UC Berkeley

The formation of saturated carbon-carbon bonds in a precise and

controlled manner is arguably the principal objective of organic synthesis.

Carbocyclic ring systems comprise the underlying structure for the

preponderance of natural products and pharmaceutical agents. Therefore,

synthetic methods capable of selectively initiating polycyclization processes in

the presence of spectating functionality are of significant value, particularly so

when multiple stereocenters are formed enantioselectively.

The emergence of phosphine gold(I) catalysis over the past decade has

opened up new avenues to carbocycle formation via π activation of alkynes

occurring under exceedingly mild conditions and with excellent chemoselectivity.

The research described herein describes the use of homogenous gold(I)

complexes to initiate electrophilic cyclization cascades. Through rational

substrate design, carbocationic centers may be generated in a predictable

manner and employed in subsequent intramolecular cyclization processes.

Chapter 1 introduces the unique reactivity observed in complexes of gold

imparted by its relativistically accelerated valence electrons. One consequence of

this perturbation is the linear geometry maintained by gold(I) complexes,

minimizing the influence of ligand-based chirality on reactions occurring at

coordinated alkynes. In spite of this challenge, moderate levels of

enantioselectivity were achieved in the desymmetrization of dienynes by

cycloisomerization using chiral bisphosphite gold(I) catalysts.

Ultimately, we were able to achieve selectivities up to 98% ee using

hindered chiral bisphosphine gold(I) catalysts during the evaluation of another

enyne cycloisomerization reaction, described in chapter 2. In this process, an

initial regioselective cyclization was used to generate a carbocationic species

poised to undergo intramolecular trapping. Consistently high enantioselectivity

was maintained using various pendant oxygen, carbon and nitrogen nucleophiles.

The diastereomerically pure bi- and tricyclization products obtained provided

support for a concerted polyene cyclization mechanism as predicted by the Stork-

Eschenmoser postulate.

Chapter 3 describes another tandem process exploiting the transient

cationic species arising from gold(I)-promoted enyne cycloisomerization. In this

case, a gold(I)-initiated tandem cyclopentannulation reaction was employed in

the total synthesis of the novel triquinane ventricosene. A cyclopropanol unit

embedded in the enyne substrate underwent a semipinacol rearrangement in

response to the carbocation, leading cleanly to bicyclo[3.2.0]heptan-6-one

products. For cyclopentenyl substrates, the hindered all-carbon quaternary center

and all of the ring fusions of the angular triquinane ring system were formed at

once. The choice of a hydrocarbon target highlighted the utility of gold(I) catalysts

as selective activators of carbon unsaturation; throughout the synthesis only a

single heteroatom was present.

This work concludes by extending the scope gold(I)-catalyzed

carbocyclization reactions which generate useful cationic intermediates. The

gold(I)-catalyzed Rautenstrauch rearrangement forms a cyclopentene-based

cationic species which was shown to undergo efficient trapping by pendant

arenes to give a saturated 5,6-ring fusion comprising a chiral benzylic quaternary

center. The chirality transfer observed in the parent process was found to be

conserved in the tandem process. Interestingly, cyclization of racemic substrates

by chiral bisphosphine digold catalysts was found to proceed with moderate

enantioselectivity, suggesting a competing mechanism is in effect which

proceeds through an achiral intermediate.