Studies toward the total synthesis of purpuromycin. Synthesis of bisbenzannelated 5,6-spiroketals via a [3+2] dipolar cycloaddition strategy

This dissertation describes studies toward the total synthesis of purpuromycin. Consisting of naphthazarin and isocoumarin ring systems linked through a unique bisbenzannelated 5,6-spiroketal core, purpuromycin shows cytotoxic activity against Gram-positive bacteria, fungi, protozoa, and a number of tumor cell lines.* Efficient syntheses of the isocoumarin and naphthalene fragments were established. Key features of the isocoumarin synthesis include the desymmetrization of a functionalized catechol and a Heck coupling/lactonization sequence. Two routes for the naphthalene fragment were established: one based on a Dötz chromium carbene cyclization and the other following a more traditional Diels-Alder approach. A new method for the construction of bisbenzannelated spiroketals was developed consisting of [3+2] cycloaddition of nitrile oxides with olefins, reduction of the resulting isoxazoline to β-keto alcohols (formal aldol products), and subsequent spirocyclization. This method was successfully utilized for the construction of the 5,6-spiroketal core of purpuromycin. Spectroscopic and crystallographic analysis of each diastereomeric spiroketal product, in conjunction with spectroscopic data obtained from a sample of natural purpuromycin, led to an assignment of the hitherto unknown relative configuration of the natural product.* Fragment coupling of the fully functionalized isocoumarin and naphthalene fragments of purpuromycin was achieved by the [3+2] cycloaddition protocol. Although subsequent spirocyclization of an advanced intermediate was not realized, the factors responsible for inefficient spiroketal formation were identified through the sequential coupling of each fragment with a suitable model counterpart. While the naphthalene fragment is a willing participant in spirocyclization, the isocoumarin fragment, due to inductive effects from the electron-deficient lactone moiety, is not sufficiently nucleophilic for attack and ring closure. From these findings, a modified synthesis is currently underway in which the isocoumarin fragment is installed in a reduced form prior to spirocyclization.* *Please refer to dissertation for diagrams