title: Total syntheses of demethylasterriquinone B1, an orally active insulin mimetic, and demethylasterriquinone A1.
abstract: Two total syntheses of the unsymmetrical bis-indolylquinone natural product demethylasterriquinone B1 (also known as L-783,281) have been accomplished. The first exploits a known base-promoted condensation of indoles with bromanil, which stops at monoaddition using the sterically hindered 2-isoprenylindole. This permits addition of the second indole, 7-prenylindole, which gives both meta- and para-substituted bis-indolylquinone products. This regiochemical control problem was solved by extension of a method we recently developed for acid-promoted addition of indoles to 2,5-dichlorobenzoquinone. Under our original mineral acid conditions, reaction of 2-isoprenylindole with dichlorobenzoquinone fails, but it succeeds with 3-bromo-2,5-dichlorobenzoquinone using acetic acid as the promoter. The regiochemistry established in such selectively bromine-substituted quinones can be exploited in Stille couplings. As a model system, the synthesis of demethylasterriquinone A1 was accomplished using as the key step a Stille coupling of a 2,5-dibromobenzoquinone with an (N-isoprenylindol-3-yl)tin, producing the para-substituted bis-indolylquinone exclusively. Use of a (7-prenylindole)tin in coupling with a bromo-2,5-dichloro-4-indolylbenzoquinone gives the demethylasterriquinone B1 precursor. The dihaloquinone products of these indole/quinone coupling processes can be hydrolyzed to the dihydroxyquinone natural products. Demethylasterriquinone B1 is of high recent interest as a small molecule insulin mimetic with oral anti-diabetic activity in mice.
authors.affiliation: Department of Chemistry, Levine Science Research Center, Duke University, Durham, North Carolina 27708-0317, USA. pirrung@chem.duke.edu
authors.forename: Michael C
authors.initials: MC
authors.lastname: Pirrung
authors.forename: Zhitao
authors.initials: Z
authors.lastname: Li
authors.forename: Kaapjoo
authors.initials: K
authors.lastname: Park
authors.forename: Jin
authors.initials: J
authors.lastname: Zhu
mesh_terms: D001230:Aspergillus / Q000737:chemistry; D001966:Bromine; D006868:Hydrolysis; D006873:Hydroquinones; D007004:Hypoglycemic Agents / Q000138:chemical synthesis*; D007211:Indoles / Q000138:chemical synthesis*
chemical_list: D006873:Hydroquinones; D007004:Hypoglycemic Agents; D007211:Indoles; C119066:L 783281; C069879:2,5-dichlorohydroquinone; C475798:demethylasterriquinone A1; D001966:Bromine