Bochum, Universiẗat, Diss., 2003.

No description available.

Introduction: Exposure to hypoxia may alter substrate utilization through diverse mechanisms. Acute hypoxia is known to increase circulating nonesterified fatty acid (NEFA) levels and reduce systemic sensitivity to insulin. The hepatic fate of NEFA is dictated by major pathways such as esterification to triglycerides and complete/partial oxidation, the latter leading to ketogenesis. To our knowledge, the effect of hypoxia on ketogenesis, more specifically ß-hydroxybutyrate (ßOHB), remains unknown in humans. Moreover, adipose tissue is a significant site of NEFA liberation into circulation, and insulin inhibits this process. Under acute hypoxia, systemic insulin resistance develops, and the suppression of lipolysis is impeded. Therefore, the objective of this study was to determine the effect of acute hypoxia on plasma circulating ßOHB levels. Furthermore, to better understand how hypoxic and prandial conditions may modulate plasma NEFA and ketonemia, we calculated the βOHB:NEFA ratio and the adipose tissue insulin resistance index (Adipo-IR), which respectively gives indications of the partial hepatic oxidation of NEFA and the adipose tissue insulin sensitivity. Methods: Plasma samples from 3 different randomized crossover studies were retrospectively assessed for ßOHB concentrations. In the first study, 14 healthy men (23 ± 3.5 years) were exposed to 6 hours of normoxia or intermittent hypoxia (IH) (15 hypoxic events per hour) following an isocaloric meal (IH-Fed). In the second study, 10 healthy men (26 ± 5.6 years) were exposed to 6 hours of continuous normobaric hypoxia (CH) (FiO2= 0.12) or normoxic conditions in the fasting state (CH-Fasted). In the third study, 9 healthy men (24 ± 4.5 years) were exposed to 6 hours of CH in a constant prandial state. ßOHB, NEFA and insulin levels were measured during all sessions (CH-Fed). The adipose tissue insulin resistance index (Adipo-IR) was also calculated from NEFA and insulin levels. Results: In study 1 (IH-Fed), ßOHB and NEFA levels tended to be greater over 6 hours of IH (condition x time interaction, p = 0.108 and p = 0.062, respectively) compared to normoxia. In study 2 (CH-Fasted), ßOHB and NEFA levels increased over time in both experimental conditions, and this effect tended to be greater under CH (condition x time interaction, p = 0.070 and p = 0.046, respectively). In study 3 (CH-Fed), ßOHB levels slightly increased up to 180 min before falling back to initial concentrations by the end of the protocol in both normoxia and CH (p = 0.062), while NEFA slightly increased under CH (p = 0.006). Adipo-IR tended to increase after 6 hours of hypoxia compared to normoxia in the first two studies (main effect of condition, p = 0.024; p = 0.097, respectively), and significantly increased over time under hypoxia in CH-Fed (condition x time interaction, p = 0.004). Conclusion: Acute normobaric hypoxia exposure significantly increases plasma ßOHB concentrations over time in healthy men. The stimulating effect of hypoxia on plasma ßOHB levels is however attenuated during postprandial and postprandial states. Contribution to advancement of knowledge: To our knowledge, this research provides some of the first evidence that an acute exposure to hypoxia increases plasma ßOHB levels in humans. It also reveals potential underlying mechanism that modulate ketogenesis upon hypoxia exposure. Overall, this thesis provides further insights into the homeostatic response of healthy men to oxygen deprivation.

No description available.

Modern organic chemistry strives to achieve rapid molecular complexity from simple achiral substrates. One method by which this may be achieved is with enolate formation followed by attack on an electrophile which can generate one, two or even more new stereocentres in one step. However regioselective generation of an enolate in the presence of several enolisable sites has always proved problematical. A partial answer to this problem has been provided by the development of the reductive aldol reaction. The first part of this thesis is concerned with describing a highly diastereoselective Co(II)-catalysed reductive aldol reaction between α,β-unsaturated amides and ketones. The reaction proceeds using substoichiometric quantities of cobalt(II) in the presence of a stoichiometric quantity of the reductant diethylzinc. Using both N,Ndimethyl and morpholine amides, the reactions are tolerant of substituted aromatic ketones as well as aliphatic ketones. The reaction also proceeded well when the β-carbon was substituted with both aromatic and aliphatic groups resulting in improved diastereoselection. The racemic work is followed by the development of an asymmetric version of the reaction using oxazolidinone chiral auxiliaries that impart high levels of diastereofacial selectivity. The reaction was found to proceed with a variety of aromatic ketones and once again, substitution of the β-carbon resulted in improved diastereoselectivity. Finally work on formal homo aldol cyclisations using substoichiometric quantities of Ni(II) also in the presence of a stoichiometric quantity of diethylzinc is described. This work aims to develop methodology that involves double cyclisations with the formation of up to five contiguous stereocentres. Although unsuccessful, useful conclusions for future work were made as well as the serendipitous discovery of a apparent base catalysed alternative cyclisation pathway that successfully generated two new rings and four contiguous stereocentres.

This thesis describes two main programmes: the synthesis of a new class of homochiral amines and the synthesis of ketone analogues of 3a-esterified tropane alkaloids. In chapter one, a scaled-up synthesis of (5)-a-(diphenylmethyl)pyrrolidine 1 is described. The key hydrogenation step of the oxazolidinone intermediate 2 was extended to the synthesis of the other chiral amines 70, 73, 76, 79 and 82. Hydrogenation of the oxazolidinones proceeded in good yields (71 - 87 %) and was not susceptible to racemisation. Thus, a convenient route from amino acid ester hydrochlorides (S)-valine 65, (S)-phenylalanine 66, (S)-alanine 67, (S)-isoleucine 68 and (S)-leucine 69 allowed a range of novel chiral amines to be prepared. In chapters two and three, a new route to ketone analogues of tropane esters is described. In chapter two, results of an attempt to prepare ketone 110 are outlined. Ketone 110 is an analogue of the tropane alkaloid littorine 101, where the bridging ester O atom is replaced by a CH2 group. The first approach to ketone 110 involved the Wittig reaction of acetylmethylenephosphorane 118 and the Homer-Wadsworth- Emmons reaction of diethylbenzoylmethanephosphonate 122 with tropinone 116. Tropinone 116 was found to be particularly unreactive in both cases. The second approach to ketone 110 involved the coupling reactions of both N-troc-3a- tosyloxymethyltropane 170 and N-troc-3 a-iodomethyltropane 185 with 2-phenylacetyl- 1,3-dithiane 147 and 1,3-ditihiane 142. These were also unreactive and as a result the synthesis of ketone 110 remains unresolved. In chapter three, the synthesis of other ketone analogues of naturally occurring 3 a- esterified tropane alkaloids is described. A six-step route to the ketones was devised and in this route the Grignard reactions of tropan-3 -ylacetaldehyde 227 emerged as the key to the success of the strategy. Three ketone analogues 218, 219 and 220 of tropate esters were successfully prepared. Ketone 220, the analogue of apoatropine 201, was found to be a muscarinic acetylcholine receptor antagonist (EC(_50) 1.9x10(^-7) M) in guinea-pigileum, showing a 500-fold less activity than atropine 202. However the activity is still within the clinical range.

No description available.

No description available.

Zugl.: Karlsruhe, Univ., Diss., 2006

Thesis (Ph.D. 1974) from the Dept. of Agricultural Biochemistry and Soil Science, University of Adelaide.