Total synthesis of rubrolide L, Yangjinhualine "A" and the development of chiral modifiers for the Orito reaction

Authors: McCann, Lucas
Advisor: Boukouvalas, John
Abstract: In first part of this thesis we describe the total synthesis of the Spanish tunicate constituent rubrolide L (32), a potent inhibitor of human aldose reductase (hARL2).19-24 Blocking this enzyme plays a key role in reducing the quantities of sorbitol found in cells that are insulin independent for glucose diffusion such as nerves, kidneys and the retina.17 Inhibitors of human aldose reductase inhibitors are few and far between with the only example available on the market in Japan. In tests, rubrolide L showed a five-fold increase in inhibitory property compared to Pfizer’s widely studied Sorbinil®. These highly sought biological properties make rubrolide L an eminent target for synthesis. Our previous works based on rubrolide C offered a scaffold upon which our synthesis was designed including a Suzuki coupling reaction, followed by utilization of our newly developed method for regio-controlled aldol condensation. Next, the alkylidene was selectively brominated leaving the methoxyphenyl ring untouched (as confirmed by the Nuclear Overhauser Effect Spectroscopy).* Leaving a final deprotection step before the final product was obtained. Recently, a method was observed by our group in which the regio-controlled aldol condensation was made effective by using a brominated substrate with an unprotected phenol, eliminating one step and opening the door to a potential three-step synthesis. The overall yield for our new synthesis of rubrolide L is 42% over 5 steps or 37% over 4 steps. In the second part of the synthesis, we further build upon our scaffolding from Rubrolide L to examine the synthesis of yangjinhualine A (70), a potential anti-inflammatory agent. The optimized conditions for the Suzuki coupling from rubrolide L served as a sturdy starting point of synthesis from the structurally similar triflate. Yangjinhualine A was synthesized in 6 steps with 33% yield. In the third part we discuss the synthetic route towards (-)-hygrine (91), (-)-norhygrine (92). Although unsuccessful in this endeavour, we have further understood the *See ‘Annexe’ reactions of alkylhalides on a nitrile moiety adjacent to a pyrrolidine center. In doing so, we have developped a synthesis towards (-)-pyrrolsedamine (93). And finally, the fourth part describes the development of chiral modifiers for the Orito reaction on a Pt(111) surface; the goal of which was to improve upon the widely used cinchonidine (CD). Reported within are the synthesis of 3-benzyl-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol (117).
Document Type: Mémoire de maîtrise
Issue Date: 2011
Open Access Date: 18 April 2018
Grantor: Université Laval
Collection:Thèses et mémoires

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