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.

Local Desymmetrization through Diastereotopic Group Selection: An Enabling Strategy for Natural Product Synthesis

“…[13] α, β-Unsaturated ester 36 was used as a starting point to synthesize the desymmetrization substrate 37 . Then, the allylic carbonate was converted into a palladium π-allyl species, which was found to undergo an intramolecular cyclodearomatization to give spirocyclohexadienone 38 in 84% yield as a mixture of diastereomers (it should be noted that one of these diastereomers arises from atropoisomerism).…”

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

“…Studies for the synthesis of the polyphenolic natural products tatanans A–C also explored the use of phosphonamide technology [50]. The discussion of the latter natural products is not included in this review, as phosphonamide technology was only used for limited exploratory studies.…”

Rapid Synthesis of Polyprenylated Acylphloroglucinol Analogs via Dearomative Conjunctive Allylic Annulation

“…2 Such an approach to PPAP core structures would take advantage of biosynthetic, innate reactivity 8,9 (phloroglucinol dearomatization, allylic alkylation) and utilize the predictably reactive reagent 2 which has been utilized extensively in conjunctive bond-forming processes. 10 Herein, we report our initial discoveries enabling the rapid construction of diverse PPAP analogs for biological evaluation through this modular and step-economic sequence.…”