Determining Excited-State Absorption Properties of a Quinoid Flavin by Polarization-Resolved Transient Spectroscopy.

As important naturally occurring chromophores, photophysical/chemical properties of quinoid flavins have been extensively studied both experimentally and theoretically. However, little is known about the transition dipole moment (TDM) orientation of excited-state absorption transitions of these important compounds. This aspect is of high interest in the fields of photocatalysis and quantum control studies. In this work, we employ polarization-associated spectra (PAS) to study the excited-state absorption transitions and the underlying TDM directions of a standard quinoid flavin compound. As compared to transient absorption anisotropy (TAA), an analysis based on PAS not only avoids diverging signals but also retrieves the relative angle for ESA transitions with respect to known TDM directions. Quantum chemical calculations of excited-state properties lead to good agreement with TA signals measured in magic angle configuration. Only when comparing experiment and theory for TAA spectra and PAS, do we find deviations when and only when the S0 → S1 of flavin is used as a reference. We attribute this to the vibronic coupling of this transition to a dark state. This effect is only observed in the employed polarization-controlled spectroscopy and would have gone unnoticed in conventional TA.

Flavin-Catalyzed, Photochemical Conversion of Dehydroalanine into 4,5-Dihydroxynorvaline.

The chemical synthesis of unnatural amino acids (UAA) is a key strategy for preparing designed peptides, including pharmaceutically active compounds. Alterations of existing amino acid residues such as dehydroalanine (Dha) are particularly important since selected positions can be addressed without the necessity of a complete de novo synthesis. The intriguing UAA 4,5-dihydroxynorvaline (Dnv) is found in a variety of naturally occurring peptides and biologically active compounds. However, no method is currently available to modify an existing peptide with this residue. We report the use of flavin catalysts and visible light irradiation for this challenge, which serves as a versatile strategy for converting Dha into Dnv. Our study shows that excited flavins are competent hydrogen atom abstraction catalysts for ethers and acetals, which allows masked 1,2-dihydroxyethylene functionalization from 2,2-dimethyl-1,3-dioxolane. The masked diol was successfully coupled to Dha residues, and a series of Dnv-containing products is reported. A mild and orthogonal protocol for deprotection of the acetal group was also identified, allowing free Dnv-modified peptides to be obtained. This method provides a straightforward strategy for Dnv functionalization, which is envisioned to be crucial for accessing natural products and synthetic analogues with pharmaceutical activity.

Enhancing Flavins Photochemical Activity in Hydrogen Atom Abstraction and Triplet Sensitization through Ring-Contraction.

The isoalloxazine heterocycle of flavin cofactors reacts with various nucleophiles to form covalent adducts with important functions in enzymes. Molecular flavin models allow for the characterization of such adducts and the study of their properties. A fascinating set of reactions occurs when flavins react with hydroxide base, which leads to imidazolonequinoxalines, ring-contracted flavins, with so far unexplored activity. We report a systematic study of the photophysical properties of this new chromophore by absorption and emission spectroscopy as well as cyclic voltammetry. Excited, ring-contracted flavins are significantly stronger hydrogen atom abstractors when compared to the parent flavins, which allowed the direct trifluoromethylthiolation of aliphatic methine positions (bond dissociation energy (BDE) of 400.8 kJ mol-1). In an orthogonal activity, their increased triplet energy (E(S0←T1)=244 kJ mol-1) made sensitized reactions possible which exceeded the power of standard flavins. Combining both properties, ring-contracted flavin catalysts enabled the one-pot, five-step transformation of α-tropolone into trans-3,4-disubstituted cyclopentanones. We envision this new class of flavin-derived chromophores to open up new modes of reactivity that are currently impossible with unmodified flavins.

Photochemical Desaturation and Epoxidation with Oxygen by Sequential Flavin Catalysis.

