The Development and Application of Gold(I)-Catalyzed Cyclization Cascades

The formation of saturated carbon-carbon bonds in a precise and/ncontrolled manner is arguably the principal objective of organic synthesis./nCarbocyclic ring systems comprise the underlying structure for the/npreponderance of natural products and pharmaceutical agents. Therefore,/nsynthetic methods capable of selectively initiating polycyclization processes in/nthe presence of spectating functionality are of significant value, particularly so/nwhen multiple stereocenters are formed enantioselectively./nThe emergence of phosphine gold(I) catalysis over the past decade has/nopened up new avenues to carbocycle formation via π activation of alkynes/noccurring under exceedingly mild conditions and with excellent chemoselectivity./nThe research described herein describes the use of homogenous gold(I)/ncomplexes to initiate electrophilic cyclization cascades. Through rational/nsubstrate design, carbocationic centers may be generated in a predictable/nmanner and employed in subsequent intramolecular cyclization processes./nChapter 1 introduces the unique reactivity observed in complexes of gold/nimparted by its relativistically accelerated valence electrons. One consequence of/nthis perturbation is the linear geometry maintained by gold(I) complexes,/nminimizing the influence of ligand-based chirality on reactions occurring at/ncoordinated alkynes. In spite of this challenge, moderate levels of/nenantioselectivity were achieved in the desymmetrization of dienynes by/ncycloisomerization using chiral bisphosphite gold(I) catalysts./nUltimately, we were able to achieve selectivities up to 98% ee using/nhindered chiral bisphosphine gold(I) catalysts during the evaluation of another/nenyne cycloisomerization reaction, described in chapter 2. In this process, an/ninitial regioselective cyclization was used to generate a carbocationic species/npoised to undergo intramolecular trapping. Consistently high enantioselectivity/nwas maintained using various pendant oxygen, carbon and nitrogen nucleophiles./nThe diastereomerically pure bi- and tricyclization products obtained provided/nsupport for a concerted polyene cyclization mechanism as predicted by the Stork-/nEschenmoser postulate./nChapter 3 describes another tandem process exploiting the transient/ncationic species arising from gold(I)-promoted enyne cycloisomerization. In this/ncase, a gold(I)-initiated tandem cyclopentannulation reaction was employed in/nthe total synthesis of the novel triquinane ventricosene. A cyclopropanol unit/nembedded in the enyne substrate underwent a semipinacol rearrangement in/nresponse to the carbocation, leading cleanly to bicyclo[3.2.0]heptan-6-one/nproducts. For cyclopentenyl substrates, the hindered all-carbon quaternary center/nand all of the ring fusions of the angular triquinane ring system were formed at/nonce. The choice of a hydrocarbon target highlighted the utility of gold(I) catalysts/nas selective activators of carbon unsaturation; throughout the synthesis only a/nsingle heteroatom was present./nThis work concludes by extending the scope gold(I)-catalyzed/ncarbocyclization reactions which generate useful cationic intermediates. The/ngold(I)-catalyzed Rautenstrauch rearrangement forms a cyclopentene-based/ncationic species which was shown to undergo efficient trapping by pendant/narenes to give a saturated 5,6-ring fusion comprising a chiral benzylic quaternary/ncenter. The chirality transfer observed in the parent process was found to be/nconserved in the tandem process. Interestingly, cyclization of racemic substrates/nby chiral bisphosphine digold catalysts was found to proceed with moderate/nenantioselectivity, suggesting a competing mechanism is in effect which/nproceeds through an achiral intermediate.

Advisor: Toste, Dean