The team of Yanxing Jia and Aili Fan from Peking University used the known ( S )-4-tert-butyldimethylsilyloxy-2-cyclopentenone as the starting material, introduced amino and hydroxyl groups through rhodium-catalyzed aziridination/ring-opening reaction, and constructed the [3.2.1] bridged ring skeleton through Prins cyclization reaction. Finally, through the increase of oxidation state and functional group transformation, they achieved the first total synthesis of hemiketal tetrodotoxin (hemiketalTTX) in 23 steps with a total yield of 0.7%, effectively solving the problem of scarce sources of hemiketalTTX.
Background:
Tetrodotoxin (TTX, 1) is one of the most well-known natural toxins. As a highly selective inhibitor of voltage-gated sodium channels, TTX has played a key role in revealing the mechanism of action potential conduction and remains an indispensable tool for inhibiting excitatory cells in neurological research. Due to its unique chemical structure and excellent biological activity, TTX and its analogs have attracted many research groups around the world for in-depth research studies. In 2014, the Yotsu-Yamashita team isolated a new TTX analogue, hemiketal tetrodotoxin (hemiketalTTX), from a variety of salamanders. In 22 salamander samples, due to similar chromatographic properties, hemiketalTTX (3) and 4,9-anhydroTTX (2) were separated as a mixture, and the content of hemiketalTTX was about 1/40 to 1/20 of TTX, which limited its subsequent biological activity research. HemiketalTTX has a unique [3.2.1] bridged ring skeleton, containing hemiketal and cyclic guanidinium groups, and contains nine consecutive chiral centers. It is extremely challenging to synthesize and no total synthesis has so far been reported.
Highlights of this article :
Targeting the unique structure of hemiketalTTX, the research team led by Yanxing Jia and Aili Fan from Peking University devised a [3.2.1] bridge-ring construction strategy, centered around a Prins cyclization reaction. Starting with the known chiral enone 4, they utilized a copper-catalyzed Michael addition followed by a Mukaiyama aldol reaction and functional group transformation to yield the nitrene precursor 8 in three steps . Subsequently, a rhodium-catalyzed aziridination/ring-opening reaction successfully provided compound 11, achieving the simultaneous introduction of both an amino group and a hydroxyl group. Following a series of protective group adjustments and primary alcohol oxidation, the Prins cyclization precursor 15 was obtained on a 10-gram scale.
The aldehyde and isopropenyl groups in precursor 15 possess a certain degree of conformational freedom, which is conducive to the Prins cyclization reaction. Through extensive screening of Lewis acids, it was found that under the action of AlCl(CH₃) ₂ , not only the target product 16 was generated, but also the chlorinated compounds 17a and 17b were obtained. All three products can be eliminated under the conditions of Martin's sulfurane to conjugated diene 18.
After double dihydroxylation of a conjugated diene, followed by protecting group manipulation and oxidation state elevation, the first total synthesis of hemiketalTTX was completed in 23 steps with a 0.7% overall yield. This synthetic route, centered on diverse olefin conversions, effectively addresses the scarce sources of hemiketalTTX and provides a novel approach for the synthesis of highly oxidized natural products with cage-like backbones.
Summary and Outlook:
In summary, this work successfully achieved the first total synthesis of hemiketalTTX. Key reactions included the introduction of amino and hydroxyl groups via rhodium-catalyzed aziridination/ring-opening reactions and the construction of the [3.2.1] bridged ring skeleton via a Prins cyclization reaction. Furthermore, the research team evaluated the preliminary biological activity of hemiketalTTX, revealing moderate inhibitory activity against human Nav1.1 channels and weaker inhibitory activity against Nav1.2 to Nav1.7 channels. This achievement not only effectively addresses the issue of scarce sources of hemiketalTTX but also provides new insights into the synthesis of other highly oxidized natural products.
The research results were published in CCS Chemistry as a Communication. Peking University doctoral students Shumi Jia and Yilong Bi are co-first authors of the paper, with Professor Yanxing Jia and Associate Researcher Aili Fan as co-corresponding authors. This research was funded by the National Key R&D Program of China (2022YFC2804200) and the National Natural Science Foundation of China (22331001 and 21925101).
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About the journal: CCS Chemistry is the Chinese Chemical Society's flagship publication, established to serve as the preeminent international chemistry journal published in China. It is an English language journal that covers all areas of chemistry and the chemical sciences, including groundbreaking concepts, mechanisms, methods, materials, reactions, and applications. All articles are diamond open access, with no fees for authors or readers. More information can be found at https://www.chinesechemsoc.org/journal/ccschem .
About the Chinese Chemical Society: The Chinese Chemical Society (CCS) is an academic organization formed by Chinese chemists of their own accord with the purpose of uniting Chinese chemists at home and abroad to promote the development of chemistry in China. The CCS was founded during a meeting of preeminent chemists in Nanjing on August 4, 1932. It currently has more than 120,000 individual members and 184 organizational members. There are 7 Divisions covering the major areas of chemistry: physical, inorganic, organic, polymer, analytical, applied and chemical education, as well as 31 Commissions, including catalysis, computational chemistry, photochemistry, electrochemistry, organic solid chemistry, environmental chemistry, and many other sub-fields of the chemical sciences. The CCS also has 10 committees, including the Woman's Chemists Committee and Young Chemists Committee. More information can be found at https://www.chinesechemsoc.org/ .
