstriction caused by endothelin-1 (ET-1). Because some derivatives of (+)-myriceric acid A were shown to have ET-1 receptor antagonistic effect, the tetracyclic terpenoid intermediates toward the total synthesis of (+)-myriceric acid A are postulated to have the similar antagonistic activities. The objective of this project is to study the release of vasoconstriction of these synthetic intermediates and compare their antagonistic potency. The ET-1 receptor antagonistic bioactivity of six (+)-myriceric acid A intermediates as well as (+)-myriceric acid A were evaluated by the in vitro spiral modiolar artery (SMA) bioassay. The synthetic intermediates which have not been reported in the literature were previously synthesized in Hua’s laboratory by Dr. Angelo Aguilar and Dr. Aibin Shi. Their synthesis was described in Dr. Aguilar’s PhD thesis. All the antagonistic effect evaluations were based on the SMA’s diameter changes. SMA’s diameter changes were induced by the superfusion of different extracellular solutions. The dose-response curves and straight lines were plotted to compare the antagonistic potency of these compounds. Based on the EC50 value of (+)-myriceric acid A intermediates (0.090 µM ~ 0.582 µM for the curves and 0.095 µM ~ 0.385 µM for the straight lines), all of the compounds have ET-1 receptor antagonistic activity, therefore the synthesis and screening of (+)-myriceric acid A intermediates is probably a promising route to develop new non-peptide ETA receptor antagonists.