The stereochemistry of compounds determines the physical and chemical properties and biological activities of molecules, which is especially important in the fields of medicinal chemistry, fragrance industry and energetic materials. In medicinal chemistry research and pharmaceutical applications, specific stereoisomers usually exhibit unique interactions with their chiral receptors, and then exhibit unique effects in pharmacokinetics and pharmacodynamics. On the other hand, in the design of catalysts and functional materials, the physicochemical properties of diastereomers will also change significantly. However, when multiple chiral centers exist in a complex molecule, the effect of selectively changing one of the stereocenters on the physicochemical properties of the molecule is often difficult to analyze. However, the construction of stereochemically well-defined and complex organic molecules remains a central challenge in the fields of organic synthesis and catalysis.
Compared with traditional stereoselective synthesis, stereochemical editing is that bond formation and stereochemical selective construction are separated. In principle, stereochemical editing can achieve the following: i) preparation of challenging chiral molecules through unconventional/non-selective synthons; ii) providing a new strategy for powerful substrate control effects in complex environments and iii) providing new opportunities for late-stage diversification of molecules. Recently, researchers published a paper, using the photocatalytic stereochemical editing strategy at room temperature to realize the selective epimerization of unactivated tertiary stereocenters, and successfully developed a method for efficient construction of different stereocenters in different synthetic environments. Using this strategy, the authors rapidly constructed chiral frameworks that are difficult to construct using existing tools, and achieved late-stage stereochemical editing of complex molecules. This method provides a new way of thinking and synthetic tools for the synthesis of complex molecules. Some people think that this achievement may revolutionize the design of total synthesis strategies.
First, the authors chose cis-cyclobutane as the template substrate to explore the epimerization of the unactivated methine stereocenter. Based on previous studies in co-catalyzed systems with different hydrogen acceptor and donor compositions, the authors investigated the effect of thiol and disulfide additives on the isomerization reaction, and the results showed that potential hydrogen donors (such as: bis(4 -chlorophenyl) disulfide) increased the reaction rate. After a lot of screening, the author determined the optimal reaction conditions: under the irradiation of 390 nm LED lamp, using catalytic amount of DT, disulfide and base in MeCN/H2O for 4h at room temperature, the separation yield of 82% can be obtained product. Under optimal conditions, the authors investigated the range of substrates, and the results showed that substrates with different ring sizes (such as: cyclobutane, cyclopentane, cyclohexane), different substitutions dimethylcyclohexane in the pattern (ortho, para, meta), 1-substituted by different groups in the para position (such as: methyl, n-pentyl, isopropyl, phenyl, tert-butyl) methylcyclohexanol and even cis-fused bicyclic substrates as well as the steroid are compatible with this reaction and give corresponding poor to isomers.
Figure 1. Condition screening and substrate expansion.
Next, the authors explored the application of DT-mediated stereochemical editing strategies in synthetic chemistry. First, the authors epimerized the cis-six-membered ring product obtained from the Diels-Alder reaction using a stereochemical editing method, and constructed a series of challenging frameworks in a one-step method with moderate to good yields, further demonstrating the broad functional group tolerance and substrate applicability of this method. Secondly, the authors used this method to edit stereocenters in different synthetic environments, and stereoselective editing could occur and corresponding products could be obtained.
The authors achieved selective epimerization of unactivated tertiary stereocenters using a strategy of photocatalytic stereochemical editing at room temperature. This strategy enables rapid construction of chiral frameworks that are difficult to construct using existing tools, enabling late-stage stereochemical editing of complex molecules. In addition, the method uses common, well-accepted reagents, which can be more easily used by researchers in the field.
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Reference
- Stereochemical editing logic powered by the epimerization of unactivated tertiary stereocenters.
Yu-An Zhang, Vignesh Palani, Alexander E. Seim, Yong Wang, Kathleen J. Wang, Alison E. Wendlandt.
