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Macrocyclic natural products and their derivatives are a valuable source for biologically active crop protection products and have had significant impact on the development of conventional agrochemicals. However, they can be challenging starting points for lead-generation efforts because of their size, structural complexity, and developability. Using molecular modeling and electrostatic analysis, alternative bicyclic isosteres were identified as replacements for the antifungal nine-membered macrocycle UK-2A. By application of a structure-based conformational approach, a series of heterocyclic replacements were derivatized to deliver promising fungicidal activity and scaffold bioisosteres were further diversified to investigate structure-activity relationships.

The axial-equatorial conformational isomer distribution of the reactant diazoacetoacetate or its metal carbene intermediate is reflected in Rh(II) catalyzed oxonium ylide forming reactions of 3-(trans-2-arylvinyl)tetrahydropyranone-5-diazoacetoacetates that afford diastereoisomeric products for both the symmetry-allowed [2,3]- and the formally symmetry-forbidden [1,2]-oxonium ylide rearrangements.

Dirhodium catalyzed reactions of aryl-substituted tetrahydropyranone diazoacetoacetates produce ylide intermediates that unexpectedly yield two oxabicyclo[4.2.1]-nonane diastereoisomers, but a single diastereoisomer is formed by increasing the steric bulk of the aryl substituent.