Catalytic desaturations are important strategies for the functionalization of organic molecules. In nature, flavoenzymes mediate the formation of α,ß-unsaturated carbonyl compounds by concomitant cofactor reduction. Contrary to many laboratory methods for these reactions, such as the Saegusa-Ito oxidation, no transition metal reagents or catalysts are required. However, a molecular flavin-mediated variant has not been reported so far. We disclose a photochemical approach for silyl enol ether oxidation, which leads to α,ß-unsaturated ketones (13 examples) in very good yields. The flavin catalysts are stable throughout the desaturation reaction, and we successfully applied them in a subsequent aerobic epoxidation by simply changing the reaction conditions. This protocol allowed us to directly convert silyl enol ethers into α,ß-epoxyketones in a one-pot fashion (12 examples). Sequential flavin catalysis is not limited to one specific reactivity combination and can, inter alia, couple the photochemical oxidation with radical additions. We anticipate that flavin-catalyzed desaturation will be applicable to other substrate classes and that its sequential catalytic activity will enable rapid substrate diversification.

Photochemical Deracemization of Chiral Alkenes via Triplet Energy Transfer.

A visible-light-mediated, enantioselective approach to axially chiral alkenes is described. Starting from a racemic mixture, a major alkene enantiomer is formed due to selective triplet energy transfer from a catalytically active chiral sensitizer. A catalyst loading of 2 mol % was sufficient to guarantee consistently high enantioselectivities and yields (16 examples, 51%-quant., 81-96% ee). NMR studies and DFT computations revealed that triplet energy transfer is more rapid within the substrate-catalyst complex of the minor alkene enantiomer. Since this enantiomer is continuously racemized, the major enantiomer is enriched in the photostationary state.

Reduced Molecular Flavins as Single-Electron Reductants after Photoexcitation.

Flavoenzymes mediate a multitude of chemical reactions and are catalytically active both in different oxidation states and in covalent adducts with reagents. The transfer of such reactivity to the organic laboratory using simplified molecular flavins is highly desirable, and such applications in (photo)oxidation reactions are already established. However, molecular flavins have not been used for the reduction of organic substrates yet, although this activity is known and well-studied for DNA photolyase enzymes. We report a catalytic method using reduced molecular flavins as photoreductants and γ-terpinene as a sacrificial reductant. Additionally, we present our design for air-stable, reduced flavin catalysts, which is based on a conformational bias strategy and circumvents the otherwise rapid reduction of O2 from air. Using our catalytic strategy, we were able to replace superstoichiometric amounts of the rare-earth reductant SmI2 in a 5-exo-trig cyclization of substituted barbituric acid derivatives. Such flavin-catalyzed reductions are anticipated to be beneficial for other transformations as well and their straightforward synthesis indicates future use in stereo- as well as site-selective transformations.

Photochemical Deracemization at sp3-Hybridized Carbon Centers via a Reversible Hydrogen Atom Transfer.

A photochemical deracemization of 5-substituted 3-phenylimidazolidine-2,4-diones (hydantoins) is reported (27 examples, 69%-quant., 80-99% ee). The reaction is catalyzed by a chiral diarylketone which displays a two-point hydrogen bonding site. Mechanistic evidence (DFT calculations, radical clock experiments, H/D labeling) suggests the reaction to occur by selective hydrogen atom transfer (HAT). Upon hydrogen binding, one substrate enantiomer displays the hydrogen atom at the stereogenic center to the photoexcited catalyst allowing for a HAT from the substrate and eventually for its conversion into the product enantiomer. The product enantiomer is not processed by the catalyst and is thus enriched in the photostationary state.

Site-Selective Nitrene Transfer to Conjugated Olefins Directed by Oxazoline Peptide Ligands.

Site-selective nitrene transfer to di- and polyene substrates has been achieved using designed peptide-embedded bioxazoline ligands capable of binding copper. In model 1,3-diene substrates, the olefinic position proximal to a directing group was selectively functionalized. Additional studies indicate that this selectivity stems from non-covalent substrate-catalyst interactions. The peptide-mediated nitrene transfer was also applied to polyene natural product retinol and selective proximal functionalization allowed access to a cis-pyrroline modified retinoid.

