Investigations into an Enantioselective Intramolecular Domino Heck Reaction: Applications Toward (+)-Halenaquinone and (+)-Xestoquinone

This dissertation describes the efforts made toward enhancing the enantioselectivity of an intramolecular asymmetric Pd-catalyzed domino Heck reaction ( 78→79), its application toward the synthesis of the natural product (+)-halenaquinone (1), and the investigations of its mechanism.;Three different approaches toward the synthesis of (+)-halenaquinone (1) were taken. The first involved performing the domino Heck reaction on alkyl enol ethers 186 and 194. Cyclization of the former gave only traces of desired product while cyclization of the latter resulted in no product. The second entailed performing a tandem asymmetric Heck reaction/intramolecular carbanion capture on beta-keto ester 211. This approach was unsuccessful. The third approach employed a tandem asymmetric Heck reaction/intermolecular carbanion capture on triflate 237 with sodium enolate 236. Although desired product 234 was not obtained, formation of compound 258 showed that a sigma-alkylpalladium complex can be captured by a carbanion.;Investigations of the mechanism of this domino Heck reaction were conducted by monitoring the reactions of compounds 78, 237, and 284-287 with the preformed catalyst [(S)-BINAP]Pd(dba) in benzene-d6, toluene-d 8, and EtOH-d6 by 31 P and 1H NMR spectroscopy. Oxidative addition intermediates were observed for each substrate. These included olefin-coordinated Pd complexes, which were observed in ratios of 74:26 in toluene-d 8 and 66:34 to 72:28 in EtOH-d6, for the reactions with triflate 237. These results disagreed with the expected ratio, 85:15. Olefin insertion may not have occurred under the conditions used to monitor these reactions. A mechanism for this reaction in EtOH was postulated invoking the pentacoordinate Pd complexes 155 and 314. An energy diagram rationalizing the enhanced enantioselectivity observed in EtOH relative to toluene was also presented.;The intramolecular asymmetric Pd-catalyzed domino Heck reaction of triflate 78 was performed using Pd2(dba)3 and PMP with a variety of ligands in toluene, EtOH, and t-BuOH at 110°C using both oil bath heating and microwave irradiation. Electron-deficient ligands such as (R)-DIFLUORPHOS (113) gave the best enantioselectivities, 94% ee to >99% ee. Performing the reaction in EtOH also resulted in enhanced enantioselectivities compared to toluene. Microwave heating accelerated the reaction without affecting the enantioselectivity and allowed for a longer catalyst lifetime. Using t-BuOH as the solvent in an oil bath suppressed the formation of byproduct 80.