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Speck, Klaus (2016): The total synthesis of tetracyclic meroterpenoid natural products, Gold(I)-catalyzed cyclizations of 1-Bromo-1,5-Enynes. Dissertation, LMU München: Fakultät für Chemie und Pharmazie
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Abstract

Part I: Tetracyclic meroterpenoid natural products are structurally fascinating molecules with intriguing biological activities. Their unique skeleton contains four to five stereogenic centers and bears a decalin ring-system which is fused to diverse aromatic moieties through a dihydropyran. The first part of this thesis presents the evolution of a novel cationic polyene cyclization cascade for the total synthesis of the meroterpenoid natural product (–)-cyclosmenospongine. A highly modular and efficient three fragment coupling strategy permitts the facile synthesis of the key cyclization precursor. The cyclization cascade forms three carbon–carbon bonds and sets four consecutive stereocenters, two of which are tetrasubstituted, to forge the tetracyclic scaffold of cyclosmenospongine in a single step on multi-gram scale. Sequential functionalization and oxidation of the arene allows the synthesis of more than 400 mg of (–)-cyclosmenospongine in one batch. Part II: In the second part of this thesis, the development of a novel gold(I)-catalyzed cyclization cascade of 1-halo-1,5-enynes in the presence of phenols is described. Reactions involving the cyclization of 1,n-enynes are of high value as they are capable of generating molecular complexity in a minimal number of steps. The developed one-pot procedure yields 2-halo-cyclopentenes, a structural motif that can be found in several bioactive molecules, through an unprecedented sequential O–H/C–H bond functionalization of phenols under mild reaction conditions. Mechanistic investigations revealed that the reaction cascade proceeds within two constitutive catalytic cycles via the intermediacy of an unstable aryl alkyl ether that collapses at ambient temperature to undergo a [1,2]-hydride shift followed by C–H insertion of the phenol. We found the reaction to be broadly applicable across a range of sterically and electronically diverse substrates by establishing a reaction scope of 18 examples.