5′-O-(2-Methoxyisopropyl) (MIP)-protected nucleoside-3′-O-phosphoramidites were synthesized and evaluated as novel building blocks for automated solid-phase oligonucleotide synthesis (SPOS). Activators and additives were screened to establish the optimal conditions for the coupling of the 5′-O-MIP building blocks. Approximately half the amount of the deblocking reagent can be used to remove 5′-O-MIP compared to 5′-O-4,4′-dimethoxytrityl (DMT) with twice the rate for its deprotection. The faster 5′-O-deprotection rate reduced overall acid consumption, while the small-molecule benign byproducts (acetone and methanol) generated via MIP deprotection permit a lower PMI during SPOS. This work potentially leverages the improved design of sustainable strategies for the manufacturing of therapeutic oligonucleotides.