The thesis entitled “Synthesis and applications of 1,4-diketones and γ-oxobutyramides derived from tartaric acid” is divided into two chapters. Chapter 1: Synthesis of TADDOL analogues by nucleophilic addition reactions and their application to the synthesis of α-methoxy arylacetic acid derivatives Synthesis of various TADDOL analogues by the addition of nucleophiles to 1,4-diketones derived from L-(+)-tartaric acid is presented in this chapter. It is found that the reduction of 1,4-Diketones 1a-d with K-Selectride pre-complexed with 18-crown-6 which is the optimized condition to attain better diastereoselectivity towards the C2-symmetric isomer 2a-d (Scheme 1). Addition of Grignard reagents to diketones 1a, 1eh is dependent on nature of Grignard reagents, solvent and temperature. (Structural formula) Scheme 1: Synthesis of TADDOL analogues Application of the synthesized TADDOL analogues in synthesis of enantiopure α-methoxy arylacetic acid derivatives is discussed. The C2-symmetric 1,4-diols 2a-d (TADDOL analogues) are utilized in the synthesis of enantiopure α-methoxy arylacetic acid derivatives as shown in scheme 2. Scheme 2: Synthesis of α-methoxy arylacetic acid derivatives. (SF) Both enantiomers of α-alkyl-α-methoxy arylacetic acids 13a-b and ent-13a are synthesized from the respective C2-symmetric diols 5a-b and 7a-b (scheme 3). (SF) Scheme 3: Synthesis of both enantiomers of α-alkyl-α-methoxy arylacetic acids. Chapter 2: Facile Synthesis of α,β-dihydroxy-γ-butyrolactones and jaspine B from γ-oxobutyramides derived from tartaric acid A short and efficient route for the synthesis of γ-alkyl/aryl-α,β-dihydroxy-γ-butyrolactones 15a-j is accomplished from γ-oxobutyramides 14a-l derived from tartaric acid. Key step includes a controlled addition of Grignard reagent and stereoselective reduction (Scheme 4). (sF) Scheme 4: Synthesis of α,β-dihydroxy-γ-butyrolactones and jaspine B. Utility of the γ-oxobutyramides is further exemplified in the synthesis of jaspine B 18 a cytotoxic anhydrophytosphingosine in 48% overall yield (Scheme 5). (SF) . Scheme 5: Synthesis of α,β-dihydroxy-γ-butyrolactones and jaspine B. Appendix: Serendipitous observation of polymorphism in TADDOL analogue induced by the presence of chiral impurity Polymorphism in one of the TADDOL analogues is serendipitously observed and demonstrated that the 2% impure diastereomer is responsible for the formation of one of the pol ymorphic crystals (Figure 1). (SF) Figure 1: Diastereomeric impurity induced polymorphism. (For structural formula pl see the pdf file)

Les foldamères – structures oligomériques artificielles adoptant une forme repliée définie – permettent la conception de récepteurs moléculaires de type capsule capables de reconnaitre sélectivement certains analytes pertinents du vin. En particulier, des récepteurs sélectifs et affins du fructose, de l’acide tartrique et de l’acide malique ont été identifiés au cours de ces dernières années. Le développement d’une méthodologie de synthèse sur support solide d’un récepteur moléculaire de l’acide gluconique sera abordé dans ce manuscrit. Cette thèse montre également comment certains de ces récepteurs peuvent être convertis en détecteurs capables d’émettre un signal en présence de l’analyte. La démarche est centrée sur l’incorporation d’un fluorophore au sein du site de reconnaissance. Une preuve de concept a ainsi été effectuée avec le dosage par fluorescence de l’acide tartrique. Enfin, le greffage de ce détecteur moléculaire à la surface de particules de silice a été réalisé et ouvre la voie au développement de dispositifs portables pour le dosage des analytes reconnus. De tels détecteurs sont requis par l’industrie du vin afin d’assurer le contrôle des processus biologiques, en particulier durant la fermentation. / Some relevant wine small molecular components can be selectively recognized by foldamer capsules – artificial oligomeric compounds able to fold into well-defined objects possessing an inner cavity. In recent years, selective and high affinity receptors for fructose, tartaric acid and malic acid have been reported. Here, a new methodology, using solid phase synthetic techniques, for the preparation of a gluconic acid receptor will be discussed. To transform these receptors into sensors, a fluorescent moiety has been incorporated in the binding site. A proof of concept has been achieved using a fluorescence titration of tartaric acid. Indeed, when the guest is encapsulated, a modification of the fluorescence emission is observed. Finally, these fluorescent receptors have been anchored to silica surfaces and pave the way to the development of mobile detection devices. Such sensors could be useful to the wine industry to ensure proper control of biological processes for example during fermentation.

