of the product derived from the lower-energy transition state. This product ratio is consistent with the computed difference in transition state energies. This is an example in which the conformer favored in the ground state, which experiences reduced A(1,3) strain, reacts through a lower-energy transition state to form the major product. Synthetic applications Synthesis of AT2433-A1 The Curtin–Hammett principle has been invoked to explain selectivity in a variety of synthetic pathways. One example is observed en route to the antitumor antibiotic AT2433-A1, in which a Mannich-type cyclization proceeds with excellent regioselectivity. Studies demonstrate that the cyclization step is irreversible in the solvent used to run the reaction, suggesting that Curtin–Hammett kinetics can explain the product selectivity. Synthesis of kapakahines B and F A Curtin–Hammett scenario was invoked to explain selectivity in the syntheses of kapakahines B and F, two cyclic peptides isolated from marine sponges. The structure of each of the two compounds contains a twisted 16-membered macrocycle. A key step in the syntheses is selective amide bond formation to produce the correct macrocycle. In Phil Baran’s enantioselective synthesis of kapakahines B and F, macrocycle formation was proposed to occur via two isomers of the substrate. The more easily accessible, lower energy isomer led to the undesired product, whereas the less stable isomer formed the desired product. However, because the amide-bond-forming step was irreversible and the barrier to isomerization was low, the major product was derived from the faster-reacting intermediate. This is an example of a Curtin–Hammett scenario in which the less-stable intermediate is significantly more reactive than the more stable intermediate that predominates in solution. Because substrate isomerization is fast, throughout the course of the reaction excess substrate of the more stable form can be converted into the less stable form, which then undergoes rapid and irreversible amide bond formation to produce the desired macrocycle. This strategy provided the desired product in >10:1 selectivity. (I think there's an error in the Scheme. See Talk pages.) Synthesis of (+)-griseofulvin In the first enantioselective synthesis of (+)-Griseofulvin, a potent antifungal agent, a Curtin–Hammett situation was observed. A key step in the synthesis is the rhodium-catalyzed formation of an oxonium ylide, which then undergoes a [2,3] sigmatropic rearrangement en route to the desired product. However, the substrate contains two ortho-alkoxy groups, either of which could presumably participate in oxonium ylide generation. Obtaining high selectivity for the desired product was possible, however, due