Like many organic chemists, I find natural products very interesting, since their structures are often things that I would never imagine making (and in some cases have trouble imagining how to make at all!) But there’s a feature of the literature in that area that not everyone appreciates: the fact that a reasonable number of structures are, in fact, artifacts.
That’s reviewed in this article. These artifacts occur during the isolation process, and can come from a variety of sources. Carboxylic acids can get turned into esters on exposure to methanol or ethanol, for example, a situation that is not made any clearer by the fact that both methyl and ethyl ester structures can be legitimate natural products themselves. Lactones can get opened up, and similarly, aminals and acetals can undergo exchange reactions with such solvents. There’s been quite a bit of confusion over the years with all of these, and by no means is it all cleared up. There are many structures whose status is still open for debate.
Another complication is the set of natural products that feature reactive groups in their structures – sometimes what you isolate is the “sprung trap” version of the real compound. In all cases, you have to be alert to what conditions the extracts and isolates have been exposed to, and be wary of solvolysis, etc. Not only alcohols, but things like acetone and dichloromethane can get involved, even under what seems like very gentle handling. Chromatography, of course, is a big source of solvolysis artifacts, as is storage in solution (even at low temperatures), but there are cases where just transferring a compound from one flask to another and evaporating it down again is more than enough to cause trouble.
The same goes for oxidation – there are plenty of organisms that live (and thrive) in low-oxygen or flat-out anaerobic environments, and they can produce some very interesting compounds. Unfortunately, those compounds are not necessarily built to last out in our oxygenated world, and can thus spit out a whole range of artifactual structures.
But perhaps the biggest section in the paper is on artifacts produced by pH changes, both acidic and basic. That’s similar to the oxidation problem – natural products are generally produced in (and for) environments whose pH is rather tightly regulated, so exposure to out-of-range conditions can set off all sorts of chemistry. As the paper notes, though, “Unfortunately, the natural products literature has many accounts where the impact of acid has not been constrained” Rearrangements, dehydrations, condensations, and cycloadditions have all been documented. And on the basic side, Michael additions, epimerizations, aldols, and decarboxylations all feature. Some of these processes can be quite elaborate.
The gold standard is to identify proposed natural products in as crude an extract as possible, saved before too much handling too place, but too many papers don’t seem to bother with that step. This new review notes that the literature clearly under-reports artifact formation, but also details how it can be a way to recognize the actual compounds when they’re too sensitive to be easily isolated. But that only happens when you’re alert to the idea that what you’re seeing may not be the real natural product, of course.
Handling samples as gently as possible (heat, light, exposure to oxygen, to pH changes, and to potentially reactive solvents) is clearly the way to go, but that’s not always compatible with actually purifying and isolating all the components of a mixture, either. So the literature itself has to be handled with care, too. . .