I present detailed mechanistic analysis on the chemistry of glyoxylate as it pertains to forming biologically relevant molecules on the Hadean Earth. Chemistry covered includes: 1) the dimerization of glyoxylate to form dihydroxyfumarate(DHF), a heretofore unknown reaction, important to substantiating Eschenmoser's glyoxylate scenario. 2) Formation of sugars from polymerization of glyoxylate. 3) Formation of tartrate and sugar acids from high pH reactions of DHF. 4) Formation of glycine polypeptides from glyoxylate by transamination and coupling promoted by hexamethylenetetramine. 5) Formation of glyoxylate under conditions which could be plausibly found on the early earth.

Das Ziel dieser Arbeit bestand in der Synthese neuartiger homochiraler Molekülstrukturen, welche nach Konzepten des Crystal Engineering über ein starres Grundgerüst sowie koordinationsfähige Haftgruppen verfügen sollten. Unter Verwendung von Wein- und Milchsäure, als Vertreter der natürlich vorkommenden, enantiomerenreinen α-Hydroxycarbonsäuren, konnten die entsprechenden Derivate mit aromatischen und/oder acetylenischen Spacerelementen hergestellt und umfassend charakterisiert werden. Die synthetisierten Wein- und Milchsäureverbindungen sowie die sich von den jeweiligen Weinsäureestern ableitenden TADDOLe wurden außerdem auf ihre optische Aktivität, ihre Affinität gegenüber verschiedenen Lösungsmitteldämpfen, ihr Einschlussverhalten gegenüber achiralen und chiralen Lösungsmitteln sowie ihre Eignung als organische Linker bei der Synthese von metallorganischen Gerüststrukturen untersucht. Mittels Röntgeneinkristallstrukturanalyse konnten die Festkörperstrukturen einiger Derivate aufgeklärt und diese hinsichtlich ihrer Konformation verglichen werden.

First chapter of the thesis describes the desymmetrization of the bis-dimethyl amide 1 derived from tartaric acid with vinyl Grignard reagents and subsequent reduction of the resultant -keto amides 2a-c to the -hydroxy amides 3a-c. Application of the -hydroxy amides 3a-c in the total synthesis of bio-active natural products such as gabosines, crassalactone C and anamarine is described in the subsequent sections. In section A of the first chapter, application of the -hydroxy amides 3a-b to the total synthesis of gabosine A 4, gabosine F 5 and gabosine H 6 was described. Key strategy in the synthesis was the use of ring closing metathesis (RCM) reaction. Incidentally, the total synthesis of gabosine H 6 was not only accomplished for the first time but the synthesis also ascertained the absolute stereochemistry of the natural product. During the course of the synthesis of gabosine A 4, an unprecedented formation of a unique 14-membered macrocycle 7 was observed. Incisive studies were conducted to elucidate the reaction sequence for the formation of the macrocyle 7. It was found that the formation of the macrocycle 7 was through a tandem cross-metathesis/intramolecular hetero Diels-Alder reaction. Section B of chapter 1 delineated the utility of the -hydroxy amide 3a in the total synthesis of (–)-crassalactone C 8a. Crassalactone C 8a is a cinnamoyl derivative of styryllactone natural product goniofufurone and was found to possess marginal in vitro cytotoxic activity. Pivotal strategies in the synthesis include the use of bis-cinnamoyl ester 10a in the ring closing metathesis reaction which also evades the selective cinnamoylation of the benzylic hydroxy group. Section C of Chapter 1 deals with the total synthesis of (+)-anamarine 11. While the - hydroxy amide 3a was employed to synthesize an important intermediate 12 enroute to the synthesis of anamarine, to mitigate the number of steps in the synthesis, the -hydroxy amide 13 was employed for the synthesis of (+)-anamarine 11. Key reactions in the total synthesis include the use of 1,3-dithiane as a surrogate for the methyl group, Brown’s allylation and ring closing metathesis. In second chapter of the thesis, formal total synthesis of iriomoteolide 3a 16 is presented. Iriomoteolide 3a 16 is a unique 15-membered marine macrolide isolated by Tusda’s group from the Amphidinium strain HYA024, with impressive in vitro cytotoxic activity against human lymphoma cell line DG-75 (IC50 0.08 g/mL) and Raji cells (IC50 0.05 g/mL). Salient features of the synthesis include the synthesis of the chiral aldehyde 19 from the oxazolidinone 17 and the use of -keto phosphonate 20 derived from D-(–)-tartaric acid in the Horner-Wadsworth-Emmons olefination reaction to construct the C1-C10 fragment 23 of iriomoteolide 3a 16. Synthesis of the C10-C18 fragment 29 was accomplished from the butyrolactone 24 using Keck allylation and olefin cross metathesis reactions as key steps. Ring closing metathesis of the ester 30, followed by selective deprotection of the primary TBS group afforded the key intermediate 31, the transformation of which to iriomoteolide 3a 16 is known in literature.

