Metal Stereogenicity in Asymmetric Transition Metal Catalysis.

Chiral transition metal catalysts represent a powerful and economic tool for implementing stereocenters in organic synthesis, with the metal center providing a strong chemical activation upon its interaction with substrates or reagents, while the overall chirality of the metal complex achieves the desired stereoselectivity. Often, the overall chiral topology of the metal complex implements a stereogenic metal center, which is then involved in the origin of the asymmetric induction. This review provides a comprehensive survey of reported chiral transition metal catalysts in which the metal formally constitutes a stereocenter. A stereogenic metal center goes along with an overall chiral topology of the metal complex, regardless of whether the ligands are chiral or achiral. Implications for the catalyst design and mechanism of asymmetric induction are discussed for half-sandwich, tetracoordinated, pentacoordinated, and hexacoordinated chiral transition metal complexes containing a stereogenic metal center. The review distinguishes between chiral metal catalysts originating from the coordination to chiral ligands and those which are solely composed of optically inactive ligands (achiral or rapidly interconverting enantiomers) prior to complexation (dubbed "chiral-at-metal" catalysts).

Asymmetric photoredox transition-metal catalysis activated by visible light.

Asymmetric catalysis is seen as one of the most economical strategies to satisfy the growing demand for enantiomerically pure small molecules in the fine chemical and pharmaceutical industries. And visible light has been recognized as an environmentally friendly and sustainable form of energy for triggering chemical transformations and catalytic chemical processes. For these reasons, visible-light-driven catalytic asymmetric chemistry is a subject of enormous current interest. Photoredox catalysis provides the opportunity to generate highly reactive radical ion intermediates with often unusual or unconventional reactivities under surprisingly mild reaction conditions. In such systems, photoactivated sensitizers initiate a single electron transfer from (or to) a closed-shell organic molecule to produce radical cations or radical anions whose reactivities are then exploited for interesting or unusual chemical transformations. However, the high reactivity of photoexcited substrates, intermediate radical ions or radicals, and the low activation barriers for follow-up reactions provide significant hurdles for the development of efficient catalytic photochemical processes that work under stereochemical control and provide chiral molecules in an asymmetric fashion. Here we report a highly efficient asymmetric catalyst that uses visible light for the necessary molecular activation, thereby combining asymmetric catalysis and photocatalysis. We show that a chiral iridium complex can serve as a sensitizer for photoredox catalysis and at the same time provide very effective asymmetric induction for the enantioselective alkylation of 2-acyl imidazoles. This new asymmetric photoredox catalyst, in which the metal centre simultaneously serves as the exclusive source of chirality, the catalytically active Lewis acid centre, and the photoredox centre, offers new opportunities for the 'green' synthesis of non-racemic chiral molecules.

Asymmetric Photocatalysis by Intramolecular Hydrogen-Atom Transfer in Photoexcited Catalyst-Substrate Complex.

3-(2-Formylphenyl)-1-pyrazol-1-yl-propenones undergo an asymmetric photorearrangement to benzo[d]cyclopropa[b]pyranones with up to >99 % ee, which is catalyzed by a bis-cyclometalated rhodium catalyst in the presence of visible light. Mechanistic experiments and DFT calculations support a mechanism in which a photoexcited catalyst/substrate complex triggers an intramolecular hydrogen-atom transfer followed by a highly stereocontrolled hetero-Diels-Alder reaction. In this reaction scheme, the rhodium catalyst fulfills multiple functions by 1) enabling visible-light π→π* excitation of the catalyst-bound enone substrate, 2) facilitating the hydrogen-atom transfer, and 3) providing the asymmetric induction for the hetero-Diels-Alder reaction.

Steering Asymmetric Lewis Acid Catalysis Exclusively with Octahedral Metal-Centered Chirality.

