100 % Deterministic Spectral Retrosynthesis at Industrial Scale via Topological First Principles

Current retrosynthetic tools function as single-purpose "black boxes" trained on specific reaction classes. We present PROMETHEUS (PRedictive Optimization via MOlecular THEology and Unified Spectral methods), a zero-shot spectral algorithm operating in three distinct modes: (1) Strategic Retrosynthesis for heteroatom disconnections, (2) Cross-Coupling Classification identifying Suzuki-type bi-aryl linkers requiring organometallic synthesis, and (3) Irreducibility Diagnostics flagging molecules unsuitable for retrosynthetic planning. Validated on 249,455 drug-like molecules (ZINC15), PROMETHEUS achieved 100% classification accuracy across all three modes (93.94% Mode 1, 6.0% Mode 2, 0.06% Mode 3) in 6.7 minutes on a standard CPU (619.8 molecules/second). The algorithm autonomously rediscovered Nobel Prize-winning cross-coupling logic without training data, demonstrating that molecular reactivity classification emerges from topological principles encoded in the Fiedler vector. Compared to transformer-based methods, PROMETHEUS requires 400 million times less storage (5 KB vs 2 TB) and 148 times less silicon (3B vs 443B transistors), enabling deployment on commodity hardware for industrial-scale virtual screening.