1,3-Dipolar Cycloaddition - Stereospecificity

Stereospecificity

1,3-dipolar cycloadditions always result in retention of stereochemistry with respect to both the 1,3-dipole and the dipolarophile. Such high degree of stereospecificity is a strong support for the concerted over the stepwise reaction mechanism. Regarding the dipolarophile, determination of stereospecificity is simple: cis-substituents on the dipolarophilic alkene end up syn, and trans-substituents end up anti in the five-membered ring product (see scheme below).

Retention of the 1,3-dipole stereochemistry is more complex to study. Out of the 18 possible second-row 1,3-dipoles shown above, only two species that possess two stereogenic centers are relevant to the determination of stereospecificity: azomethine ylide and carbonyl ylide. The stereochemistry of these molecules are challenging to control because rotation about the single bond would scramble the stereochemistry of the 1,3-dipole reagent. Nonetheless, it is possible to generate these 1,3-dipoles in a stereocontrolled manner through cycloreversion of aziridines, and then rapidly trap them with dipolarophiles before rotation about the single bond can take place. The scheme below shows the thermal or photochemical conversion of aziridines into azomethine ylide with the desired stereochemistry. Trapping of these dipoles with strong dipolarophile indeed reveals the retention of stereochemistry of the dipole. However, non-stereospecific products are observed when weaker electrophiles are utilized as the trap; the slow cycloaddition allows rotation about the single bond and thus stereochemical scrambling to take place (see scheme below). Consequently, the reaction is stereospecific with respect to both the 1,3-dipole and the dipolarophile, giving retention to both of them in the same reaction. Generation of stereospecific carbonyl ylide can also be achieved by cycloreversion of epoxides.

Lastly, the stereochemistry of the central atom of a 1,3-dipole has been found to follow the principle of least motion; i.e., the position of this substituent on the central atom does not change much going from the starting material to the product. For example, in the cycloaddition of nitronic esters (N-alkoxy nitrones) to alkenes, the central-atom alkoxy group ends up axial in the envelope of the five-membered ring product as predicted by least motion (see scheme below).