Lysergic acid diethylamide (LSD), a semisynthetic ergoline alkaloid analogue and hallucinogen, is a potent psychoplastogen with promising therapeutic potential. While a variety of synthetic strategies for accessing ergoline alkaloids have emerged, the complexity of the tetracyclic ring system results in distinct challenges in preparing analogues with novel substitution patterns. Methods of modulating the hallucinogenic activity of LSD by functionalization at previously inaccessible positions are of continued interest, and efficient syntheses of the ergoline scaffold are integral toward this purpose. Here, we report novel C-C bond forming strategies for preparing the ergoline tetracyclic core, focusing on the relatively unexplored strategy of bridging the B- and D-ring systems last. Following cross-coupling to first join the A- and D-rings, we explored a variety of methods for establishing the C-ring, including intramolecular α-arylation, borrowing hydrogen alkylation, and rhodium-catalyzed C-H insertion. Our results led to a seven-step formal synthesis of LSD and the first methods for readily introducing substitution on the C-ring. These strategies are efficient for forming ergoline-like tetracyclic compounds and analogues, though they each face unique challenges associated with elaboration to ergoline natural products. Taken together, these studies provide important insights that will guide future synthetic strategies toward ergolines.

Azoheteroarenes make up an emerging class of photoswitchable compounds with unique photophysical properties and advantages over traditional azobenzenes. Therefore, methods for synthesizing azoheteroarenes are highly desirable. Here, we utilize azide-alkyne click chemistry to access arylazo-1,2,3-triazoles, a previously unexplored class of azoheteroarenes that exhibit high thermal stabilities and near-quantitative bidirectional photoconversion. Controlling the catalyst or 1,3-dipole grants access to both regioisomeric arylazotriazoles and arylazoisoxazoles, highlighting the versatility of our approach.

Azobenzenes are widely used as dyes and photochromic compounds, with the Baeyer-Mills reaction serving as the most common method for their preparation. This transformation is often plagued by low yields due to the formation of undesired azoxybenzene. Here, we explore electronic effects dictating the formation of the azoxybenzene side-product. Using calculated oxidation potentials, we were able to predict reaction outcomes and improve reaction efficiency simply by modulating the oxidation potential of the arylamine component.

Photoswitches capable of accessing two geometric states are highly desirable, especially if their design is modular and incorporates a pharmacophore tethering site. We describe a redox isomerization strategy for synthesizing p-formylazobenzenes from p-nitrobenzyl alcohol. The resulting azo-aldehydes can be readily converted to photoswitchable compounds with excellent photophysical properties using simple hydrazide click chemistry. As a proof of principle, we synthesized a photoswitchable surfactant enabling the photocontrol of an emulsion with exceptionally high spatiotemporal precision.