The Future of Retrosynthesis and Synthetic Planning: Algorithmic, Humanistic or the Interplay?

Abstract

The practice of deploying and teaching retrosynthesis is on the cusp of considerable change, which in turn forces practitioners and educators to contemplate whether this impending change will advance or erode the efficiency and elegance of organic synthesis in the future. A short treatise is presented herein that covers the concept of retrosynthesis, along with exemplified methods and theories, and an attempt to comprehend the impact of artificial intelligence in an era when freely and commercially available retrosynthetic and forward synthesis planning programs are increasingly prevalent. Will the computer ever compete with human retrosynthetic design and the art of organic synthesis?

The (±)-6-Aza[1.0]triblattane Skeleton: Contraction beyond the Wilder–Culberson Ring System

“…Retrosynthetically, adoption of the Wilder–Culberson ring-closure method enables a first-order retrosynthetic analysis . That is, disconnection of the C5–N6 bond unveils the fused bicyclo[2.2.1] skeleton (i.e., 9 ), which can be further translated back to alkene 10 (Scheme ).…”

“…4 In light of the fact this type of ring closure is highly favored for norbornyl systems (i.e., bicyclo[2.2.1]heptane), 5 the possibility of accessing more highly strained polycyclic tertiary amines is potentially opportune via this concept. 6 In particular, it seemed feasible that a ring-contracted 6-aza[1.0]triblattane skeleton (i.e., 7), which would constitute the first nitrogen analogue of the [1.0]triblattane system (i.e., tetracyclo-[4.3.0.0 2,5 .0 3,8 ]nonane, 8) 7 might be achievable (Scheme 2). Efforts toward this goal are disclosed herein.…”

“…Retrosynthetically, adoption of the Wilder−Culberson ringclosure method enables a first-order retrosynthetic analysis. 8 That is, disconnection of the C5−N6 bond unveils the fused bicyclo[2.2.1] skeleton (i.e., 9), which can be further translated back to alkene 10 (Scheme 2). The fused cyclobutene unit would likely be derived from an intramolecular electrocyclic ring closure of diene 11, which in turn could be accessed from cycloheptatriene (12) (Scheme 2).…”

Contemporary Computational Applications and Tools in Drug Discovery

“…In addition to discussing generative models, as well as a plethora of software tools developed to generate and test a variety of hypotheses, it is important to consider methods related to prediction of chemical synthesis. 6 Over the past few years, several new tools have emerged (Table 3) that allow medicinal chemistry teams to quickly assess the synthesis of difficult-to-synthesize or novel chemotypes. These approaches range from ML-based methods trained on large reaction datasets (e.g., USPTO dataset) to hand-coded rules.…”

Network search algorithms and scoring functions for advanced‐level computerized synthesis planning

“…While this dichotomy in performance is now becoming recognized, [36][37][38][39] the source of Chematica's successful synthetic planning has most often been attributed to its superior knowledge base of reaction rules which-based on the underlying reaction mechanism-are coded to delineate a broad spectrum of functional groups and structural fragments incompatible with a given reaction. 20 Indeed, in this way, the rules can indirectly map the space of "impossible" reactions to which literature-based AI methods have really no access (other than stipulating that putative reactions not reported in the literature are impossible, which is a dangerous oversimplification; see footnote #9 in [ 40 ]).…”