title: Enantioselective synthesis of tatanans A-C and reinvestigation of their glucokinase-activating properties.
abstract: The tatanans are members of a novel class of complex sesquilignan natural products recently isolated from the rhizomes of Acorus tatarinowii Schott plants. Tatanans A, B and C have previously been reported to have potent glucokinase-activating properties that exceed the in vitro activity of known synthetic antidiabetic agents. Here, using a series of sequential [3,3]-sigmatropic rearrangements, we report the total synthesis of tatanan A in 13 steps and 13% overall yield. We also complete a concise enantioselective total synthesis of more complex, atropisomeric tatanans B and C via a distinct convergent strategy based on a palladium-catalysed diastereotopic aromatic group differentiation (12 steps, 4% and 8% overall yield, respectively). A plausible biosynthetic relationship between acyclic tatanan A and spirocyclic tatanans B and C is proposed and probed experimentally. With sufficient quantities of the natural products in hand, we undertake a detailed functional characterization of the biological activities of tatanans A-C. Contrary to previous reports, our assays utilizing pure recombinant human enzyme demonstrate that tatanans do not function as allosteric activators of glucokinase.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Xiao
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Jackson
authors.forename: Ashok
authors.initials: A
authors.lastname: Basak
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Bowler
authors.forename: Brian G
authors.initials: BG
authors.lastname: Miller
authors.forename: Armen
authors.initials: A
authors.lastname: Zakarian
mesh_terms: D004789:Enzyme Activation; D005941:Glucokinase / Q000378:metabolism*; D017705:Lignans / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D017705:Lignans; C561065:tatanan A; C561066:tatanan B; C561067:tatanan C; D005941:Glucokinase