As a part of a continuing search for bioactive compounds with the International Cooperative Biodiversity Group (ICBG), and in collaboration with the Natural Products Discovery Institute of the Institute for Hepatitis and Virus Research (IHVR), twelve plant extracts were investigated for their antiproliferative activity against the A2780 cell line, three plant extracts were investigated for their antimalarial activity against Plasmodium falciparum, and three plant extracts were investigated for their anti-inflammatory activity (PPAR-y inhibition). Bioassay-guided fractionation of extracts led to the identification of four new antiproliferative compounds (2.1-2.3, 3.1), five new anti-inflammatory compounds (6.4a, 6.5a-b, 6.6a, 6.6c), and twenty-eight known compounds from eight of the extracts. In addition, mallotojaponin C, an antimalarial natural product, and derivatives were synthesized and investigated for their antimalarial activity. / Ph. D.

As part of an International Cooperative Biodiversity Group (ICBG) program and a continuing search for antiproliferative natural products from the Madagascar rainforest, and a collaborative research project established between Virginia Tech and the Institute for Hepatitis and Virus Research (IHVR) focusing on searching for bioactive natural products from tropical forests in South Africa, 20 extracts were selected for investigation based on their antiproliferative activities against A2780 human ovarian cancer cell line or antimalarial activities against the Dd2 strain of Plasmodium falciparum. Bioassay-guided fractionation of seven of the extracts yielded twenty new compounds and twenty-four known compounds, and their structures were elucidated by using a combination of 1D (1H and 13C) and 2D NMR spectroscopy including COSY, HASQC, HMQC, HMBC, and NOESY sequences, mass spectrometry, UV, IR, ECD, optical rotation, and chemical conversions. In addition, ten known compounds were isolated from another five of the extracts, while studies on the remaining extracts were suspended due to loss of activity, unworkable small amounts of material, or low structural interest. The plants and their metabolites are discussed in the following order: five new antimalarial 5,6-dihydro-𝛼-pyrones and six bicyclic tetrahydro-𝛼-pyrone derivatives from Cryptocarya rigidifolia (Lauraceae); two new and five known antiproliferative lignans from Cleistanthus boivinianus (Phyllanthaceae); two new and two known antiproliferative sesquiterpenes lactones from Piptocoma antillana (Asteraceae); one new antiproliferative 1,4-naphthoquinone, one known antiproliferative isoflovonoid, and five known antiproliferative stilbenoids from Stuhlmannia moavi (Leguminosae); four known antiproliferative bisbenzylisoquinoline alkaloids from Anisocycla grandidieri (Menispermaceae); one new and two known antiproliferative butanolides, and two new antiproliferative secobutanolides from Ocotea macrocarpa (Lauraceae); one new antiproliferative and five known antiproliferative diterpenoids from Malleastrum rakotozafyi (Meliceae); and 10 known compounds from Monoporus sp. (Myrsinaceae), Premna corymbosa (Verbenaceae), Premna perplexanes (Verbenaceae), Epallage longipes (Asteraceae), and Cinnamosma fragrans (Canellaceae). / Ph. D.

As a part of the continuing search for bioactive compounds with the Madagascar International Cooperative Biodiversity Group (ICBG), and in collaboration with the Natural Products Discovery Institute of the Institute for Hepatitis and Virus Research (IHVR), thirteen plant extracts were investigated for antiplasmodial activity, thirteen plant extracts were investigated for antiproliferative activity, and one extract was investigated for inhibitors of the shikimate pathway in Plasmodium falciparum. Bioassay-guided fractionation of the extracts led to the identification of nineteen compounds with both antiplasmodial and antiproliferative activity, and thirteen compounds with only antiproliferative activity. Thirteen of these compounds (2.1 – 2.9, 3.3, 3.4, 4.5, and 5.1) were previously unknown. In addition total synthesis was used to confirm the structure of one new compound (4.5) and two other new natural-product like compounds (4.6 and 4.7) were also synthesized and investigated for antiplasmodial activity. / Ph. D. / Plants have a long history of producing compounds (Natural Products) that have been used as medicines. This dissertation focuses on the isolation of potential anticancer and antimalarial natural products from plants and their structure determination. The isolation of compounds was aided by the use of cell-based bioassays to determine the inhibition of cell growth. Growth inhibition of human ovarian cancer cells (the A2780 cell line) was used to test for potential anticancer activity, and growth inhibition of the malaria-causing parasite Plasmodium falciparum was used to test for potential antimalarial activity. Twenty-seven plant extracts from two different plant libraries were found to have biological activity in one of these bioassays, and bioassay-guided isolation performed on nine of these extracts led to the isolation of thirteen new compounds and fourteen known compounds. The isolation, structure determination, and biological evaluation of all isolated compounds are discussed in this work.

