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5.1 Introduction

The electrochemical oxidation reactions discussed in the previous chapters provide not only unique opportunities for bond formation, but also demonstrate a movement toward greener, chemical oxidant-free chemistry.1 The potentially greener electrochemistry itself, however, does not provide a full picture; in taking a green approach to chemical synthesis one must consider not just sustainable factors of the reactions themselves but also of the starting materials employed. To this end, we are interested in the role electrochemical reactions can play in developing sustainable routes to synthetic platform chemicals.

Most chemical building blocks are currently obtained via fossil fuels and the petroleum industry, a less than sustainable approach to obtaining fine chemical building blocks. This is especially true for synthetic building blocks that contain electron-rich aromatic rings. Such electron-rich aromatic motifs form the core of many natural product ring scaffolds, however they are not found in petroleum at all.

Lignin, a biopolymer that makes up 15-30% of dry weight woody biomass, is comprised largely of electron-rich aromatics.2 As such, it would appear to be an ideal source for aryl-based synthetic building blocks. Due to the structural uniqueness and availability of lignin, many research efforts are currently underway in the chemical community in disassembling lignin into smaller compounds. While attention seems to be focused on breaking down lignin into smaller monomer units, little work has been done to actually obtain pure monomers from lignin and then convert these monomers into value-added products. With this goal in mind, we sought to

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convert lignin-derived monomers obtained directly from raw wood into synthetic products that will demonstrate lignin’s viability as a sustainable chemical feedstock.

5.2 Structure and Disassembly of Lignin

5.2.1 Structural Motifs in Lignin

The majority of the lignin biopolymer is composed of three “monolingol” monomers: p- coumaryl alcohol, coniferyl alcohol, and sinapyl alcohol (Figure 5-1). These electron –rich aromatic motifs are incorporated into the inhomogenous structural polymer, with different relative amounts being included based on the identity of the particular lignin plant source.

Figure 5-1. Lignin Structure.

With lignin being a biological source of these electron-rich aromatic rings, it is no surprise that many biologically active core structures of natural products contain similar electron-rich aromatic motifs, such as those shown in Figure 5-2. Note that the structures contain not only the

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core hydroxyl- or alkoxy-substitued aromatic rings, but also the carbon chains branching off these aromatic rings. Hence, the side-chains could also originate from the lignin monomer.

Figure 5-2. Aromatic electron-rich natural product scaffolds.

5.2.2 Disassembly of Lignin into Monomers for Synthetic Processing

Extensive efforts are currently underway in the community to disassemble lignin into smaller monomers. These efforts have employed a wide variety of techniques, including reductive methods3, oxidative methods4, redox neutral methods5, and solvolytic approaches. Many of these approaches have shown success on model systems for lignin, though few actually break down natural lignin itself. Furthermore, these methods often lead to complex mixtures of aromatic substrates that give no reasonable yield of any single lignin-derived monomer and require difficult separations to isolate.

In contrast, efforts by former Moeller group members Dr. Bichlien Nguyen and Dr. Jake Smith have demonstrated that the direct methanolysis of sawdust in a pressure reactor can allow for selective extraction of aldehyde or cinnamyl ether derivatives from the wood.6 In these experiments, birch sawdust was washed with 2:1 benzene:ethanol in a Soxhlet extractor to remove oils from the wood. The sawdust was then heated in a pressure reactor with methanol,

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followed by a very simple column filtration to isolate the small molecule solvolysis products (Figure 5-3). At higher temperature and pressure (155⁰C, 17 atm), syringealdehyde (1) was obtained in 1% yield by mass from the raw sawdust, or approximately 5% from the estimated lignin content of the sawdust.6 At lower temperature and pressure (114⁰C, 5 atm), the methyl ether of sinapyl alcohol (2) and the methyl ether of coniferyl alcohol (3) were obtained in 0.6% yield by mass from the raw sawdust, or about 3% from the lignin content.

Figure 5-3. Isolated solvolysis products from birch sawdust.

Alternatively (Figure 5-4), switching to cedar sawdust as the lignin source gave vanillin and its corresponding methyl ester (1.4% from wood by mass, 7% from lignin) and the methyl ether of coniferyl alcohol at lower temperature and pressure (1.4% from wood by mass, 7% from lignin in a 1:1.3 ratio). No syringealdehyde or methyl ether of sinapyl alcohol was obtained with the cedar sawdust, in contrast to the sovolysis of the birch sawdust. Thus, the selectively of the process with the cedar mirrored that of the birch, however the different lignin sources led to products with different levels of aryl ring oxidation.

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Figure 5-4. Isolated solvolysis products from cedar sawdust.

These results suggested that a target-driven approach to obtaining electron-rich aromatic monomers directly from sawdust for further processing was viable. For example, if

syringealdehyde was a desired starting material for a synthetic sequence, then birch sawdust could be solvolyzed at higher temperature and pressure to selectively extract it. If a coniferyl alcohol moiety with its styrene-based alkyl chain was desired for a synthesis, lower temperature and pressure could be employed. If different oxidation levels of the aryl ring were desired for a particular synthesis, the type of wood used could be changed.

Following the demonstration of this method to directly obtain electron-rich aromatic building blocks from sawdust, focus was shifted to processing these lignin-derived monomers into value- added synthetic building blocks or natural product scaffolds.

5.3 Processing Lignin-Derived Monomers into Synthetic

Building Blocks

With this in mind, processing of syringealdehyde (1) and methyl ether of sinapyl alcohol (2) into larger synthetic building blocks was performed. A select few of these compounds were ultimately further elaborated into benzodiazepine, indenone, and anthroquinone core scaffolds.

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5.3.1 Small Molecule Building Blocks Derived from Syringealdehyde

The first synthetic diversification reactions were carried out using syringealdehyde (1). The effort was started by phenolic –OH of 1 with a methyl group in order to avoid difficulties with chromatographing an acidic, unprotected –OH in subsequent steps. Protection with a pivoyl group was also tested, however hydrolysis back to the phenol during subsequent synthetic steps proved troublesome. The methyl group is a reasonable protecting group here, because it can be later be selectively removed with trimethysilyl iodide.