Total synthesis of anti-addictive alkaloid in just seven steps

A short modular synthesis has been developed to produce the psychoactive substance ibogaine and related compounds.¹ The approach could help to reduce dependency on natural plant sources for these products and generate new compounds with potential applications in the treatment of drug addiction and depression.

‘Anecdotal reports and some open-label clinical trials have suggested that ibogaine has profound anti-addictive and anti-depressant properties that last long after the drug has been cleared from the body,’ says David Olson from the University of California, Davis in the US who led the study. But despite these promising properties, the therapeutic use of this alkaloid has been limited due to its poor safety profile, he adds. ‘The cardiac risks associated with ibogaine have tempered enthusiasm for its development as a medicine. To solve this issue, our group and others have developed analogues that are safer for the heart.² Our new synthetic strategy will allow more structurally complex ibogaine analogues to be created that might have better safety profiles or improved efficacy.’

Currently, ibogaine and other similar alkaloids are obtained via extraction or semi-synthesis from natural plant sources, so sourcing enough of these compounds for clinical trials is challenging. Developing efficient synthetic routes could help to solve this problem, allowing scientists to explore the effects of these drugs at larger scales. While there have been many attempts to produce iboga alkaloids in recent decades, only a few total syntheses of ibogaine have been reported so far, with step counts ranging between nine and 15 and yields of 4.6% and below.

With their new strategy, Olson and his colleagues have now been able to produce ibogaine in only seven steps, achieving yields of up to 14%. ‘Our synthesis has several advantages over previous efforts to construct ibogaine,’ says Olson. ‘It is short, reasonably high-yielding, can be performed asymmetrically and is modular.’

The gram-scale synthesis begins with pyridine, an inexpensive and readily available starting material. ‘We construct the propeller-like portion of ibogaine through a Diels-Alder reaction and tack on the ethyl group using a radical coupling,’ explains Olson. ‘Next, we expand a strained three-member ring into the seven-membered, nitrogen-containing heterocycle that is a hallmark of iboga alkaloids. Finally, we install the indole through a classic cyclisation reaction involving an aryl hydrazone.’

Using common organic starting materials, reagents and solvents, the US team also demonstrated an enantioselective total synthesis of (+)-ibogaine in 11 steps and produced three additional iboga alkaloids, as well as four non-natural analogues. This allowed them to compare the properties of the different substances. ‘Ibogaine and its active metabolite noribogaine are believed to produce antidepressant and anti-addictive effects by promoting the growth of cortical neurons in the brain and modulating the function of the serotonin transporter,’ Olson explains. ‘Our synthetic strategy enabled us to access the unnatural enantiomer of ibogaine for the first time and we demonstrated that it does not have the same biological effects as ibogaine.’

‘Ibogaine is a complex natural product with tantalising potential for treatment of opioid addiction, but this compound has some serious side effects,’ comments Sarah O’Connor at the Max-Planck Institute for Chemical Ecology in Germany, who wasn’t involved in the research. ‘The development of this streamlined synthesis of ibogaine mimics is a breakthrough for exploring the pharmacological potential of this plant-derived natural product.’