Issue Date: September 11, 2017 | Web Date: September 6, 2017
Synthetic simplification of hallucinogen pays off
Salvinorin A, a hallucinogen produced by the Mexican plant Salvia divinorum, holds promise for treating itch and pain because it activates the kappa opioid receptor while avoiding the mu opioid receptor, a sister receptor that’s been associated with opioid abuse. Chemists have tried to synthesize salvinorin A so that they could alter the structure to sidestep the compound’s psychoactive effects while preserving its analgesic properties. But salvinorin A’s scaffold has been challenging to recreate.
Now, a team of scientists at the California and Florida branches of Scripps Research Institute, as well as at the University of Southern California, report a 10-step total synthesis of 20-norsalvinorin A (ChemRxiv 2017, DOI: 10.26434/chemrxiv.5318188). The compound differs from salvinorin A by a single methyl group and binds to the kappa opioid receptor with an affinity similar to that of the natural product. When given to mice, it also relieves itch.
The report is one of the first manuscripts posted on the ChemRxiv Beta site, a preprint server operated by ACS in partnership with the Royal Chemical Society, the German Chemical Society, and other organizations. The authors declined to discuss the work with C&EN for this story except to confirm its factual accuracy, in compliance with the embargo policies of the journal in which the paper has been submitted.
A long-standing problem for the total synthesis of salvinorin A and its analogs is the molecules’ propensity to epimerize, or switch chirality at a particular stereogenic center, according to synthetic chemist Mark Rizzacasa of the University of Melbourne. When salvinorin A epimerizes, it twists itself into the more stable, less active 8-epi isomer.
On the basis of calculations and experimental data, the researchers, led by Scripps’s Ryan Shenvi, proposed that this epimerization is driven by an unfavorable interaction between a hydrogen atom and the C20 methyl group within the molecule. They hypothesized that deleting the C20 methyl group to make 20-norsalvinorin A would stabilize the structure. This analog’s ability to bind to the target kappa opioid receptor was unknown, but the researchers performed computational studies that suggested the molecule would indeed bind with an affinity similar to that of salvinorin A.
“Careful attention to modeling gave a measure of confidence to the venture, although to some extent, it was still a leap of faith,” says Jonathan Scheerer, an organic chemist at William & Mary.
Salvinorin A had previously been made in 20–29 steps. The team’s route reaches 20-norsalvinorin A in 10 steps and includes a six-step sequence to an intermediate in 13% yield that can then be diversified to make similar analogs.
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