title: Total Synthesis of (-)-Lasonolide A.
abstract: The lasonolides are novel polyketides that have displayed remarkable biological activity in vitro against a variety of cancer cell lines. Herein we describe our first-generation approach to the formal synthesis of lasonolide A. The key findings from these studies ultimately allowed us to go on and complete a total synthesis of lasonolide A. The convergent approach unites two highly complex fragments utilizing a Ru-catalyzed alkene-alkyne coupling. This type of coupling typically generates branched products; however, through a detailed investigation, we are now able to demonstrate that subtle structural changes to the substrates can alter the selectivity to favor the formation of the linear product. The synthesis of the fragments features a number of atom-economical transformations which are highlighted by the discovery of an engineered enzyme to perform a dynamic kinetic reduction of a β-ketoester to establish the absolute stereochemistry of the southern tetrahydropyran ring with high levels of enantioselectivity.
authors.affiliation: Department of Chemistry, Stanford University , Stanford, California 94305-5080, United States.
authors.forename: Barry M
authors.initials: BM
authors.lastname: Trost
authors.affiliation: Department of Chemistry, Stanford University , Stanford, California 94305-5080, United States.
authors.forename: Craig E
authors.initials: CE
authors.lastname: Stivala
authors.affiliation: Department of Chemistry, Stanford University , Stanford, California 94305-5080, United States.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Fandrick
authors.affiliation: Department of Chemistry, Stanford University , Stanford, California 94305-5080, United States.
authors.forename: Kami L
authors.initials: KL
authors.lastname: Hull
authors.affiliation: Department of Chemistry, Stanford University , Stanford, California 94305-5080, United States.
authors.forename: Audris
authors.initials: A
authors.lastname: Huang
authors.affiliation: Department of Chemistry, Stanford University , Stanford, California 94305-5080, United States.
authors.forename: Caroline
authors.initials: C
authors.lastname: Poock
authors.affiliation: Department of Chemistry, Stanford University , Stanford, California 94305-5080, United States.
authors.forename: Rainer
authors.initials: R
authors.lastname: Kalkofen
mesh_terms: D000475:Alkenes / Q000737:chemistry; D000480:Alkynes / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D002384:Catalysis; D060326:Chemistry Techniques, Synthetic; D007700:Kinetics; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry; D012428:Ruthenium / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D000475:Alkenes; D000480:Alkynes; D000970:Antineoplastic Agents; D018942:Macrolides; C450700:lasonolide A; D012428:Ruthenium