Synthetic C6-Functionalized Aminoflavin Catalysts Enable Aerobic Bromination of Oxidation-Prone Substrates.

Flavoenzymes catalyze oxidations via hydroperoxide intermediates that result from activation of molecular O2 . These reactions-such as hydroxylation and halogenation-depend on the additional catalytic activity of functional groups in the peptide environment of the flavin cofactor. We report synthetic flavin catalysts that contain C6 amino modifications at the isoalloxazine core and are consequently capable of mediating halogenations outside the peptide surrounding. The catalysts are competent in the selective, biomimetic bromination of oxidation-prone phenols, flavones, and flavanones using a halide salt in combination with 2,6-lutidinium oxalate as a flavin reductant under visible-light irradiation. Our studies show the beneficial effect of stacked bisflavins as well as the catalytic activity of the flavin modifications. The designed flavin catalysts outperform isolated natural (-)-riboflavin and contribute to the continuing search for tailored flavins in oxidation reactions.

Intramolecular [2+2] Photocycloaddition of Cyclic Enones: Selectivity Control by Lewis Acids and Mechanistic Implications.

The intramolecular [2+2] photocycloaddition of 3-alkenyl-2-cycloalkenones was performed in an enantioselective fashion (nine representative examples, 54-86 % yield, 76-96 % ee) upon irradiation at λ=366 nm in the presence of an AlBr3 -activated oxazaborolidine as the Lewis acid. An extensive screening of proline-derived oxazaborolidines showed that the enantioface differentiation depends strongly on the nature of the aryl group at the 3-position of the heterocycle. DFT calculations of the Lewis acid-substrate complex indicate that attractive dispersion forces may be responsible for a change of the binding mode. The catalytic [2+2] photocycloaddition was shown to proceed on the triplet hypersurface with a quantum yield of 0.05. The positive effect of Lewis acids on the outcome of a given intramolecular [2+2] photocycloaddition was illustrated by optimizing the key step in a concise total synthesis of the sesquiterpene (±)-italicene.

Investigation of Strain-Promoted Azide-Alkyne Cycloadditions in Aqueous Solutions by Capillary Electrophoresis.

The Cu-free 1,3-dipolar cycloaddition of cyclooctynes and azides is an up-and-coming method in bioorganic chemistry and other disciplines. However, broad application is still hampered by major drawbacks such as poor solubility of the reactants in aqueous media and low reaction rates. It is thus of high demand to devise a fast and user-friendly strategy for the optimization of reaction conditions and reagent design. We describe a capillary electrophoresis (CE) study of reaction kinetics in strain-promoted azide-alkyne cycloadditions (SPAAC) using substrates with acidic or basic functionalities. This study reveals that the pH value has a significant effect on reaction rates as a result of changes in the reactants' charge state via protonation or deprotonation, and the concomitant changes of electronic properties. This novel experimental setup also enables the study of even more challenging conditions such as reactions in micelles and we did indeed observe much faster SPAAC reactions in the presence of surfactants. Careful combination of the above-mentioned parameters resulted in the identification of conditions enabling remarkable rate enhancement by a factor of 80. This electrophoretic method may thus serve as a versatile, fast and reliable tool for screening purposes in all research areas applying SPAAC reactions.

Supramolecular chirality transfer in a stereodynamic catalysts.

We present rhodium catalysts that contain stereodynamic axially chiral biphenol-derived phosphinite ligands modified with non-stereoselective amides for non-covalent interactions. A chirality transfer was achieved with (R)- or (S)-acetylphenylalanine methyl amide, and the interaction mechanism was investigated by NMR measurements. These interactions at the non-stereoselective interaction sites and the formation of supramolecular complexes result in an enrichment of either the (Rax )- or (Sax ) enantiomer of the tropos catalysts, which in turn provide the (R)- or (S)-acetylphenylalanine methyl ester in the hydrogenation of (Z)-methyl-α-acetamidocinnamate.

