title: Transannular [6 + 4] and Ambimodal Cycloaddition in the Biosynthesis of Heronamide A.
abstract: The transannular [6 + 4] cycloaddition proposed as a step in the biosynthesis of heronamide A has been modeled using density functional theory. The proposed cycloaddition is highly stereoselective, affording a single product. The reaction proceeds through an ambimodal transition state that directly leads to a [4 + 2] adduct in addition to the observed [6 + 4] adduct. Interconversion of these adducts is possible via a facile Cope rearrangement. The [6 + 4] adduct is thermodynamically more stable than the [4 + 2] adduct by 5.2 kcal mol(-1) due to a combination of the ring and steric strain in the [4 + 2] product. The results strongly support the plausibility of the proposed transannular [6 + 4] cycloaddition in the biogenesis of heronamide A and may provide insights to designing substrates that selectively undergo [6 + 4] cycloaddition to form unbridged 10-membered rings.
authors.affiliation: Department of Chemistry and Biochemistry, ‡Department of Chemical and Biomolecular Engineering, University of California , Los Angeles, California 90095, United States.
authors.forename: Peiyuan
authors.initials: P
authors.lastname: Yu
authors.affiliation: Department of Chemistry and Biochemistry, ‡Department of Chemical and Biomolecular Engineering, University of California , Los Angeles, California 90095, United States.
authors.forename: Ashay
authors.initials: A
authors.lastname: Patel
authors.affiliation: Department of Chemistry and Biochemistry, ‡Department of Chemical and Biomolecular Engineering, University of California , Los Angeles, California 90095, United States.
authors.forename: K N
authors.initials: KN
authors.lastname: Houk
mesh_terms: D003198:Computer Simulation; D003500:Cyclization; D061565:Cycloaddition Reaction; D047029:Lactams, Macrocyclic / Q000138:chemical synthesis / Q000737:chemistry*; D015394:Molecular Structure; D013816:Thermodynamics
chemical_list: D047029:Lactams, Macrocyclic; C000609105:heronamide A