Geldanamycin possesses various biological activities as seen in the NCI 60 cell line panel (13 nM avg., 70 nM SKBr-3 cells). The predominant mode of action providing these unique results arises from the ability of geldanamycin (GA) to bind to the chaperone heat shock protein 90 (Hsp90). Despite its complicated functionality, the first total synthesis of GA was accomplished, which included two new reactions developed specifically to address the stereochemical features. The final step in the synthesis of GA was a demethylation-oxidation sequence to generate the desired para-quinone. This step could only be accomplished with HNO3/AcOH, producing GA in 5% yield. A GA model study, which closely resembled the aromatic core, was extensively investigated to solve this critical oxidation issue. A protected hydroquinone model compound was determined to be the optimum choice. Using Pd in the presence of air with a 1,4-hydroquinone provided the desired para-quinone quickly and nearly quantitatively in 98% yield. This study formulated the recipe of success for para-quinone formation of GA and future synthetic analogs. Asymmetric glycolate alkylation has been developed using phase-transfer-catalysis (PTC). Diphenylmethoxy-2,5-dimethoxyacetophenone with trifluorobenzyl cinchonidinium catalyst and cesium hydroxide provided alkylation products at —35 °C in high yield (80-99%) and with excellent enantioselectivity (up to 90% ee). Useful α-hydroxy products were obtained using bis-TMS peroxide Baeyer—Villiger conditions and selective transesterification. The intermediate aryl esters can be obtained with >99% ee after a single recrystallization. The newly developed PTC glycolate alkylation was applied to the asymmetric syntheses of ragaglitazar and kurasoin A. Ragaglitazar is a potent antihyperglycemic and lipid modulator, currently in phase II clinical trials. Kurasoin A is a relatively potent protein farnesyltransferase (PFTase) inhibitor with an IC50 value of 59.0 micromolar. PTC glycolate alkylation was optimized to provide 4-benzyloxy glycolate intermediates in excellent overall yield and with 96% ee after recrystallization. Ragaglitazar was then synthesized after considerable experimentation to provide the potent lipid modulator with yields and enantiopurity rivaling the best-known routes produced by industry standards. Kurasoin A was produced through an α-triethylsiloxy Weinreb amide to provide the highest overall yielding route to this PFTase inhibitor currently disclosed.

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.