Toward an asymmetric synthesis of 5-fluoronorepinephrine and epinephrine for hemodynamic support during systemic inflammatory response syndrome/septic shock

Systemic inflammatory response syndrome (SIRS) and septic shock are terms used to describe a severe systemic illnesses characterized by hypotension, poor tissue perfusion, and progressive organ dysfunction following a physiological insult. Astoundingly, it is estimated that >50% of all intensive care unit patients show signs of the systemic illness. There are approximately 750,000 people being treated each year and deaths due to the illness numbering in the hundreds of thousands. Successful treatment ultimately depends on adequate tissue perfusion through intravenous fluid and vasopressor agent support. The most common and effective vasopressor agents are the adrenergic hormones dopamine, norepinephrine, and epinephrine. Unfortunately, there is a large subset of patients which show little or no response to these agents. In recent years, a new etiology has emerged suggesting that oxidation of the vasopressor agents during SIRS/sepsis is the cause of the poor response to these agents.; This dissertation reports a study to investigate the potential asymmetric synthesis of adrenergic hormones which are more stable to the oxidative condition observed during SIRS/septic shock. Computational studies using an isodesmic reaction scheme indicated that fluorine, in position 5 of the catecholic ring, would increase the oxidation potential of the system by 2.50 kcal/mol.; A series of investigation into various synthetic routes and complications contained therein, with the ultimate goal of the asymmetric synthesis of 5-fluoronorepinephrine and epinephrine are presented. Syntheses of a variety of olefins for candidates in Sharpless' asymmetric dihydroxylation were undertaken. The most active olefin was shown to be 3,4-bis(benzyloxy)-5-fluoro-β-triisopropylsiloxystyrene, but the product from the reaction suffered from decomposition during purification.; A new synthesis of 3,4-bis(benzyloxy)-2-fluorobenzaldehyde, key intermediate for the synthesis of the β-receptor selective adrenergic hormones is presented. This work paves the path for the eventual asymmetric synthesis of the 5-fluoro adrenergic hormones for use in treatment of SIRS/septic shock.