No / The tetracyclic nucleus of puupehenone, 15-oxopuupehenol and other sesquiterpene¿phenol natural products can be assembled stereoselectively in three steps, the last of these being the 6-endo-trig cyclisation of an alpha-keto radical generated from a substituted 2-(2-cyclohexenyl)ethyl 3-bromo-4-chromanone under metal-free conditions. / EPSRC

No / New antimalarial drugs are urgently needed to combat emerging multidrug resistant strains of malaria parasites. This Highlight focuses on plant-derived natural products that are of interest as potential leads towards new antimalarial drugs including synthetic analogues of natural compounds, with the exception of artemisinin derivatives, which are not included due to limited space. Since effective antimalarial treatment is often unavailable or unaffordable to many of those who need it, there is increasing interest in the development of locally produced herbal medicines; recent progress in this area will also be reviewed in this Highlight.

No

<p dir="ltr">Dihydro-β-agarofurans are a class of polyester sesquiterpene secondary metabolites isolated from the <i>Celastraceae</i> plant family. Many compounds in this class have demonstrated biological activity and have therefore generated much synthetic interest. However, their <i>trans</i>-decalin/tetrahydrofuranyl ring system and high levels of oxidation make them synthetically challenging. The first chapter presents a discussion on the biological activity and various historical methods used to construct this ring system. The second chapter describes the new dearomative oxidation/cyclization method developed by our group to rapidly synthesize the tricyclic ring system in only 9 steps from commercially available 6-methoxy-1-tetralone. Other key steps include a MHAT reduction of a b,b-disubstituted dienone, stereospecific reduction of an enone, and hydroxyl-directed Simmons-Smith cyclopropanation. The large-scale synthesis of these advanced synthetic intermediates and the attempted elaboration to the dihydro-β-agarofuran core is described in detail.</p>

Polycyclic polyprenylated acylphloroglucinols (PPAPs) are structurally complex natural products with promising biological activities. These compounds have interesting anticancer and anti-HIV properties as well as other biological activities making them highly attractive synthetic targets. We report a stereodivergent, asymmetric total synthesis of (−)-clusianone in six steps from commercial materials. We have implemented a challenging cationic cyclization forging a bond between two sterically encumbered quaternary carbon atoms. Mechanistic studies point to the unique ability of formic acid to mediate the cyclization forming the clusianone framework. We also present a biosynthesis-inspired, diversity-oriented synthesis approach for rapid construction of PPAP analogs via palladium-catalyzed dearomative conjunctive allylic alkylation (DCAA). These efficient palladium-catalyzed protocols construct the [3.3.1]-bicyclic PPAP core in a single step from their stable aromatic precursors. The first syntheses of 13,14-didehydroxyisogarcinol and garcimultiflorone A stereoisomers are reported in six steps from a commercially available phloroglucinol. Lewis acid-controlled, diastereoselective cationic oxycyclizations enabled asymmetric syntheses of (−)-6-epi-13,14-didehydroxyisogarcinol and (+)-30-epi-13,14-didehydroxyisogarcinol. A similar strategy enabled production of the meso-derived isomers (±)-6,30-epi-13,14-didehydroxyisogarcinol and (±)-6,30-epi-garcmultiflorone A. A convenient strategy for gram scale synthesis of these stereoisomers was developed utilizing diastereomer separation at a later stage in the synthesis that minimized the number of necessary synthetic operations to access all possible stereoisomers. Finally, we report cationic rearrangements of dearomatized acylphloroglucinols leading to the formation of unprecedented PPAP scaffolds. A novel type A [3.3.1]-bicyclic PPAP was produced as a major product and the structure confirmed by X-ray crystallographic analysis. A novel [3.3.1]-bicyclolactone was also produced utilizing an alternative substrate. Efforts will be described to determine the scope of these rearrangements and type A-selective cyclizations. / 2018-08-09T00:00:00Z

Leiodolide A is a unique natural product isolated from Pacific marine sponges which has provided an interesting target for total synthesis due to its complex structure and undefined stereochemistry. Although synthetic work towards the synthesis of sister compound leiodolide B has been published, the total synthesis of leiodolide A is yet to be achieved but remains an important target due to high potency against leukaemia, non-small lung and ovarian cancers. The convergent strategy towards the synthesis of leiodolide A involved the synthesis of three subunits; a synthetic route to the C21-C25 vinyl stannane is described, and efforts towards the synthesis of the bidirectional C11-C20 subunit are detailed. Asymmetric vinylogous aldol methodology was developed for the installation of the 1,2-syn propionate motif found in the C1-C10 subunit and in other polypropionate natural products, and was shown to be applicable to a range of substrates in moderate diastereoselectivity and excellent enantioselectivity.

