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Leveraging enzymes for asymmetric synthesis and new in situ combinatorial screening methods

Jacob A Friest, University of Nebraska - Lincoln

Abstract

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.^

Subject Area

Chemistry, Organic

Recommended Citation

Friest, Jacob A, "Leveraging enzymes for asymmetric synthesis and new in situ combinatorial screening methods" (2012). ETD collection for University of Nebraska - Lincoln. AAI3546796.
http://digitalcommons.unl.edu/dissertations/AAI3546796

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