Department of Chemistry and Biochemistry, University of California, Santa Barbara, California 93106, USA.
Nat Chem. 2013 May;5(5):410-6. doi: 10.1038/nchem.1597. Epub 2013 Mar 24.
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.
塔坦南是一类新型复杂倍半萜天然产物的成员，最近从菖蒲根茎中分离得到。塔坦南 A、B 和 C 先前被报道具有很强的葡萄糖激酶激活特性，超过了已知的合成抗糖尿病药物的体外活性。在这里，我们通过一系列连续的[3,3]-σ重排反应，以 13 步和 13%的总收率完成了塔坦南 A 的全合成。我们还通过基于钯催化的非对映选择性芳基基团差异化的独特会聚策略，完成了更复杂的、手性异构的塔坦南 B 和 C 的简洁对映选择性全合成（分别为 12 步，总收率为 4%和 8%）。提出并实验性地探讨了无环塔坦南 A 与螺环塔坦南 B 和 C 之间可能的生物合成关系。与之前的报道相反，我们利用纯重组人酶进行的详细功能特征分析表明，塔坦南不是葡萄糖激酶的变构激活剂。
