Asymmetric Nazarov Cyclizations of Unactivated Dienones by Hydrogen-Bond-Donor/Lewis Acid Co-Catalyzed, Enantioselective Proton-Transfer.

We report an enantioselective Nazarov cyclization catalyzed by chiral hydrogen-bond-donors in concert with silyl Lewis acids. The developed transformation provides access to tri-substituted cyclopentenones in high levels of enantioselectivity (up to 95% e.e.) from a variety of simple unactivated dienones. Kinetic and mechanistic studies are consistent with a reversible 4π-electrocyclization C-C bond-forming step followed by rate- and enantio-determining proton-transfer as the mode of catalysis.

Stereospecific Furanosylations Catalyzed by Bis-thiourea Hydrogen-Bond Donors.

We report a new method for stereoselective O-furanosylation reactions promoted by a precisely tailored bis-thiourea hydrogen-bond-donor catalyst. Furanosyl donors outfitted with an anomeric dialkylphosphate leaving group undergo substitution with high anomeric selectivity, providing access to the challenging 1,2-cis substitution pattern with a range of alcohol acceptors. A variety of stereochemically distinct, benzyl-protected glycosyl donors were engaged successfully as substrates. Mechanistic studies support a stereospecific mechanism in which rate-determining substitution occurs from a catalyst-donor resting-state complex.

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.

Covalent Immobilization of (-)-Riboflavin on Polymer Functionalized Silica Particles: Application in the Photocatalytic E→Z Isomerization of Polarized Alkenes.

The covalent immobilization of the biomimetic, photo-organocatalyst (-)-riboflavin on silica micro- and nanoparticles via atom transfer radical polymerization (ATRP) is disclosed. Given the effectiveness of (-)-riboflavin as a versatile, environmentally benign photocatalyst, an immobilization strategy based on acrylate-linker modification of the catalyst core and controlled polymerization on initiator pre-functionalized silica particles has been developed. Validation of this approach is demonstrated in the E→Z isomerization of a benchmark cinnamonitrile (Z/E up to 88:12) with 0.97 mol % catalyst loading. Characterization of the immobilized photocatalyst supports covalent embedding of the catalyst in the polymeric brushes on the silica particle surface.

Contra-Thermodynamic, Photocatalytic E→Z Isomerization of Styrenyl Boron Species: Vectors to Facilitate Exploration of Two-Dimensional Chemical Space.

Designing strategies to access stereodefined olefinic organoboron species is an important synthetic challenge. Despite significant advances, there is a striking paucity of routes to Z-α-substituted styrenyl organoborons. Herein, this strategic imbalance is redressed by exploiting the polarity of the C(sp2 )-B bond to activate the neighboring π system, thus enabling a mild, traceless photocatalytic isomerization of readily accessible E-α-substituted styrenyl BPins to generate the corresponding Z-isomers with high fidelity. Preliminary validation of this contra-thermodynamic E→Z isomerization is demonstrated in a series of stereoretentive transformations to generate Z-configured trisubstituted alkenes, as well as in a concise synthesis of the anti-tumor agent Combretastatin A4.

Spatiotemporal Control of Pre-existing Alkene Geometry: A Bio-Inspired Route to 4-Trifluoromethyl-2H-chromenes.

Routes to prepare C4-trifluoromethyl analogues of the 2H-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.

Photocatalytic E → Z Isomerization of Polarized Alkenes Inspired by the Visual Cycle: Mechanistic Dichotomy and Origin of Selectivity.

Iteratively executed with exquisite spatial and temporal control, the selective isomerization of polarized alkenes underpins a plethora of complex biological processes ranging from natural product biosynthesis through to the mammalian visual cycle. However, nature's proficiency conceals the inherent difficulties in replicating this contra-thermodynamic transformation in the laboratory. Recently, we disclosed the first highly Z-selective isomerization of polarized alkenes, employing the cinnamoyl chromophore as a retinal surrogate under UV-irradiation (402 nm) with (-)-riboflavin (vitamin B2) as an inexpensive, organic photocatalyst (J. Am. Chem. Soc. 2015, 137, 11254-11257). This study was inspired by the propensity of crystalline (-)-riboflavin in the eyes of vertebrates to invert the intrinsic directionality of retinal isomerization. Herein, we extend this methodology to include a bioinspired, catalytic E → Z isomerization of α,ß-unsaturated nitriles, thereby mimicking the intermediate Opsin-derived, protonated Schiff base in the visual cycle with simple polarized alkenes. Replacement of the iminium motif by a cyano group is well tolerated and gives an additional degree of versatility for postisomerization functionalization. Broad substrate scope is demonstrated (up to 99:1 Z:E) together with evidence of mechanistic dichotomy via both singlet and triplet energy transfer mechanisms. Kinetic studies, temperature dependent photostationary state correlations and investigation of substituent-based electronic perturbation of the alkene identified polarization combined with increased Z-isomer activation barriers as the selectivity governing factors in catalysis. This investigation demonstrates the importance of internal structural preorganization on photostationary composition and explicates the augmented Z-selectivity upon hydrogen-alkyl exchange at the ß-position of the alkene.

One Photocatalyst, n 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 (ET) 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 E → Z Isomerization of Activated Olefins.

Herein, Nature's flavin-mediated activation of complex (poly)enes has been translated to a small molecule paradigm culminating in a highly (Z)-selective, catalytic isomerization of activated olefins using (-)-riboflavin (up to 99:1 Z/E). In contrast to the prominent Z → E isomerization of the natural system, it was possible to invert the directionality of the isomerization (E → Z) 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 (ET) and reaction efficiency, together with the study of additive effects and mechanistic probes, is consistent with a triplet energy transfer mechanism.

Continuous flow chemistry: a discovery tool for new chemical reactivity patterns.

Continuous flow chemistry as a process intensification tool is well known. However, its ability to enable chemists to perform reactions which are not possible in batch is less well studied or understood. Here we present an example, where a new reactivity pattern and extended reaction scope has been achieved by transferring a reaction from batch mode to flow. This new reactivity can be explained by suppressing back mixing and precise control of temperature in a flow reactor set up.