Origins of reversing diastereoselectivity of alpha,beta-dichloro-gamma-butenolides and gamma-butyrolactams in direct vinylogous aldol addition: a computational study

Oxygenated five-membered ring compounds are more widespread in nature than the corresponding aza-analogues due to their more interesting biological activity. In our earlier studies, we have reported a simple methodology to synthesize novel synthons like 5-(1'-hydroxy)-gamma-butenolide and 5-(1'-hydroxy)-gamma-butyrolactam through the direct vinylogous aldol addition reaction. The observed diastereoselectivities for gamma-butyrolactones and gamma-butyrolactams were not understood in that report. We have reported herein a detailed computational study to understand the observed diastereoselectivity of alpha,beta-dichloro-gamma-butenolides and alpha,beta-dichloro-gamma-butyrolactams. The transition state calculations performed with B3LYP/cc-pVDZ level of theory to examine the diastereoselectivity of alpha,beta-dichloro-gamma-butenolides and alpha,beta-dichloro-gamma-butyrolactams have been found to be in good agreement with the observed experimental results. The origin of selectivity is examined by an activation strain model and molecular electrostatic potential (MESP) surfaces. The distortion energies calculated using the activation strain model revealed the origin of diastereoselectivities for butenolides and butyrolactams. The reversal in stereochemical outcome of alpha,beta-dichloro-gamma-butenolides and alpha,beta-dichloro-gamma-butyrolactams is due to the presence of a large substituent at the nitrogen center of the gamma-butyrolactams. We have further revealed the enhanced diastereoselectivity of these butenolides while reacting with the aromatic aldehydes bearing ortho substituents. The generated molecular electrostatic potential (MESP) surfaces have shown an additional V-min of value = -115.0 kcal mol(-1) responsible for enhanced diastereoselectivity with ortho-substituted benzaldehydes as compared to unsubstituted benzaldehyde. The difference in transition state distortion energies of syn and anti aldol products are found to correlate with their corresponding differences in activation energies.