UC Berkeley

The development of new heterocycloisomerization reactions as a tactic to access natural product scaffolds is an active area of research. Chapter 1 describes the development of a new heterocycloisomerization reaction of alkynyl-[4.1.0]-bicycloheptanones using W(CO)5•THF complex to access 4,5-dihydrobenzo[b]-furans and –indoles. Specifically, the methodology developed provides a unique entry into dihydro-benzofurans and –indoles that contain carbon substitution at the C4-position, which is a common motif in many biologically active indole alkaloid natural products (e.g. the ergot alkaloids). The unique reactivity of dihydro-benzofurans and –indoles as it pertains to accessing natural product scaffolds is also described.

Chapter 2 describes a mechanistic investigation of the trace-metal catalyzed cycloisomerization of alkynyl-[4.1.0]-bicycloheptanones to access annulated aminopyrroles by heating the ketone substrates with p-toluenesulfonylhydrazide in methanol. From our mechanistic studies, we demonstrate that the cycloisomerization reaction, which was previously thought to have been metal free, is actually catalyzed by trace copper salts at parts-per-million loading. Furthermore, we demonstrate the presence of E- and Z-hydrazone intermediates and conclusively demonstrate that, the more sterically encumbered Z-hydrazone is initially formed in the reaction and is thermodynamically lower in energy than its corresponding E- isomer. These studies were carried out in collaboration with the Hein group at the University of California, Merced and the Tantillo Group at the University of California, Davis and are a testament to the importance and power of collaborative research.

Chapter 3 describes our efforts to leverage a Pt(II)-catalyzed carbocycloisomerization reaction as a means for accessing functionalized tetrahydrofluorenes through the use of 2-substituted indene compounds. We were able to synthesize a variety of functionalized tetrahydrofluorenes using a Diels—Alder cycloaddition reaction of 2-vinylindenes and various dienophiles. We also describe our attempts to effect a double Diels—Alder cycloaddition reaction using bisketenes or bisketene equivalents with 2-vinylindenes to access the dimeric lomaiviticin natural products. Though we were unable to realize the desired double Diels—Alder cycloaddition reactivity, we discovered a new method for generating 3-oxidopyrylium ions from bis(1-cyanovinyl acetate). Furthermore, we were able to access a variety of 2-alkynyl indenes and utilize these substrates to access the carbocyclic core of the diterpenoid euphorbactin using Rh(II)-catalyzed cycloaddition chemistry.