UC Berkeley

En route to a total synthesis of tetrapetalone A, we have discovered an unexpected steric facilitation of the Nazarov cyclization of aryl dienyl ketones. Chapter 1 describes the success of the Nazarov cyclization of substrates possessing substituents at both the &alpha- and &gamma-positions of the acyclic dienone. Substrates possessing only one substituent at either the &alpha- or &gamma-position proceed much more slowly, or not at all. Density functional theory calculations on the Lewis acid-bound substrates and their respective transition states were performed by Rebecca Davis in the research group of Prof. Dean Tantillo at the University of California, Davis. The computations correlate closely with the observed reactivity. The effect is observed across a series of aryl dienyl ketones with an electron-rich arene portion. Further evidence for this effect was shown by the difficulty of effecting the Nazarov cyclization of a cyclic aryl dienone at room temperature.

Chapter 2 describes the application of the findings of the Nazarov study to the synthesis of the indanone portion of tetrapetalone A. Difficulties in differentiation of the C-12 and C-14 positions (tetrapetalone numbering) of the indanone led to the investigation of a meta-bromo-containing aryl dienone, which successfully underwent the Nazarov cyclization with 13:1 regioselectivity. Formation of the C-N bond was achieved by performing a lithium-halogen exchange on the aryl bromide and quenching with tosyl azide, the product of which was then reduced to the free amine using lithium aluminum hydride.

Chapter 3 describes the elaboration of the aniline intermediate to a late-stage tetracycle en route to tetrapetalone A. Closure of the tetracycle was achieved by Friedel-Crafts acylation onto a pyrrole in a double oxidation cascade. This sequence is promoted by Dess-Martin periodinane as both the oxidant and the activating agent for the carbonyl moiety. Installation of the angular ethyl group at C-4 was achieved by Birch reduction of the resulting 2-ketopyrrole followed by quenching with iodomethane. The correct substitution pattern on the tetramic acid was achieved following oxidation to the &alpha,&beta-unsaturated lactam and subsequent copper-mediated conjugate addition of bis(pinacolato)diboron, followed by further oxidation.