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DFT and NMR Rationalization of Diastereoselectivity in Glycomimetic Synthesis by Modified Passerini Reaction

The bis-isopropylidene-protected D-fructose-derived aldehyde was utilized in the Passerini reaction with various acids and isocyanides thus obtaining functionalized glycomimetics in high yields and diastereoselectivities. To ascertain the stereochemistry of the newly created stereocentre, NOE contacts observed in 2D NOESY NMR experiments were compared to calculated interatomic distances in optimized structures of four different Passerini products. The measured correlation between hydrogen atom of the new stereocentre and neighbouring hydrogen atoms was not decisive on observed stereospecificity of the product. In order to elucidate the observed stereoselectivity of Passerini reactions performed with sugar aldehyde, we conducted DFT calculations at the SMD/M062X/6-311++G(2d, p)//M062X/6-31G(d) level of theory employing dichloromethane as a solvent starting from two different configurations leading to the final product with S (path-a) and R (path-b) configuration, following the mechanistic pathway proposed recently by Ramozzi and Morokuma.[1] The reason for different stability of intermediates, transition states and final products lies in the stabilizing noncovalent van der Waals interactions between nonpolar cyclohexyl and adjacent isopropylidene fragments which are especially pronounced in the final product with S configuration due to their closer proximity.[2] References: [1] R. Ramozzi, K. Morokuma, J. Org. Chem. 80 (2015) 5652‒5657. [2] (a) J. D. Chai, M. Head-Gordon, Phys. Chem. Chem. Phys. 10 (2008) 6615‒6620. (b) L. Yang, C. Adam, G. S. Nicholand, S. L. Cockroft, Nat. Chem. 5 (2013) 1006‒1010.

Diastereoselectivity ; Passerini reaction ; DFT calculation ; SMD model ; NMR

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