Lignin is an abundant natural biopolymer that has the potential to act as a renewable feedstock for valuable aromatic compounds via selective catalytic depolymerization. In recent years, elegant, mild, catalytic hydrogen neutral C-O bond cleavage methodologies have been developed on model compounds yielding acetophenone derivatives. However, none of these have been reported to be effective once applied to lignin. One of the reasons for this is the highly functionalized nature of the native lignin beta-O-4 motif; which is often not taken into account in the beta-O-4 model compounds used for methodology development. In this work, we demonstrate the development of a stepwise modification protocol on lignin beta-O-4 model compounds to overall yield a partially defunctionalized beta-O-4 motif. This was achieved by making use of an a-ethoxylated beta-O-4 motif that is readily available from ethanosolv extraction of lignocellulosic biomass. This specific motif allowed us to apply selective copper catalyzed aerobic oxidation and subsequent rhodium catalyzed decarbonylation of the primary hydroxyl group in the y position. The obtained partially defunctionalized beta-O-4 lignin motif allowed effective homogeneous ruthenium catalyzed hydrogen neutral C-O bond cleavage (>99% of 3,4-dimethoxyacetophenone and >99% of guaiacol). The stepwise modification strategy was extended to walnut ethanosolv lignin, demonstrating that the specific structural motifs are accessible from such a readily available lignin. Overall, this work illustrates that the structure of lignin can be strategically modified to allow access to otherwise inaccessible specific aromatic compounds via selective depolymerization methodologies.