One Photocatalyst, <i>n</i> Activation Modes Strategy for Cascade Catalysis: Emulating Coumarin Biosynthesis with (−)-Riboflavin

Generating molecular complexity using a single catalyst, where the requisite activation modes are sequentially exploited as the reaction proceeds, is an attractive guiding principle in synthesis. This requires that each substrate transposition exposes a catalyst activation mode (AM) to which all preceding or future intermediates are resistant. While this concept is exemplified by MacMillan’s beautiful merger of enamine and iminium ion activation, examples in other fields of contemporary catalysis remain elusive. Herein, we extend this tactic to organic photochemistry. By harnessing the two discrete photochemical activation modes of (−)-riboflavin, it is possible to sequentially induce isomerization and cyclization by energy transfer (<i>E</i>_T) and single-electron transfer (SET) activation pathways, respectively. This catalytic approach has been utilized to emulate the coumarin biosynthesis pathway, which features a key photochemical E → Z isomerization step. Since the ensuing SET-based cyclization eliminates the need for a prefunctionalized aryl ring, this constitutes a novel disconnection of a pharmaceutically important scaffold

A Bio-Inspired, Catalytic <i>E</i> → <i>Z</i> Isomerization of Activated Olefins

Herein, <i>Nature’s</i> flavin-mediated activation of complex (poly)­enes has been translated to a small molecule paradigm culminating in a highly (<i>Z</i>)-selective, catalytic isomerization of activated olefins using (−)-riboflavin (up to 99:1 <i>Z</i>/<i>E</i>). In contrast to the prominent <i>Z</i> → <i>E</i> isomerization of the natural system, it was possible to invert the directionality of the isomerization (<i>E</i> → <i>Z</i>) by simultaneously truncating the retinal scaffold, and introducing a third olefin substituent to augment A1,3-strain upon isomerization. Consequently, conjugation is reduced in the product chromophore leading to a substrate/product combination with discrete photophysical signatures. The operationally simple isomerization protocol has been applied to a variety of enone-derived substrates and showcased in the preparation of the medically relevant 4-substituted coumarin scaffold. A correlation of sensitizer triplet energy (<i>E</i>_T) and reaction efficiency, together with the study of additive effects and mechanistic probes, is consistent with a triplet energy transfer mechanism

A Bio-Inspired, Catalytic <i>E</i> → <i>Z</i> Isomerization of Activated Olefins

Herein, <i>Nature’s</i> flavin-mediated activation of complex (poly)­enes has been translated to a small molecule paradigm culminating in a highly (<i>Z</i>)-selective, catalytic isomerization of activated olefins using (−)-riboflavin (up to 99:1 <i>Z</i>/<i>E</i>). In contrast to the prominent <i>Z</i> → <i>E</i> isomerization of the natural system, it was possible to invert the directionality of the isomerization (<i>E</i> → <i>Z</i>) by simultaneously truncating the retinal scaffold, and introducing a third olefin substituent to augment A1,3-strain upon isomerization. Consequently, conjugation is reduced in the product chromophore leading to a substrate/product combination with discrete photophysical signatures. The operationally simple isomerization protocol has been applied to a variety of enone-derived substrates and showcased in the preparation of the medically relevant 4-substituted coumarin scaffold. A correlation of sensitizer triplet energy (<i>E</i>_T) and reaction efficiency, together with the study of additive effects and mechanistic probes, is consistent with a triplet energy transfer mechanism

Vitamin Catalysis: Direct, Photocatalytic Synthesis of Benzocoumarins via (−)-Riboflavin-Mediated Electron Transfer

An operationally simple protocol is disclosed to facilitate entry to benzo-3,4-coumarins directly from biaryl carboxylic acids without the need for substrate prefunctionalization. Complementary to classic lactonization strategies, this disconnection relies on the oxidation competence of photoactivated (−)-riboflavin (vitamin B₂) to generate the heterocyclic core via photoinduced single electron transfer. Collectively, the inexpensive nature of the catalyst, ease of execution, and absence of external metal additives are a convincing endorsement for the incorporation of simple vitamins in contemporary catalysis

Spatiotemporal Control of Pre-existing Alkene Geometry: A Bio-Inspired Route to 4‑Trifluoromethyl‑2<i>H</i>‑chromenes

Routes to prepare C4-trifluoromethyl analogues of the 2<i>H</i>-chromene scaffold are scarce: this is particularly striking given the importance of fluorine in pharmaceutical development. To address this limitation, a facile strategy has been developed that is reliant on catalytic, geometric isomerization of easily accessible allylic alcohols (up to >95:5) followed by intramolecular cyclization via Pd catalysis (up to 96%). This concise biomimetic approach emulates the photoisomerization/cyclization cascade inherent to phenylpropanoid biosynthesis