title: Total synthesis of cyclo-mumbaistatin analogues through anionic homo-Fries rearrangement.
abstract: The structurally unique polyketide mumbaistatin is the strongest naturally occurring inhibitor of glucose-6-phosphate translocase-1 (G6P-T1), which is a promising target for drugs against type-2 diabetes mellitus and angiogenic processes associated with brain tumor development. Despite its high relevance, mumbaistatin has so far withstood all attempts towards its total synthesis. In the present study an efficient total synthesis of a deoxy-mumbaistatin analogue containing the complete carbon skeleton and a spirolactone motif closely resembling the natural product in its cyclized form was elaborated. Key steps of the synthesis are a Diels-Alder cycloaddition for the construction of the fully functionalized anthraquinone moiety and an anionic homo-Fries rearrangement to build up the tetra-ortho-substituted benzophenone core motif, from which a spiroketal lactone forms in a spontaneous process. The elaborated strategy opens an entry to a variety of new analogs of mumbaistatin and cyclo-mumbaistatin and may be exploited for the total synthesis of the natural product itself in the future.
authors.affiliation: Department of Chemistry, Institute of Organic Chemistry, University of Cologne, Köln, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Neufeind
authors.forename: Nils
authors.initials: N
authors.lastname: Hülsken
authors.forename: Jörg-Martin
authors.initials: JM
authors.lastname: Neudörfl
authors.forename: Nils
authors.initials: N
authors.lastname: Schlörer
authors.forename: Hans-Günther
authors.initials: HG
authors.lastname: Schmalz
mesh_terms: D000880:Anthraquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017920:Antiporters / Q000037:antagonists & inhibitors*; D001688:Biological Products / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003500:Cyclization; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D015394:Molecular Structure; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000880:Anthraquinones; D017920:Antiporters; D001688:Biological Products; D005663:Furans; D009004:Monosaccharide Transport Proteins; C503531:SLC37A4 protein, human; D013141:Spiro Compounds; C430985:mumbaistatin; C520774:spiroketal