A Stereodynamic Redox-Interconversion Network of Vicinal Tertiary and Quaternary Carbon Stereocenters in Hydroquinone-Quinone Hybrid Dihydrobenzofurans.

Reversible redox processes involving hydroquinones and quinones are ubiquitous in biological reaction networks, materials science, and catalysis. While extensively studied in intermolecular settings, less is known about intramolecular scenarios. Herein, we report hydroquinone-quinone hybrid molecules that form two-stereocenter dihydrobenzofurans via intramolecular cyclization under thermodynamic control. A π-methylhistidine peptide-catalyzed kinetic resolution allowed us to study the stereodynamic behavior of enantio- and diastereo-enriched dihydrofurans. In the course of this study, it was revealed that a reversible intramolecular redox-interconversion network connects all four possible stereoisomers via inversion of a quaternary carbon stereocenter without achiral intermediates. As a result, these findings on hydroquinone-quinone hybrid molecules provide insights into potential natural origin and synthetic access of the common dihydrobenzofuran motif.

Stereodynamic Quinone-Hydroquinone Molecules That Enantiomerize at sp3-Carbon via Redox-Interconversion.

Since the discovery of molecular chirality, nonsuperimposable mirror-image organic molecules have been found to be essential across biological and chemical processes and increasingly in materials science. Generally, carbon centers containing four different substituents are configurationally stable, unless bonds to the stereogenic carbon atom are broken and re-formed. Herein, we describe sp3-stereogenic carbon-bearing molecules that dynamically isomerize, interconverting between enantiomers without cleavage of a constituent bond, nor through remote functional group migration. The stereodynamic molecules were designed to contain a pair of redox-active substituents, quinone and hydroquinone groups, which allow the enantiomerization to occur via redox-interconversion. In the presence of an enantiopure host, these molecules undergo a deracemization process that allows observation of enantiomerically enriched compounds. This work reveals a fundamentally distinct enantiomerization pathway available to chiral compounds, coupling redox-interconversion to chirality.

Attracting Enantiomers: Chiral Analytes That Are Simultaneously Shift Reagents Allow Rapid Screening of Enantiomeric Ratios by NMR Spectroscopy.

The rapid and direct determination of enantiomeric ratios is of increasing interest due to the significantly reduced effort compared to chromatographic methods and the large number of analytes, for instance in enantioselective catalysis. Current strategies include colorimetric assays, (a)chiral solvating reagents for NMR spectroscopy and metal complexes for CD sensing. We report the determination of enantiomeric ratios based on the self-induced diastereomeric anisochronism (SIDA) effect. Alanine derivatives that represent chiral products of enantioselective catalysis, such as the well-established hydrogenation of dehydroamino acids, were investigated. The SIDA effect was significantly enhanced by attachment of 3,5-dinitrobenzoyl π-π interactions sites. This simple modification enabled simultaneous determination of enantiomeric ratios and conversions by NMR spectroscopy.

A stereodynamic phosphoramidite ligand derived from 3,3'-functionalized ortho-biphenol and its rhodium(I) complex.

Stereodynamic ligands and complexes bearing functional groups to attach chiral or achiral binding sites and auxiliaries are highly attractive due to the interesting opportunities for controlling the stereochemical outcome of enantioselective transformations. In this study we report the preparation of a 3,3'-functionalized biphenol (BIPOL) phosphoramidite ligand (PAm ) bearing 3,5-dichlorobenzoyl (3,5-DCB) amide binding sites for noncovalent interactions. Upon coordination to [Rh(COD)2 ]BF4 this substitution pattern directs one of the 3,5-DCB binding sites in close proximity of the metal center resulting in liberation of both COD ligands and the formation of a [Rh(PAm )2 ]BF4 complex. Coordination of the amide carbonyl unit was found to be reversible, since the complex acted as an active catalyst in the hydrogenation of dehydroamino acid derivatives. X-ray crystallographic investigation revealed that the second 3,5-DCB unit is capable of forming noncovalent π-π interactions connecting both phosphoramidite ligands.