Resin found within Canaanite amphorae from the Late Bronze Age shipwreck discovered off the coast of southwest Turkey at Uluburun has previously been identified as Pistacia sp. Although evidence from Egypt suggests that this resin was in high demand and typically transported in such amphorae, it has also been proposed that the amphorae contained wine, with the resin used to seal the interior surfaces and to flavour and/or preserve the wine. To attempt to resolve this question, we have analysed five samples of pistacia resin found in amphorae from the shipwreck using a range of analytical techniques which have used in the past for the analysis of wine residues: spot tests, FT-IR, and HPLC-MS-MS. As well as the archaeological samples, we have analysed modern samples of pistacia resin, leaves and fruit to determine the effectiveness of each technique and to exclude the possibility of false positive results. In addition to the analyses for wine we also detail analysis (GC-MS) of the terpenoids for the purpose of further molecular characterisation of the resin. Bulk stable isotope analysis was used in comparison with similar resins to attempt to identify the geographical origin of the resin.

<i>Cryptosporidium parvum</i> is a protozoan parasite historically associated with waterborne and more recently foodborne outbreaks of diarrheal illness. Contamination of certain foods, such as unpasteurized apple cider, with infective oocysts may occur as oocysts are shed in the feces of common ruminants like cattle and deer that graze in and around orchards. Cryptosporidiosis can result in a severe illness for previously healthy individuals and a life-threatening illness in immunocompromised individuals. Disease occurs after the ingestion of small infective oocysts (4 to 5 mm in size). The relatively thick membrane of the oocysts allows them to be resistant to chlorine and many other environmental pressures, making oocysts difficult to inactivate. In this study, alternative treatments to pasteurization were evaluated for their ability to inhibit <i>C. parvum</i> oocyst viability in fruit juices. Oocyst viability was analyzed with a cell culture infectivity assay, using a human illeocecal cell line (HCT-8) that is most similar to human infection. The percent inhibition of infection by each treatment was determined along with the corresponding log reduction for the treatments found to be most effective. Infection by treated oocysts was compared to that of control untreated oocysts. Cell monolayers were infected with 10⁶ treated oocysts or a series of 10-fold dilutions. Parasitic life stages were visualized using an immunohistochemistry system and 100 microscope fields counted per monolayer. Organic acids and H₂O₂ were added on a wt/vol basis to apple cider, orange juice, and grape juices. Malic, citric, and tartaric acids at concentrations from 1%-5% inhibited <i>C. parvum</i> infectivity of HCT-8 cells by up to 88%. Concentrations ranging from 0.025%-3% H₂O₂ were evaluated where addition of 0.025% H₂O₂ to each juice resulted in a >5 log reduction of C. parvum infectivity as determined with an MPN-based cell culture infectivity assay. Treating apple cider, orange juice, and grape juice with ozone for a time period of 30 seconds up to 15 minutes at 6° and 22°C (0.9 g/L flow rate) inhibited C. parvum viability to > 90% as monitored in the cell culture assay. It is hypothesized that oocyst wall proteins that are necessary for infection are oxidized by the reactive oxygen species generated from the decomposition of the ozone and hydrogen peroxide treatments. These treatments or combinations thereof may offer potential alternatives to traditional pasteurization for fruit juices to successfully inhibit <i>C. parvum</i> viability. / Ph. D.