Catalysts for asymmetric synthesis must be chiral. Metal-based asymmetric catalysts are typically constructed by assembling chiral ligands around a central metal. In this Account, a new class of effective chiral Lewis acid catalysts is introduced in which the octahedral metal center constitutes the exclusive source of chirality. Specifically, the here discussed class of catalysts are composed of configurationally stable, chiral-at-metal Λ-configured (left-handed propeller) or Δ-configured (right-handed propeller) iridium(III) or rhodium(III) complexes containing two bidentate cyclometalating 5-tert-butyl-2-phenylbenzoxazole (dubbed IrO and RhO) or 5-tert-butyl-2-phenylbenzothiazole (dubbed IrS and RhS) ligands in addition to two exchange-labile acetonitriles. They are synthetically accessible in an enantiomerically pure fashion through a convenient auxiliary-mediated synthesis. Such catalysts are of interest due to their intrinsic structural simplicity (only achiral ligands) and the prospect of an especially effective asymmetric induction due to the intimate contact between the chiral metal center and the metal-coordinated substrates or reagents. With respect to chiral Lewis acid catalysis, the bis-cyclometalated iridium and rhodium complexes provide excellent catalytic activities and asymmetric inductions for a variety of reactions including Michael additions, Friedel-Crafts reactions, cycloadditions, α-aminations, α-fluorinations, Mannich reactions, and a cross-dehydrogenative coupling. Mechanistically, substrates such as 2-acyl imidazoles are usually activated by two-point binding. Exceptions exist as for example for an efficient iridium-catalyzed enantioselective transfer hydrogenation of arylketones with ammonium formate, which putatively proceeds through an iridium-hydride intermediate. The bis-cyclometalated iridium complexes catalyze visible-light-induced asymmetric reactions by intertwining asymmetric catalysis and photoredox catalysis in a unique fashion. This has been applied to the visible-light-induced α-alkylation of 2-acyl imidazoles (and in some instances 2-acylpyridines) with acceptor-substituted benzyl, phenacyl, trifluoromethyl, perfluoroalkyl, and trichloromethyl groups, in addition to photoinduced oxidative α-aminoalkylations and a photoinduced stereocontrolled radical-radical coupling, each employing a single iridium complex. In all photoinduced reaction schemes, the iridium complex serves as a chiral Lewis acid catalyst and at the same time as precursor of in situ assembled photoactive species. The nature of these photoactive intermediates then determines their photochemical properties and thereby the course of the asymmetric photoredox reactions. The bis-cyclometalated rhodium complexes are also very useful for asymmetric photoredox catalysis. Less efficient photochemical properties are compensated with a more rapid ligand exchange kinetics, which permits higher turnover frequencies of the catalytic cycle. This has been applied to a visible-light-induced enantioselective radical α-amination of 2-acyl imidazoles. In this reaction, an intermediate rhodium enolate is supposed to function as a photoactivatable smart initiator to initiate and reinitiate an efficient radical chain process. If a more efficient photoactivation is required, a rhodium-based Lewis acid can be complemented with a photoredox cocatalyst, and this has been applied to efficient catalytic asymmetric alkyl radical additions to acceptor-substituted alkenes. We believe that this class of chiral-only-at-metal Lewis acid catalysts will be of significant value in the field of asymmetric synthesis, in particular in combination with visible-light-induced redox chemistry, which has already resulted in novel strategies for asymmetric synthesis of chiral molecules. Hopefully, this work will also pave the way for the development of other asymmetric catalysts featuring exclusively octahedral centrochirality.

Catalytic Asymmetric Dearomatization by Visible-Light-Activated [2+2] Photocycloaddition.

A novel method for the catalytic asymmetric dearomatization by visible-light-activated [2+2] photocycloaddition with benzofurans and one example of a benzothiophene is reported, thereby providing chiral tricyclic structures with up to four stereocenters including quaternary stereocenters. The benzofurans and the benzothiophene are functionalized at the 2-position with a chelating N-acylpyrazole moiety which permits the coordination of a visible-light-activatable chiral-at-rhodium Lewis acid catalyst. Computational molecular modeling revealed the origin of the unusual regioselectivity and identified the heteroatom in the heterocycle to be key for the regiocontrol.

Octahedral Ruthenium Complex with Exclusive Metal-Centered Chirality for Highly Effective Asymmetric Catalysis.

A novel ruthenium catalyst is introduced which contains solely achiral ligands and acquires its chirality entirely from octahedral centrochirality. The configurationally stable catalyst is demonstrated to catalyze the alkynylation of trifluoromethyl ketones with very high enantioselectivity (up to >99% ee) at low catalyst loadings (down to 0.2 mol%).

Direct Visible-Light-Excited Asymmetric Lewis Acid Catalysis of Intermolecular [2+2] Photocycloadditions.

