Off-campus UNL users: To download campus access dissertations, please use the following link to log into our proxy server with your NU ID and password. When you are done browsing please remember to return to this page and log out.
Non-UNL users: Please talk to your librarian about requesting this dissertation through interlibrary loan.
Leveraging enzymes for asymmetric synthesis and new in situ combinatorial screening methods
The Berkowitz group has developed an in situ enzymatic screening (ISES) method that allows for real time kinetic readout on a reaction of interest under biphasic conditions. In the newest iteration of this ISES method, a colorimetric variant has been developed. This approach employs two reporting enzymes, alcohol oxidase and peroxidase, the latter of which utilizes a dye cofactor (ABTS = 2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonate) giving rise to a green radical cation for reactions releasing an alcoholic (by)product. Using this method, 1152 nucleophile/metal/substrate combinations were screened for a targeted halometalation/carbocyclization transformation. Two new reaction manifolds were identified in this manner; a formal bromorhodiation/carbocyclization reaction and a formal thiocyanopalladation/carbocyclization. In the former case, significant diastereoselectivity was observed for closure to 5- and 6-ring systems in the carbocyclization. A post-cyclization ring-closing metathesis (RCM) step then allows for the synthesis of 5,7-fused xanthanolide core scaffolds, bearing a halovinyl moiety that can be functionalized/extended to decorate the core. The 6-ring manifold of this bromorhodiation/carbocyclization transformation is then exploited for a streamlined entry into the oxabicyclo[4.3.1]decyl exomethylene-δ- lactone cores of linearifolin and zaluzanin A. In this case, the absolute stereochemistry derives from kinetic resolution of 5-benzyloxypentene-1,2-oxide, utilizing a β-pinene-derived-Co(III)-salen catalyst discovered by ISES screening. Post-carbocyclization RCM with the Grubbs-II catalyst yields oxabicyclo[4.3.1]decyl exomethylene-δ-lactone cores. RCM with the Grubbs-I catalyst provides the ring-contracted oxabicyclo[3.3.1]nonyl exomethylene-δ-lactone cores of xerophilusin R and zinagrandinolide. In related work, collaboratively with the Blum group in the NU School of Biological Sciences, new synthetic/screening applications have been discovered for a dehydrogenase from an archaeal hyperthermophile. SsADH-10 ( Sulfolobus solfataricus alcohol dehydrogenase, isozyme-10) was found to be a useful enzyme in asymmetric synthesis; namely for a dynamic reductive kinetic resolution (DYRKR) entry into the (S)-profen family of non-steroidal anti-inflammatory drugs. Interestingly, this enzyme permits for "thermal switching," allowing for DYRKR at elevated temperatures and product recovery by simple filtration at room temperature. For screening applications, SsADH-10 is being leveraged for a "thermal"-variant of ISES. This thermal-ISES has been applied to the exploration of intramolecular allylic aminations at elevated temperatures (50-90 °C), with the aim of developing new, catalytic asymmetric synthetic entries into quaternary, &agr;-vinyl amino acids.
Friest, Jacob A, "Leveraging enzymes for asymmetric synthesis and new in situ combinatorial screening methods" (2012). ETD collection for University of Nebraska - Lincoln. AAI3546796.