title: Concise total syntheses of amphidinolides C and F.
abstract: The marine natural products amphidinolide C (1) and F (4) differ in their side chains but share a common macrolide core with a signature 1,4-diketone substructure. This particular motif inspired a synthesis plan predicating a late-stage formation of this non-consonant ("umpoled") pattern by a platinum-catalyzed transannular hydroalkoxylation of a cycloalkyne precursor. This key intermediate was assembled from three building blocks (29, 41 and 47 (or 65)) by Yamaguchi esterification, Stille cross-coupling and a macrocyclization by ring-closing alkyne metathesis (RCAM). This approach illustrates the exquisite alkynophilicity of the catalysts chosen for the RCAM and alkyne hydroalkoxylation steps, which activate triple bonds with remarkable ease but left up to five other π-systems in the respective substrates intact. Interestingly, the inverse chemoselectivity pattern was exploited for the preparation of the tetrahydrofuran building blocks 47 and 65 carrying the different side chains of the two target macrolides. These fragments derive from a common aldehyde precursor 46 formed by an exquisitely alkene-selective cobalt-catalyzed oxidative cyclization of the diunsaturated alcohol 44, which left an adjacent acetylene group untouched. The northern sector 29 was prepared by a two-directional Marshall propargylation strategy, whereas the highly adorned acid subunit 41 derives from D-glutamic acid by an intramolecular oxa-Michael addition and a proline-mediated hydroxyacetone aldol reaction as the key steps; the necessary Me3 Sn-group on the terminus of 41 for use in the Stille coupling was installed via enol triflate 39, which was obtained by selective deprotonation/triflation of the ketone site of the precursor 38 without competing enolization of the ester also present in this particular substrate.
authors.affiliation: Max-Planck-Institut für Kohlenforschung, 45470 Mülheim/Ruhr (Germany).
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Valot
authors.forename: Damien
authors.initials: D
authors.lastname: Mailhol
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Regens
authors.forename: Daniel P
authors.initials: DP
authors.lastname: O'Malley
authors.forename: Edouard
authors.initials: E
authors.lastname: Godineau
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takikawa
authors.forename: Petra
authors.initials: P
authors.lastname: Philipps
authors.forename: Alois
authors.initials: A
authors.lastname: Fürstner
mesh_terms: D002384:Catalysis; D003035:Cobalt / Q000737:chemistry; D003500:Cyclization; D003516:Cycloparaffins / Q000737:chemistry; D018942:Macrolides / Q000138:chemical synthesis* / Q000737:chemistry; D010084:Oxidation-Reduction; D010984:Platinum / Q000737:chemistry; D013237:Stereoisomerism; D000097442:Amphidinolides
chemical_list: D003035:Cobalt; D003516:Cycloparaffins; D018942:Macrolides; D010984:Platinum; C429132:amphidinolide C; D000097442:Amphidinolides; C072156:amphidinolide F
keywords: alkyne metathesis; molybdenum; natural products; platinum; total synthesis