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Despite the enormous potential for the use of stereospecific cross-coupling reactions to rationally manipulate the three-dimensional structure of organic molecules, the factors that control the transfer of stereochemistry in these reactions remain poorly understood. Here we report a mechanistic and synthetic investigation into the use of enantioenriched alkylboron nucleophiles in stereospecific Pd-catalyzed Suzuki cross-coupling reactions. By developing a suite of molecular descriptors of phosphine ligands, we could apply predictive statistical models to select or design distinct ligands that respectively promoted stereoinvertive and stereoretentive cross-coupling reactions. Stereodefined branched structures were thereby accessed through the predictable manipulation of absolute stereochemistry, and a general model for the mechanism of alkylboron transmetallation was proposed.
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Multi‐Threshold Analysis for Chemical Space Mapping of Ni‐Catalyzed Suzuki‐Miyaura Couplings
Abstract A key challenge in synthetic chemistry is the selection of high‐performing ligands for cross‐coupling reactions. To address this challenge, this work presents a classification workflow to identify physicochemical descriptors that bin monophosphine ligands as active or inactive in Ni‐catalyzed Suzuki‐Miyaura coupling reactions. Using five previously published high‐throughput experimentation datasets for training, we found that a binary classifier using a phosphine's minimum buried volume and Boltzmann‐averaged minimum electrostatic potential is most effective at distinguishing high and low‐yielding ligands. Experimental validations are also presented. Using the two physicochemical descriptors from the binary classifier to represent the chemical space of monophosphine ligands leads to a more predictive guide for structure‐reactivity relationships compared with classic chemical space representations.
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- Award ID(s):
- 2202693
- PAR ID:
- 10643058
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- European Journal of Organic Chemistry
- Volume:
- 27
- Issue:
- 36
- ISSN:
- 1434-193X
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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