Vinigrol is a structurally unique diterpenoid natural product featuring a tricyclo[4.4.4.0.4a,8a]tetradecene carbon skeleton containing eight contiguous stereocenters and a challenging oxygenation pattern. Vinigrol has been demonstrated to possess a wide array of biological activities including tumor necrosis factor (TNF) antagonism, antihypertensive activity, and platelet aggregation inhibitory activity. Our first-generation plan for the synthesis of vinigrol utilized a cascade reaction sequence involving: (1) diastereoselective alkylation of an α-alkenyl-β-ketoester, (2) retro-aldol-aldol equilibration (3) anion-accelerated oxy-Cope rearrangement, and (4) transannular Dieckmann condensation to afford the bicyclo[5.3.1]undecene ring system of vinigrol in a single operation. Discoveries concerning the limitations of this process are disclosed. Our second-generation approach to vinigrol employed a cis-decalin substrate in an alternative cascade reaction sequence, which was expected to deliver the complete tricyclo[4.4.4.0.4a,8a]tetradecene carbon skeleton of vinigrol in one step. An unexpected deviation from the envisioned reaction pathway instead afforded an alternative tricyclic enol silane. / Chemistry and Chemical Biology

β-Lactones are a class of structurally unique compounds. The versatile reactivity patterns offered by β-lactones have enable chemists to utilize them as powerful synthetic vehicles in complex molecule synthesis. In the total syntheses of the naturally occurring, α-glucosidase inhibitors schulzeines B & C, a readily available trichloromethyl β-lactone was used as a versatile masked surrogate for bishomoserine aldehyde, which led to a highly efficient construction of the core structures through a pivotal Pictet-Spengler condensation and a Corey-Link reaction. The first total synthesis of (+)-omphadiol was achieved in ten steps from (R)-carvone. This synthesis features a three-step synthesis of a bicyclic β-lactone, which constitutes the key intermediate for the highly stereocontrolled introduction of the six contiguous stereogenic centers in the natural product. In efforts toward the total syntheses of scabrolides A & B and sinulochmodin C via transannular C-H insertions, β-lactones served as the key intermediates for the synthesis of complex macrocyclic model substrates. These model studies provided valuable insights into the reactivity and selectivity issues for transannular C-H insertion reactions.

The indole alkaloids, a class of natural products, have received much synthetic attention for years due to their diverse structures and interesting biological properties. We are particularly interested in synthesizing some of the yohimbine alkaloids extracted from the bark of a tall evergreen African tree (Corynanthe yohimbe, commonly known as fringe tree). Yohimbine and its stereoisomers have been tempting targets for synthetic organic chemists for more than fifty years. These compounds feature a pentacyclic ring system with two heteroatoms and five stereogenic centers. Broadly, the fifteen different synthetic approaches that led to the successful completion of yohimbine alkaloids relied only on two basic synthetic strategies. In the first strategy, the last step almost always was the formation of the C(2)-C(3) bond by either Pictet-Spengler reaction or by Bischler-Napieralski reaction with the concomitant formation of the C ring. The second strategy involved the annulation of the D and E rings onto the intact ABC ring system. With our double annulation methodology, herein, we report a completely different synthetic approach to access the yohimbine alkaloids, and our disconnections are not even remotely close to the synthetic designs used in the past. Our key steps include double Michael reaction to construct the E ring, an intramolecular cyclization to construct the D ring, and finally, the functionality on the D ring can be elaborated to form the C ring of the yohimbine alkaloids.

Vinigrol was isolated in 1987 from the fungal strain Virgaria nigra F-5408 by Hashimoto and co-workers. This compound was identified as having antihypertensive and platelet aggregation properties as well as being recognized as a tumor necrosis factor inhibitor. Aside from its interesting biological activities, vinigrol also possesses a unique structural motif consisting in a decahydro-1,5-butanonaphthalene core decorated with 8 contiguous stereocenters. Despite synthetic efforts by many research groups since its isolation, it wasn’t until 2009 that the first total synthesis of vinigrol was reported by Baran and co-workers. Herein is presented a formal synthesis of this highly compact molecule which relies upon a highly diastereoselective ketal Claisen rearrangement as the stereodefining step and an intramolecular Diels-Alder reaction to access the tricyclic structure of the molecule. (+)-Digitoxigenin is a cardiac glycoside used in the treatment of many ailments such as congestive heart failure. It is a member of the cardenolides, a sub-type of steroid containing certain structural differences such as cis A/B and C/D ring junctions, a tertiary hydroxyl group at C14 and a butenolide substituent at C17. Although a few syntheses of this class of compounds have been reported, general strategies to access their framework is scarce. Herein we report our studies towards the total synthesis of digitoxigenin which rely upon a cascading gold-catalyzed cycloisomerization (or enyne metathesis)/Diels-Alder reaction.

