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A collaboration between the Mascal Lab at UC Davis, the McCorvy Lab at the Medical College of Wisconsin, and HepatoChem demonstrates how UV LEDs in the Lucent360™ transform a 60-year-old photocyclization into a practical tool for serotonin receptor drug discovery, accessing a previously inaccessible region of indole chemical space.<\/p>\n
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The Witkop photocyclization, discovered in 1966, builds an eight-membered lactam bridging the C3- and C4-positions of the indole nucleus. It is a rare way to directly functionalize indole at C4, an important position for medicinally active compounds, without protecting groups, directing groups, or transition metals.<\/p>\n
Despite its appeal, the reaction has remained a curiosity rather than a synthetic tool. Classical conditions use low-pressure mercury lamps at 254 nm and suffer from three persistent problems:<\/p>\n
For drug discovery, this combination has been disqualifying. Generations of chemists have walked past the Witkop cyclization because the cost of optimizing it has been higher than the value of the product.<\/p>\n
In their recent publication in the Journal of the American Chemical Society<\/i>, Beckett<\/a>, Buzdygon, Nguyen, and coworkers from the Mascal and McCorvy labs took a different approach. Rather than start with the classical \u03b1-chloroacetyl tryptamides, they coupled the 20 protein amino acids (plus norleucine, tert<\/i>-leucine, and theanine) to tryptamine and irradiated the resulting protonated \u03b1-amino tryptamides directly in aqueous medium.<\/p>\n The substrate scope is broad: the team prepared more than 30 cyclized lactams, including N-methylated, 5-methoxy-substituted, and \u03b1,\u03b1-dimethylated tryptamine variants relevant to known serotonergic pharmacophores. A complementary \u03b1-acetoxytryptamide route, derived from the same amino acids extends the method to substrates where the amine route stalls.<\/p>\n The team’s initial attempts to optimize the reaction in a standard Rayonet photoreactor were promising but slow. Optimizing a photochemical reaction in a single-vessel system means changing one variable, running the reaction, working it up, analyzing it, and starting over. With dozens of variables to investigate, this is a multi-month commitment.<\/p>\n HepatoChem integrated 275 nm and 310 nm UV-LEDs into the Lucent360 specifically for this collaboration. The Lucent360’s geometry \u2014 16 reaction vessels irradiated in parallel under matched conditions \u2014 collapsed each optimization study into a single 4-hour experiment.<\/p>\n A concrete example: the acid-effect screen described in Figure 1 of the paper, comparing HCl, TFA, and acetic acid at multiple equivalents, was completed in a single 4-hour Lucent360 run. The authors state that acquiring the same dataset with a single-vessel mercury lamp setup would have required 15 days of irradiation time more than 10% of the rated bulb life.<\/b><\/p>\n The Lucent360 enabled the team to systematically optimize:<\/p>\n <\/p>\n <\/p>\n <\/p>\n Once optimized, the same Lucent360 was reconfigured for flow chemistry. Gln NHEt-Tmn cyclized in 74% yield at 0.005 M with a 1 h residence time in the Lucent360 flow cell, demonstrating that the method scales beyond the multigram batch reactions reported. The ability to perform screening, batch synthesis, and flow scale-up in a single photoreactor \u2014 with the same light source and temperature control \u2014 was central to making this method practical.