Phase-transfer catalysts derived from the cinchona alkaloids cinchonine and cinchonidine are widely used in the asymmetric alkylation of substrates bearing moieties that resonance stabilize their enolates. The investigation of α-oxygenated esters revealed decreased α-proton acidity, indicating the oxygen's overall destabilizing effect on enolates by electron-pair repulsion. Alkylation of α-oxygenated aryl ketones with various alkyl halides proved successful with a cinchonidine catalyst, giving products with high yield and enantioselectivity. The resulting compounds were converted to esters through modified Baeyer-Villiger oxidation. Alkylation with indolyl electrophiles gave products that underwent decomposition under Baeyer-Villiger conditions. Alternative N-methylimidazolyl ketones were explored. Alkylated imidazolyl ketones, obtained in high yield and enantioselectivity, could be converted to esters through treatment with methyl triflate and basic methanol. This technique has the advantage of not requiring stoichiometric addition of chiral reagents, which is requisite when employing traditional chiral auxiliaries. This method's utility is demonstrated in the total asymmetric syntheses of (+)-kurasoin B and analogs, and 12-(S)-HETE. Kurasoin B is a fungal-derived natural compound possessing moderate farnesyl transfer (FTase) inhibitive activity (IC50 = 58.7 μM). FTase catalyzes post-translation modifications of membrane-bound Ras proteins, which function in signal cell transduction that stimulates cell growth and division. The oncogenic nature of mutated Ras proteins is demonstrated by their commonality in human tumors. Thus, FTase inhibitors like (+)-kurasoin B possess potential as cancer chemotherapy leads. Derivatization may enable structure-activity-relationship studies and greater FTase inhibition activity to be found. 12-(S)-HETE, a metabolite from a 12-lipoxygenase pathway from arachidonic acid, has been found to participate in a large number of physiological processes. Its transient presence in natural tissues makes total synthesis an attractive avenue for obtaining sufficient quantities for further study. Five asymmetric syntheses of 12-(S)-HETE have been reported. Three require chiral resolutions of racemates, with the undesired enantiomers being discarded or used for other applications. Asymmetric PTC alkylation is also described for aryl acetates, whose products were enantioenriched through recrystallization. This technique is applied to a total synthesis of the anti-inflammatory drug (S)-Naproxen.
College and Department
Physical and Mathematical Sciences; Chemistry and Biochemistry
BYU ScholarsArchive Citation
Christiansen, Michael Andrew, "The Asymmetric Phase-Transfer Catalyzed Alkylation of Imidazolyl Ketones and Aryl Acetates and Their Applications to Total Synthesis" (2010). Theses and Dissertations. 2400.
phase-transfer catalysis, asymmetric alkylation, kurasoin, 12-(S)-HETE, farnesyl transferase, acyl imidazole, aryl acetate, (S)-Naproxen