CANDOR (Computed Affinity / Dynamically Ordered Retrosynthesis).
Every molecule extends numerous retrosynthetic paths. But different molecules, even molecules that differ by a single atom, will possess different retrosyntheses: some longer, some shorter. Therefore small alterations of a complex molecule may reveal a shorter synthesis than is possible for the native molecule itself. This structural perturbation with retrosynthetic analysis we will define as 'dynamic retrosynthetic analysis' since it follows exactly the same thought process as retrosynthetic analysis itself, where the TGT is static. Structural changes to the TGT will increase, maintain, or decrease structural complexity, which affects downstream transforms to reach starting materials. The key difference is that these initial perturbations to the TGT can include nonsense transforms that need not correspond to possible reactions. This logic allows changes to natural products that retain their structural complexity but reduce synthetic burden. In contrast to our major inspiration for this approach—Wender's Function-Oriented Synthesis (FOS)—structural complexity and synthetic complexity (# steps) are not linearly correlated. Structural and synthetic complexity are, instead, distinct.
(to calculate molecular complexity using a SMILES string, try the tool developed by Forli Lab)
The value of this approach is in deployment of natural products against biological targets. A validated target can also narrow the field of possible analogs by in silico docking. This workflow (see below) is now being investigated as a general tool for synthetic chemistry.
Roach, J. J.; Sasano, Y.; Schmid, C. L.; Zaidi, S.; Katrich, V.; Stevens, R. C.; Bohn, L. M.; Shenvi, R. A.* Dynamic Strategic Bond Analysis Yields a 10-step Synthesis of 20-nor-SalA, a Potent κ-OR Agonist, A(CS)2, 2017, 1329. ChemRxiv DOI: 10.26434/chemrxiv.5318188
Huffman, B.; Shenvi, R. A. "Natural Products in the ‘Marketplace’: Interfacing Synthesis and Biology," [invited Perspective] JACS 2019, 141, 3332–3346.
Crossley, S. W. M.; Tong, G.; Lambrecht, M.; Burdge, H. E.; Shenvi, R. A. Synthesis of Picrotoxinin via Late-Stage Strong Bond Activations, J. Am. Chem. Soc. 2020, 142, 11376–11381.
Woo, S.; Shenvi, R. Natural Product Synthesis Through the Lens of Informatics Acc. Chem. Res. 2021, 54, 1157–1167.