<\/p>\n The cyclized azocinoindoles are structural isomers of known serotonergic tryptamines \u2014 DMT, 5-MeO-DMT, psilocin \u2014 with the ethylamine side chain conformationally constrained into a ring. This constraint is exactly the kind of medicinal chemistry handle that has historically been hard to install in the tryptamine series.<\/p>\n The biological data are striking. Five reduced azocinoindoles (D1\u2013D5) were profiled at the 5-HT2A receptor using a BRET Gq dissociation assay. Efficacies ranged from 61% (partial agonist) to 93% (near-full agonist, approaching LSD). In vivo head-twitch response (HTR) testing in mice showed that none of the compounds elicited a head-twitch response<\/b> \u2014 the standard behavioral proxy for hallucinogenic activity \u2014 and all three tested compounds robustly attenuated DOI-induced HTR.<\/p>\n This points to a class of non-hallucinogenic 5-HT2A agonists<\/b>, a long-standing goal in the development of psychedelic-inspired therapeutics for depression, anxiety, PTSD, and substance use disorder. The azocinoindole scaffold \u2014 previously inaccessible at this scale \u2014 is now available for systematic structure-activity exploration.<\/p>\n If you are sitting on a UV photochemical reaction that has been \u00ab\u00a0uneconomical to optimize\u00a0\u00bb with a mercury lamp, the calculation has changed.<\/p>\n Learn more about UV LEDs and the Lucent360<\/a><\/strong><\/p>\nThe key chemistry:<\/b> a light-induced cyclization via a radical spin-center shift (SCS) process, in which single electron transfer to the amide carbonyl generates an electrophilic radical that adds selectively to C4 of indole. With ammonium as the leaving group, the reaction gives 100% C4-selectivity<\/b> \u2014 the C2-isomer that has historically plagued Witkop chemistry simply does not form.<\/div>\nHow the Lucent360 made it possible<\/h2>\n
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Acid effect Study<\/h4>\n
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\n \nTime (min)<\/th>\n HCl
1 equiv.<\/th>\nHCl
2 equiv.<\/th>\nHCl
5 equiv.<\/th>\nHCl
10 equiv.<\/th>\n<\/tr>\n<\/thead>\n\n 60<\/td>\n 61<\/td>\n 58<\/td>\n 55<\/td>\n 52<\/td>\n<\/tr>\n \n 120<\/td>\n 76<\/td>\n 71<\/td>\n 71<\/td>\n 52<\/td>\n<\/tr>\n \n 240<\/td>\n 87<\/td>\n 77<\/td>\n 75<\/td>\n 64<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<\/div>\n \n\n\n
\n \nTime (min)<\/th>\n AcOH
1 equiv.<\/th>\nAcOH
2 equiv.<\/th>\nAcOH
5 equiv.<\/th>\nAcOH
10 equiv.<\/th>\nAcOH
15 equiv.<\/th>\nAcOH
20 equiv.<\/th>\n<\/tr>\n<\/thead>\n\n 60<\/td>\n 47<\/td>\n 56<\/td>\n 54<\/td>\n 60<\/td>\n 54<\/td>\n 59<\/td>\n<\/tr>\n \n 120<\/td>\n 60<\/td>\n 69<\/td>\n 68<\/td>\n 80<\/td>\n 76<\/td>\n 81<\/td>\n<\/tr>\n \n 240<\/td>\n 73<\/td>\n 89<\/td>\n 89<\/td>\n 95<\/b><\/td>\n 91<\/td>\n 95<\/b><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<\/div>\n \n\n\n
\n \nTime (min)<\/th>\n TFA
1 equiv.<\/th>\nTFA
2 equiv.<\/th>\nTFA
5 equiv.<\/th>\nTFA
10 equiv.<\/th>\nTFA
15 equiv.<\/th>\nTFA
20 equiv.<\/th>\n<\/tr>\n<\/thead>\n\n 60<\/td>\n 57<\/td>\n 58<\/td>\n 55<\/td>\n 53<\/td>\n 40<\/td>\n 43<\/td>\n<\/tr>\n \n 120<\/td>\n 71<\/td>\n 74<\/td>\n 70<\/td>\n 63<\/td>\n 50<\/td>\n 53<\/td>\n<\/tr>\n \n 240<\/td>\n 93<\/td>\n 83<\/td>\n 77<\/td>\n 66<\/td>\n 54<\/td>\n 54<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<\/div>\n From screen to scale in the same instrument<\/h3>\n
Why it matters: a new platform for serotonin receptor drug discovery<\/h2>\n
Takeaways for the photochemist<\/h2>\n
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