title: Approaches to the total synthesis of chaetochalasin A.
abstract: Chaetochalasin A is a complex natural product whose biosynthesis may involve two domino Diels-Alder reactions. Approaches to the total synthesis of chaetochalasin A using this approach have been studied. Methyl (6R,8S,2Z,4E,10E,12E,14E)-6,8,10,14-tetramethylhexadeca-2,4,10,12,14-pentaenoate was identified as a key intermediate and was synthesized from (E)-1-bromo-4-tert-butyldimethylsilyloxy-2-methylbut-2-ene using diastereoselective alkylations of derivatives of (+)-pseudoephedrine to introduce the stereogenic centres, a modified Julia reaction to prepare the conjugated triene and a phosphonate condensation to provide the (2Z)-alkene. However, during the synthesis, facile geometrical isomerisation of the (14E)-trisubstituted and (2Z)-double-bonds was observed and attempts to incorporate this pentaene into a synthesis of chaetochalasin A led to the formation of mixtures of products. The analogous ethyl 6,8,10,14-tetramethylhexadeca-4,10,12,14-tetraenoate [that lacks the (2Z)-double-bond] was incorporated into a Diels-Alder precursor by acylation of a valine-derived N-acylpyrrolidinone followed by oxidative elimination of the corresponding 3-(phenylselanyl)pyrrolidinone. However, preliminary studies of the macrocycle-forming Diels-Alder reaction for a synthesis of chaetochalasin A were complicated by (E,Z)-isomerisation of the (10E)-double-bond of the conjugated triene and three Diels-Alder adducts were isolated and characterised. Further studies of this approach to chaetochalasin A will require an alternative procedure for the generation of the acylpyrrolinone in the presence of the acid sensitive conjugated triene.
authors.affiliation: The School of Chemistry, The University of Manchester, Manchester, M13 9PL, UK. e.j.thomas@manchester.ac.uk.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Thomas
authors.forename: Mark
authors.initials: M
authors.lastname: Willis
mesh_terms: D001688:Biological Products / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D060326:Chemistry Techniques, Synthetic; D005231:Fatty Acids, Unsaturated / Q000737:chemistry; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D001688:Biological Products; D005231:Fatty Acids, Unsaturated; D006576:Heterocyclic Compounds, 4 or More Rings; D011758:Pyrroles; C000597996:chaetochalasin A