Stereodynamic tetrahydrobiisoindole "NU-BIPHEP(O)"s: functionalization, rotational barriers and non-covalent interactions.

Stereodynamic ligands offer intriguing possibilities in enantioselective catalysis. "NU-BIPHEPs" are a class of stereodynamic diphosphine ligands which are easily accessible via rhodium-catalyzed double [2 + 2 + 2] cycloadditions. This study explores the preparation of differently functionalized "NU-BIPHEP(O)" compounds, the characterization of non-covalent adduct formation and the quantification of enantiomerization barriers. In order to explore the possibilities of functionalization, we studied modifications of the ligand backbone, e.g., with 3,5-dichlorobenzoyl chloride. Diastereomeric adducts with Okamoto-type cellulose derivatives and on-column deracemization were realized on the basis of non-covalent interactions. Enantioselective dynamic HPLC (DHPLC) allowed for the determination of rotational barriers of ΔG (‡) 298K = 92.2 ± 0.3 kJ mol(-1) and 99.5 ± 0.1 kJ mol(-1) underlining the stereodynamic properties of "NU-BIPHEPs" and "NU-BIPHEP(O)s", respectively. These results make the preparation of tailor-made functionalized stereodynamic ligands possible and give an outline for possible applications in enantioselective catalysis.

Tautomerization-mediated molecular switching between six- and seven-membered rings stabilized by hydrogen bonding.

1,3,4,6-Tetraketones typically undergo keto-enol tautomerism forming bis-enols stabilized by intramolecular hydrogen bonding in two six-membered rings. However, 1,3,4,6-tetraketones derived from the terpene ketone camphor and norcamphor exist as isomers with two distinguishable modes of intramolecular hydrogen bonding, namely, the formation of six- or seven-membered rings. The structural requirements for this so far unknown behavior were investigated in detail by synthesis and comparison of structural analogues. Both isomers of such 1,3,4,6-tetraketones were fully characterized in solution and in the solid state. Intriguingly, they slowly interconvert in solution by means of tautomerism-rotation cascades, as was corroborated by DFT calculations. The influence of temperature and complexation with the transition metals Pd, Rh, and Ir on the interconversion process was investigated.

Temperature-controlled bidirectional enantioselectivity in a dynamic catalyst for asymmetric hydrogenation.

Asymmetric catalysis using enantiomerically pure catalysts is one of the most widely used methods for the preparation of enantiomerically pure compounds. The separate synthesis of both enantiomerically pure compounds requires tedious and time-consuming preparation of both enantiomerically pure catalysts or chiral separation of the racemic products. Here, we report a stereochemically flexible diastereomeric rhodium(I) catalyst for asymmetric hydrogenations of prochiral (Z)-α-acetamidocinnamates and α-substituted acrylates, which changes its enantioselectivity depending on the temperature to produce each enantiomerically pure compound in high yield with constant high enantioselectivity over time. The same axially chiral rhodium(I) catalyst produces (R)-phenylalanine derivatives in enantiomeric ratios of up to 87:13 (R/S) at low temperature and up to 3:97 (R/S) of the corresponding S enantiomers after re-equilibration of the same catalyst at elevated temperature.

Skeleton decoration of NHCs by amino groups and its sequential booster effect on the palladium-catalyzed Buchwald-Hartwig amination.

A challenging synthetic modification of PEPPSI-type palladium pre-catalysts consisting of a stepwise incorporation of one and two amino groups onto the NHC skeleton was seen to exert a sequential enhancement of the electronic donor properties. This appears to be positively correlated with the catalytic performances of the corresponding complexes in the Buchwald-Hartwig amination. This is illustrated, for example, by the quantitative amination of 4-chloroanisole by morpholine within 2 h at 25 °C with a 2 mol% catalyst/substrate ratio or by a significant reduction of catalytic loading (down to 0.005 mol%) for the coupling of aryl chlorides with anilines (max TON: 19,600).