The influence of rootstock and canopy density on grape berry composition was investigated over the summer of 2003-2004 on a commercial vineyard at Waipara, North Canterbury. This experiment was designed to investigate the influence of rootstock and canopy density on the acid composition, potassium (K) content and final pH of harvested fruit (Pinot Noir AM 10/5 Lincoln Selection). The trial block consisted of eight rootstocks laid out to an 8 x 8 latin square, each plot consisting of five vines of the same rootstock. Two canopy treatments were overlaid the block (down whole rows, assigned randomly, four rows to each treatment); one treatment allowed to grow naturally, in the other treatment the canopy was thinned removing double burst shoots and laterals. The bunch numbers were adjusted in the Unthinned canopy treatment (UCT) to match the Thinned canopy treatment (TCT). Information was gathered to assess: the canopy size and density (Pinot Quadrat Leaf Layer and Percent Gaps and canopy porosity), the plant yield (and berry size, berries per cluster, cluster weight, clusters per plant), plant K levels at flowering and veraison (from petioles and leaf blades) and berry composition at harvest (soluble solids (as brix), K, titratable acidity (TA), tartaric acid concentration, malic acid concentration and pH). The trial area was non-irrigated on clay loam soils and viticultural management was to best commercial practice. It was found that although rootstock influenced the levels of K in the plant and in the juice at harvest, the level of K in the juice did not influence pH in this experiment (range of rootstock juice K: 808 ppm to 928 ppm, l.s.d. = 75 ppm). The level of tartaric acid concentration in the juice was found to be the dominant influence on the level of pH in this experiment (rootstock pH range: 3.21 to 3.39, l.s.d. = 0.05). The juice concentration of tartaric acid was influenced by both rootstock (rootstock range 4.0 to 4.7 g/L, l.s.d = 0.4) and canopy density (UCT = 4.1, TCT = 4.7, l.s.d. = 0.4), decreased shading positively increasing the level of tartaric acid. The malic acid concentration in the juice was positively influenced by increasing canopy density (UCT = 4.7 g/L, TCT = 4.1 g/L, l.s.d = 0.4) and this played a minor role in the determination of pH in this experiment; an influence of rootstock on the level of malic acid concentration was found. The malic acid concentration strongly influenced the determination of TA (UCT = 11.0 g/L, TCT = 10.2 g/L, l.s.d = 0.5); tartaric acid concentration had a minor influence on the recorded TA. Attempts to characterise the influence of rootstock on malic acid, tartaric acid and pH were inconclusive. Rootstock was found to influence the canopy variables measured in this experiment and the recorded average plant yield. Crosses of Vitis rupestris were found to exhibit the most canopy vigour and those derived from Vitis berlandieri and Vitis riparia the least. The Canopy treatment did not show an influence over yield but the rootstock was found to influence plant yield, through the numbers of berries set in a cluster and the final harvest cluster weight. The influence of rootstock on pH may be described by the influence it exerts on canopy growth and yield but this was thought unlikely. Further research is required to describe the nature of the rootstock influence on K, malic acid, tartaric acid and pH.

Les effets du changement climatique ont d’ores et déjà été observés sur la vigne : avancement des stades de développement, augmentation des teneurs en alcool des vins, baisse excessive de leur acidité. Une des voies d’adaptation possible de la viticulture est la création de nouvelles variétés. J’ai caractérisé la variabilité phénotypique de 120 descendants de croisements entre Riesling (RI) et Gewurztraminer (GW) pour (1) les stades de développement, décrits à l’aide de sommes de températures (2) la capacité à accumuler des sucres dans les raisins (3) les paramètres de l’acidité des raisins. L’utilisation de marqueurs moléculaires sur l’ADN a permis de mettre en évidence des relations entre données génétiques et phénotypiques pour tous les caractères étudiés (QTLs ou Quantitative trait loci). La principale conclusion est que la variabilité génétique pour les paramètres de l’acidité des raisins est la voie à valoriser en priorité pour l’adaptation de la vigne au changement climatique. / The effects of climate change have already been observed on the grapevine : advance of phenological stages, increase in the alcohol content of the wines, excessive decrease of their acidity. Breeding new varieties is one of the possible means of adaptation. I have characterized the phenotypic variability of 120 genotypes, offspring from crossings between Riesling (RI) and Gewurztraminer (GW)for (1) the developmental stages, described with heat sums (2) the ability to accumulate sugars in the berries (3) the parameters for acidity. The use of DNA molecular markers allowed the detection of quantitative trait loci (QTLs) for all the traits studied. The main conclusion is that the genetic variability for the parameters determining the acidity of the berries is the most promising for the adaptation of grapevine cultivation to climate change.

Das Ziel dieser Arbeit bestand in der Synthese neuartiger homochiraler Molekülstrukturen, welche nach Konzepten des Crystal Engineering über ein starres Grundgerüst sowie koordinationsfähige Haftgruppen verfügen sollten. Unter Verwendung von Wein- und Milchsäure, als Vertreter der natürlich vorkommenden, enantiomerenreinen α-Hydroxycarbonsäuren, konnten die entsprechenden Derivate mit aromatischen und/oder acetylenischen Spacerelementen hergestellt und umfassend charakterisiert werden. Die synthetisierten Wein- und Milchsäureverbindungen sowie die sich von den jeweiligen Weinsäureestern ableitenden TADDOLe wurden außerdem auf ihre optische Aktivität, ihre Affinität gegenüber verschiedenen Lösungsmitteldämpfen, ihr Einschlussverhalten gegenüber achiralen und chiralen Lösungsmitteln sowie ihre Eignung als organische Linker bei der Synthese von metallorganischen Gerüststrukturen untersucht. Mittels Röntgeneinkristallstrukturanalyse konnten die Festkörperstrukturen einiger Derivate aufgeklärt und diese hinsichtlich ihrer Konformation verglichen werden.