The ascidian isolation artifact didemnaketal A is a highly oxygenated polyisoprenoid capable of inhibiting HIV-1 protease through an unusual dissociative mechanism. However, recent synthetic efforts have cast doubt on stereochemical assignments in the originally published structure. In the interest of elucidating the true structure of didemnaketal A through total synthesis, we present a strategy for rapidly accessing the putative spiroketal fragment by exploiting its latent symmetry. In a single step, double Sharpless asymmetric dihydroxylation reactions (SAD) allowed us to simultaneously set all seven stereogenic centers and assemble this complex fragment from non-chiral material. The precursor was obtainable through a racemic synthesis in which the geometric isomers of a nine-membered cyclic enone converged in a ring-opening cross metathesis reaction (ROCM). / Graduate / 0490 / jdavy@uvic.ca

This thesis explores new synthetic routes for the formation of CDE & EFG fragments of pectenotoxin-4. Chapter 1: Introduction and Previous Work: This chapter reviews the discovery and biological activities of members of the pectenotoxin family. Two previous total syntheses are discussed, and previous work regarding the synthesis of ABC, E and FG fragments within the group is introduced. Chapter 2: Synthesis of the E Ring Fragment of Pectenotoxin-4: The synthesis of the E ring fragment is discussed. Key reactions include Negishi coupling and osmium mediated oxidative cyclisation. Chapter 3: First Generation Strategy for the Synthesis of the D ring: A simple model towards the D ring core was completed using alkyne-epoxide opening strategy. The application on a more sophisticated system was tested. Chapter 4: Second Generation Strategy for the Synthesis of the D ring: Sonogashira coupling was successfully tested as key step to unite two coupling partners; and further functionalisation towards the D ring skeleton was studied. Chapter 5: Third Generation Strategy for the Synthesis of the D ring: The new strategy including a Lewis acid assisted coupling and mercury mediated hydration of alkyne sequence was completed on a simple model. The application on a more sophisticated system was tested. Chapter 6: Synthesis of EFG Fragment of Pectenotoxin-4: Key Julia-Kocienski olefination between E ring fragment and FG ring fragment was examined. The further functionalisation of the resulting coupling product towards EFG fragment was finished. Chapter 7: Experimental: Full experimental procedures and characterisation of compounds are reported.

Rubriflordilactones A and B are highly oxygenated nortriterpenoid natural products isolated from Schisandra rubriflora. The latter is of particular biological interest as it shows significant anti-HIV activity. Two transition metal-catalysed cascade cyclisation approaches for the formation of the CDE rings of the rubriflordilactones were developed. Palladium-catalysed cyclisation of bromoenediynes and cobalt-catalysed triyne cyclotrimerisation both transform acyclic precursors into 7,6,5-bisannelated arenes in a single step. Two enantioselective syntheses of the AB ring fragment common to both rubriflordilactones, with bromoene or alkyne functional groups required for the respective cyclisation methods, are described; along with the refinement of a route to the CDE diyne fragment of rubriflordilactone A. From these fully functionalised bromoenediyne and triyne substrates, both metal-catalysed cyclisation methods were successful; these strategies converged on a late-stage intermediate bearing the ABCDE ring system of rubriflordilactone A. Construction of the F ring, followed by attachment of the G ring by an intriguing oxo-carbenium ion addition reaction completed two enantioselective total syntheses of (+)-rubriflordilactone A.

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.

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)

Lomaiviticin A (1) and B (2) are natural products with remarkably complex C2-symmetric structures and potent antiproliferative properties. Achieving total syntheses of 1 and 2 has been a long-standing project in the Shair group and part one of this thesis describes our first successful synthesis of the C4-epi-lomaiviticin A and B core structures. A key stereoselective oxidative enolate dimerization of an oxanorbornanone system was employed to establish the highly hindered C2-C2' bond. Crucial to our completion of the lomaiviticin core structures was the discovery of subtle yet far-reaching stereoelectronic effects imparted by the C4/C4'-stereocenters. The Lycopodium alkaloids are a family of complex polycyclic alkaloid natural products that have long served as popular targets for developing synthetic chemistry. More recently, select members have been reported to exhibit neurological effects. Part two of this thesis presents the development of a biomimetic, unified strategy for the synthesis of 7-membered ring-containing Lycopodium alkaloids and its successful application toward the first total syntheses of the proposed structure of (-)-himeradine A (38), (-)-lycopecurine (39), and (-)-dehydrolycopecurine (199), and the syntheses of (+)-lyconadin A (31) and (-)-lyconadin B (32). A biosynthetically inspired one-pot cascade reaction sequence was developed to construct the strained polycyclic core structure shared amongst these alkaloids. Additionally, the syntheses of 38, 39, and 199 featured a biomimetic intramolecular Mannich reaction to furnish the tetracyclic ring system. The successful application of our unifying strategy toward the synthesis of a diverse set of alkaloids lends support to our biosynthetic hypothesis that 7-membered ring-containing Lycopodium alkaloids arise from a common precursor. Our synthetic approach can potentially provide access to all such natural products. / Chemistry and Chemical Biology