UC Berkeley

Abstract

Total Synthesis of Illicium Sesquiterpenoids Through an Aliphatic

C–H Functionalization Approach

by

Kevin Hung

Doctor of Philosophy in Chemistry

University of California, Berkeley

Professor Thomas J. Maimone, Chair

The Illicium sesquiterpenoids are a family of natural products exclusively produced by plant species in the genus Illicium. Certain species in the genus are known for their use as spices and fragrance, while others are notorious for their potentially lethal toxicity. In Chapter I, the intricate structural features of the three main subtypes of Illicium sesquiterpenoids, namely the seco-prezizaane, allo-cedrane, and anislactone subtype, along with a brief history of past isolation efforts were reviewed. Next, biological effects such as neurotoxicity and more importantly, neurotrophic activities and their implications were briefly discussed. The neuroprotective effects displayed by select sesquiterpenoids have led to their proposed application as small-molecule drug targets for neuro-degenerative diseases. The apparent interplay between toxicity and neurotrophic activity with oxidative decorations on the carbon skeleton of seco-prezizaane natural products was also noted by us. This was followed by a survey of previous total synthesis endeavors of the seco-prezizaane- and allo-cedrane- type natural products with emphasis on the disparate and ingenious solutions past contributors have devised for the synthesis of their respective cores. Finally, the proposed biosynthetic origin of these sesquiterpenoids was examined with the intention of gaining critical insight for a de novo synthesis of these architecturally ornate natural products.

In Chapter II, the overarching retrosynthetic analysis of our approach to the seco-prezizaane sesquiterpenoids was presented. Whereas past synthetic efforts have relied on embedded oxidation states in the starting materials, our strategy incorporated various site-selective and orthogonal aliphatic C–H functionalization chemistry for the installation of the requisite oxidations on the carbon scaffold. In turn, taking inspiration from the proposed biosynthetic origin, the seco-prezizaane carbon system was envisioned to arise from the cedrane core in a biomimetic manner. Furthermore, we sought a unified strategy to access all members of the seco-prezizaane family of natural products. Our initial plan for the construction of the seco-prezizaane core through the allo-cedrane skeleton was presented. Although this path was fraught with challenging transformations, it nevertheless showed that a skeletal reorganization of the cedrane framework was feasible. Next, we were able to successfully arrive at the seco-prezizaane motif via a modified strategy involving an -ketol rearrangement. From this scaffold, the key C–H functionalization of the C-4 methine position was achieved through a non-heme iron(oxo) catalysis methodology. Subsequent oxidative transformations furnished (–)-14-dehydroxydunnianin, a precursor to the natural product (–)-debenzoyldunnianin. Although the final late-stage C–H functionalization of the C-14 methyl position was met with significant difficulties, we have garnered critical insights into the reactivity of synthetic intermediates we have encountered along the way.

Building upon the lessons we learned in Chapter II, the eventual first synthesis of pseudoanisatinoids such as (+)-pseudoanisatin and (–)-3-deoxypseudoanisatin was recounted in Chapter III. Instead of a late-stage C–H functionalization of the C-14 methyl position, we accomplished the desired transformation via an early-stage radical-mediated methodology. This material was then carried forward under optimized reaction conditions following those we have discovered in the previous Chapter to allow access to pseudoanisatinoid sesquiterpenoids. In the process, we were confronted with functional group compatibility issues for the aforementioned C–H functionalization of the C-4 methine position. This was ultimately overcome with uncovering an optimal catalyst and also reagent conditions for this daunting transformation after substantial experimentation. Hence, we have demonstrated the viability of our overarching retrosynthetic approach in utilizing two aliphatic C–H functionalizations for the synthesis of pseudoanisatinoid natural products.

Moving forward to higher oxidized Illicium sesquiterpenoids in the majucinoid series, we investigated a different strategy in Chapter IV to obviate problematic transformations we experienced in our synthesis of pseudoanisatinoids. Both the C-14 position and the C-4 methine site was oxygenated with a radical-mediated methodology. This procedure eliminated the use of the esoteric designer iron catalyst that was previous applied. Then, two remarkable reactions involving ruthenium and selenium for the installment of the prerequisite oxidation states was accomplished. The majucinoid scaffold was forged from the resulting intermediate through a similar but no-less impressive -ketol rearrangement. A first total synthesis of four sesquiterpenoids, (–)-3,4-dehydroneomajucin, (–)-neomajucin, (–)-majucin, and (–)-jiadifenoxolane A, along with a formal synthesis of (–)-jiadifenolide, (–)-jiadifenin, and (–)-(1R,10S)-2-oxo-3,4-dehydroxyneomajucin was completed in this manner. Thus, our retrosynthetic approach was broadened to include entry to majucinoids in addition to pseudoanisatinoids.

Finally, in Chapter V, we detailed our expansion of the synthetic platform we have designed for other Illicium natural products. A formal synthesis of allo-cedrane sesquiterpenoid (–)-11-O-debenzoyltashironin was realized from an intermediate described in Chapter IV by way of non-heme iron(oxo) C–H functionalization technology. Furthermore, we disclosed our efforts to polyoxygenated natural product (–)-anisatin via a rhodium-catalyzed C–H silylation of the C-13 methyl group, providing an avenue toward the last subset of seco-prezizaane-containing Illicium sesquiterpenoids.

To conclude, we have developed a versatile synthetic platform to allow access to not only all of the seco-prezizaane but also the allo-cedrane families of Illicium sesquiterpenoids through an aliphatic C–H functionalization approach. We hope that our endeavors will stimulate further incorporation of this retrosynthetic paradigm in the broader field of total synthesis. We have also laid the foundation to support future interrogations into the fascinating biological properties of these natural products.