Mossy synthesis: Sieboldine

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  • Published: Jan 6, 2017
  • Author: David Bradley
  • Channels: Infrared Spectroscopy
thumbnail image: Mossy synthesis: Sieboldine

Alkaloid analysis

Chisato Mukai, Kanazawa University website

A new, shorter total synthesis of a complex and intriguing compound, the Lycopodium alkaloid, (+)-sieboldine A, has been carried out by researchers in Japan. Infrared and nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry, as well as optical rotation measurements validated the procedure.

According to Mohammed Abd El-Gaber, Shigeo Yasuda, Eisuke Iida, and Chisato Mukai of the Division of Pharmaceutical Sciences, at Kanazawa University, Japan, the Lycopodium alkaloids, of which there are more than 200 structurally diverse examples known are important natural product targets for the synthetic organic chemist. Lycopodium species are types of fern-like club mosses also known as ground pines or creeping cedar and are epiphytic plants that are as diverse in their form as they are in the natural products they produce. Given that molecular diversity of natural products is often the focus of medicinal chemists it is natural that the metabolites and other biomolecules these species produce would be targets for scientists hoping to find new physiologically active molecules that might be developed into novel pharmaceutical compounds.

Enzyme target

The species Lycopodium sieboldii, native to Asia, produces a fawcettimine-type alkaloid (+)-sieboldine A along with another (+)-alopecuridine, first isolated and identified in 2003. The former compound has some potentially useful activity in that it inhibits the enzyme acetylcholinesterase at micromolar concentrations. This enzyme is, also known as AChE, is the main cholinesterase enzyme in the body and catalyses the breakdown of the neurotransmitter acetylcholine, making it an important target in a wide range of neurological diseases, including Alzheimer's disease. Moreover, the same compound has cytotoxic activity against lymphoma cells at low concentration.

As such, organic chemists have expended considerable energy in attempting to find ways to synthesise this compound from simpler starting materials. Once a total synthesis is in hand, after all, it is then possible to make sufficient quantities for testing and to modify the synthetic scheme to make derivatives of the parent compound with greater efficacy or fewer side effects.

Synthetic complexity

(+)-Sieboldine A (1) contains a distinctive, and unprecedented fused tetracyclic skeleton with a cis-hydrindane ring system and an N-hydroxyazacyclononane ring embedded in the compound bicyclo[5.2.1]decane-N,O-acetal. This represents what the team refers to as an "unusual and unique skeleton". Although two other research teams have successfully homed in on (+)-sieboldine A, there is always a need to take a shorter route and to be more specific with the stereochemistry and to reduce side products.

Mukai and colleagues have now devised a relatively short - for a complicated natural product - synthetic scheme, just 19 steps long that begins with the readily available starting material 5-(p-methoxybenzyloxy)pentyne. Writing in the journal Organic Letters, the team explains how an enantioselective Keck allylation gives them the dienyne derivative of that starting compound. They were then able to exposed it to Pauson–Khand conditions to generate a bicyclo[4.3.0]nonenone derivative with high stereoselectivity (93% enantiomeric excess). They then applied a Ueno–Stork reaction to make the cis-hydrindane core of the target compound with a quaternary carbon centre. A Schmidt glycosylation at a late stage in the scheme then leads to the formation of the N-hydroxyazacyclononane ring in the final structure.

"The enantioselective route for construction of the cis-hydrindane core is convergent and flexible, thus providing new avenues to access other fawcettimine-type Lycopodium alkaloids," the team concludes.

Related Links

Org Lett 2017, online: "Enantioselective Total Synthesis of (+)-Sieboldine A"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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