then rapidly trapped with strong dipolarophiles before bond rotation can take place (see scheme below). If weaker dipolarophiles are used, bonds in the dipole have the chance to rotate, resulting in impaired cycloaddition stereospecificity. These results altogether confirm that 1,3-dipolar cycloaddition is stereospecific, giving retention of both the 1,3-dipole and the dipolarophile. Diastereoselectivity When two or more stereocenters are generated during the reaction, diastereomeric transition states and products can be obtained. In the Diels-Alder cycloaddition, the endo diastereoselectivity due to secondary orbital interactions is usually observed. In 1,3-dipolar cycloadditions, however, two forces influence the diastereoselectivity: the attractive π-interaction (resembling secondary orbital interactions in the Diels-Alder cycloaddition) and the repulsive steric interaction. Unfortunately, these two forces often cancel each other, causing poor diastereoselection in 1,3-dipolar cycloaddition. Examples of substrate-controlled diastereoselective 1,3-dipolar cycloadditions are shown below. First is the reaction between and methyl acrylate. In the transition state, the phenyl and the methyl ester groups stack to give the cis-substitution as the exclusive final pyrroline product. This favorable π-interaction offsets the steric repulsion between the phenyl and the methyl ester groups. Second is the reaction between nitrone and dihydrofuran. The exo-selectivity is achieved to minimize steric repulsion. Last is the intramolecular azomethine ylide reaction with alkene. The diastereoselectivity is controlled by the formation of a less strained cis-fused ring system. Directed 1,3-dipolar cycloaddition Trajectory of the cycloaddition can be controlled to achieve a diastereoselective reaction. For example, metals can chelate to the dipolarophile and the incoming dipole and direct the cycloaddition selectively on one face. The example below shows addition of nitrile oxide to an enantiomerically pure allyl alcohol in the presence of a magnesium ion. The most stable conformation of the alkene places the hydroxyl group above the plane of the alkene. The magnesium then chelates to the hydroxyl group and the oxygen atom of nitrile oxide. The cycloaddition thus comes from the top face selectively. Such diastereodirection has been applied in the synthesis of epothilones. Regioselectivity For asymmetric dipole-dipolarophile pairs, two regioisomeric products are possible. Both electronic/stereoelectronic and steric factors contribute to the regioselectivity of 1,3-dipolar cycloadditions. Electronic/stereoelectronic effect The dominant electronic interaction is the combination between the largest HOMO and the largest LUMO. Therefore, regioselectivity is governed by the atoms that bear the largest orbital HOMO and LUMO coefficients. For example, consider the cycloaddition of diazomethane to three dipolarophiles: methyl acrylate, styrene or methyl cinnamate. The carbon of diazomethane