The reason is the unfavorable steric interactions of ethylenedioxy analogues with the enzyme.

An example is 1,2,4,5-tetrathiane, an organosulfur compound where four of the methylene bridges are replaced by a sulfide group (thus removing unfavorable 1,3-diaxial interactions).

On the contrary, when the electrophile attacks from the bottom face, such unfavorable interaction does not exist.

These inverse micelles are proportionally less likely to form on increasing headgroup charge, since hydrophilic sequestration would create highly unfavorable electrostatic interactions.

A hypersensitivity to pregabalin or another component of the product may develop, resulting in an unfavorable interaction with the body.

The most energetically unfavorable interaction involves axial substitution at the vertex of the boat portion of the ring (6.1 kcal/mol).

Purines are too large to fit in the active site, while unfavorable interactions with other pyrimidines discourage binding alternative substrates.

An ion can associate diffusely with the RNA backbone, shielding otherwise unfavorable electrostatic interactions.

The β-trans-axial substituent influences the transition state by also causing an unfavorable steric interaction between the two groups.

In the example below, the silyl-group acts to direct the cyclization by preventing the distant alkene from rotating "towards" it via unfavorable steric interaction.