Section I of the thesis deals with the enantiospecific total synthesis of phomopsolide B. Phomopsolide B was isolated from a strain of Phomopsis Oblonga. Enantiospecific total synthesis of phomopsolide B was accomplished in 13 overall yield in 12 linear steps using (S)-lactic acid and L-tartaric acid as chiral pool precursors. Present approach involves the efficient use of -keto phosphonate derived from commercially available (S)-ethyl lactate. Horner-Wadsworth-Emmons reaction and Still-Gennari olefination were employed as key reactions in the synthesis (scheme 1). Scheme 1: Total synthesis of phomopsolide B. [This work has been published: Prasad, K. R.; Gutala, P. Tetrahedron 2012, 68, 7489-7493.] Section II of the thesis describes the total synthesis of macrosphelides A and E which are isolated from a culture broth of Microsphaeropsis sp. FO-5050 and from the strain Periconia byssoides. Total synthesis of macrosphelides A and E was accomplished in 19 overall yield from commercially available (S)-ethyl lactate. Horner-Wadsworth-Emmons reaction and Yamaguchi lactonization were employed as key reactions for the total synthesis of macrosphelides A and E (scheme 2). Scheme 2: Total synthesis of macrosphelides A and E. [This work has been published: Prasad, K. R.; Gutala, P. Tetrahedron 2011, 67, 4514-4520.] Section III of the thesis deals with total synthesis and determination of absolute configuration of synargentolide B 1. Synargentolide B 1 is a 5,6-dihydro--pyrone containing natural product and was isolated from Syncolostemon Argenteus by Rivett et al. in 1998 (fig 1). The relative stereochemistry at C-6, C-6′ positions in synargentolide B 1 was assigned to be R, S respectively based on the positive cotton effect in the CD spectrum. Threo stereochemistry was proposed for the C1′-C2′ diol unit in synargentolide B 1 based on the NMR studies. The stereochemistry at C-5 could not be assigned, hence the structure of synargentolide B 1 was tentatively proposed as 6R-[5,6S-(diacetyloxy)-1,2-(dihydroxy)-3Eheptenyl]-5,6-dihydro-2H-pyran-2-one (fig. 1). Figure 1: Putative structure of synargentolide B 1. Based on the tentative stereochemistry at the C-6, C-6′ positions proposed by Rivett et al. and taking into consideration the threo relationship for the C-1′-C-2′ diol unit, it is anticipated that the structure of synargentolide B 1 could be one of the four possible diastereomers 1a-1d (fig 2). Figure 2: Possible diastereomers of synargentolide B (1a-d). Incidentally, one of the diastereomers 6R-[5R,6S-(diacetyloxy)-1S,2R-(dihydroxy)- 3E-heptenyl]-5,6-dihydro-2H-pyran-2-one 1d was a reported natural product isolated in 1990 from Hyptis oblangifolia by Pereda-Miranda, R. et al. along with its corresponding diacetylated product 2 (fig 3). Fig. 3: Natural products isolated from Hyptis oblangifolia by Pereda-Miranda, R. et al. Total synthesis and determination of absolute configuration of synargentolide B 1 were accomplished by synthesizing four possible diastereomers of the natural product (1a-1d) and by comparison of the spectral data of all synthesized diastereomers with that of reported for the natural product. Wittig-Horner reaction of -keto phosphonate derived from (S)-lactic acid and ring closing metathesis reaction were employed as key reactions in the total synthesis of synargentolide B 1 (scheme 3 and 4). Scheme 3: Total synthesis of possible diastereomers of synargentolide B (1a, 1b). Scheme 4: Total synthesis of possible diastereomers of synargentolide B (1c, 1d). [This work has been published: Prasad, K. R.; Gutala, P. J. Org. Chem. (in press)]. It was found that spectral data of 1a, 1b, 1c were not in agreement with that reported for synargentolide B 1. However spectral data of 1d was in complete agreement with the data reported for synargentolide B 1. Spectral data of 1d was also in complete agreement with the data reported for the natural product isolated by Pereda-Miranda, R. et al. Since the absolute stereochemistry of tetraacetate 2 is identical to the absolute stereochemistry of 1d, we wanted to confirm the integrity of the diol 1d by synthesizing the corresponding acetate 2 which was also a natural product isolated by Pereda-Miranda et al. 1H NMR data of the synthesized tetraacetate 2 was in agreement with that reported for the isolated tetraacetate, while discrepancies were observed in the 13C NMR spectral data. To clear the uncertainty, X-ray crystal structure analysis of the tetraacetate 2 was performed. It was comprehensively proved that the structure of synthesized tetraacetate 2 was indeed same as the putative structure proposed for the isolated tetraacetate by Pereda-Miranda et al. The crystal structure analysis also confirmed the absolute stereochemistry of the tetraacetate 2 and 1d (synargentolide B 1). (For structural formula pl refer the abstract pdf file)