UC Berkeley

The following dissertation discusses the development and applications of bond cleavage strategies in organic synthesis. The main focus of this work will be directed toward the diversification of unstrained saturated aza-cycles through C–C bond cleavage/functionalization. Another focus of the dissertation will be directed toward the total syntheses of reverse-prenylated indole alkaloids which feature a bicyclo[2.2.2]diazaoctane core.

Chapter 1 describes our initial efforts toward the deconstructive functionalization of cyclic amines. A method for the deconstructive fluorination of cyclic amines by coupling Csp3¬–Csp3 bond cleavage with Csp3¬–F bond formation was developed. This method has been applied to the late-stage diversification of peptides to arrive at novel fluorinated peptides and mechanistic insight also led to the development of a catalytic gem-difluorination of enamides.

Chapter 2 describes our efforts to arrive at a general method for deconstructive diversification of saturated cyclic amines. Notably, the combination of silver salts and persulfate oxidant allowed access to versatile halogen containing acyclic amine derivatives by sequential C(sp3)–N and C(sp3)–C(sp3) bond cleavage followed by C(sp3)–X bond formation. The alkyl halides formed in this process are versatile synthetic intermediates that can be used for a variety of processes such as skeletal remodeling, peptide diversification, and ring contraction.

Chapter 3 details our efforts toward the mild peripheral functionalization of cyclic amines by leveraging inherently strained systems. Specifically, using visible light, we effect a Norrish–Yang reaction, generating N-fused bicyclo -hydroxy--lactams. The inherent strain embedded in these heterocycles can be exploited to achieve mild cross-couplings arriving at peripherally functionalized saturated aza-cycles. Notably, this work represents the first palladium catalyzed C–C cleavage/functionalization of -hydroxy--lactams.

Chapter 4 describes our efforts toward the synthesis of secondary metabolites isolated from Penicillium and Aspergillus species which feature a bicyclo[2.2.2]diazaoctane core. Our unified approach resulted in the syntheses of (+)-VM55599, preparaherquamide, and premalbrancheamide as well as provide access to ketomalbrancheamide which can be elaborated to malbrancheamides B, C, stephacidin A, notoamides F, I and R, aspergamide B, and waikialoid A. Key to the success of this strategy was leveraging a common intermediate facilitated a divergent approach and forging the pentacyclic indole skeleton through a one-pot Hoffmann rearrangement followed by Fischer indole synthesis.