A reaction design is reported in which a substrate-bound chiral Lewis acid complex absorbs visible light and generates an excited state that directly reacts with a cosubstrate in a highly stereocontrolled fashion. Specifically, a chiral rhodium complex catalyzes visible-light-activated intermolecular [2+2] cycloadditions, providing a wide range of cyclobutanes with up to >99% ee and up to >20:1 d.r. Noteworthy is the ability to create vicinal all-carbon-quaternary stereocenters including spiro centers in an intermolecular fashion.

Enantioselective Alkynylation of Aromatic Aldehydes Catalyzed by a Sterically Highly Demanding Chiral-at-Rhodium Lewis Acid.

The enantioselective catalytic alkynylation of aromatic aldehydes is reported using a sterically highly hindered bis-cyclometalated rhodium-based Lewis acid catalyst featuring the octahedral metal as the only stereogenic center. Yields of 58-98% with 79-98% enantiomeric excess were achieved using 1-2 mol % of catalyst. This work complements previous work from our laboratory on the enantioselective alkynylation of 2-trifluoroacetyl imidazoles (Chem. - Eur. J. 2016, 22, 11977-11981) and trifluoromethyl ketones (J. Am. Chem. Soc. 2017, 139, 4322-4325) using catalysts with octahedral metal-centered chirality.

Enantioselective Alkynylation of 2-Trifluoroacetyl Imidazoles Catalyzed by Bis-Cyclometalated Rhodium(III) Complexes Containing Pinene-Derived Ligands.

Chiral rhodium(III) complexes containing two cyclometalating 2-phenyl-5,6-(S,S)-pinenopyridine ligands and two additional acetonitriles are introduced as excellent catalysts for the highly enantioselective alkynylation of 2-trifluoroacetyl imidazoles. Whereas the ligand-based chirality permits the straightforward synthesis of the complexes in a diastereomerically and enantiomerically pure fashion, the metal-centered chirality is responsible for the asymmetric induction over the course of the catalysis. For comparison, the analogous iridium congeners provide only low enantioselectivity, and previously reported benzoxazole- and benzothiazole-based catalysts do not show any catalytic activity for this reaction under standard reaction conditions.

Merger of visible light induced oxidation and enantioselective alkylation with a chiral iridium catalyst.

A single chiral octahedral iridium(III) complex is used for visible light activated asymmetric photoredox catalysis. In the presence of a conventional household lamp and under an atmosphere of air, the oxidative coupling of 2-acyl-1-phenylimidazoles with N,N-diaryl-N-(trimethylsilyl)methylamines provides aminoalkylated products in 61-93 % yields with high enantiomeric excess (90-98 % ee). Notably, the iridium center simultaneously serves three distinct functions: as the exclusive source of chirality, as the catalytically active Lewis acid, and as a central part of the photoredox sensitizer. This conceptionally simple reaction Scheme may provide new avenues for the green synthesis of non-racemic chiral molecules.

Cloning of two 5-aminolevulinic acid synthase isozymes HemA and HemO from Rhodopseudomonas palustris with favorable characteristics for 5-aminolevulinic acid production.

5-Aminolevulinic acid (ALA) synthase (ALAS) HemA from non-sulfur photosynthetic bacteria has been used for the ALA bioproduction, whereas the isoenzyme HemT/HemO is less studied and not used for ALA production. Two ALAS-encoding genes, hemA and hemO from Rhodopseudomonas palustris were cloned, purified and characterized. The ALASs had very high specific activity, 3.6 and 2.7 U/mg, respectively, and strong affinity for one of its substrates, succinyl-CoA, K m with values of 11 and 4.4 µM, respectively. HemO retained up to 60 % maximum activity within a broad range of concentrations of hemin, while HemA kept only 20 % at 10 µM hemin. Escherichia coli overexpressing HemA or HemO produced 5.7 and 6.3 g ALA/l, respectively, in a 5 l bioreactor.

Synthesis and properties of the simplified nucleic acid glycol nucleic acid.

The nucleosides of glycol nucleic acid (GNA), with the backbone comprising just the three carbons and one stereocenter of propylene glycol (1,2-propanediol), probably constitute the simplest possible building blocks for a chemically stable nucleic acid that contains phosphodiester bonds. However, it was not until 2005 that the astonishing duplex formation properties of GNA homoduplexes were discovered in our laboratory. The R- and S-enantiomers of GNA, (R)-GNA and (S)-GNA, pair in like-symmetric combinations to form highly stable antiparallel duplexes in a Watson-Crick fashion, with thermal and thermodynamic stabilities exceeding those of analogous duplexes of DNA and RNA. Interestingly, (R)-GNA and (S)-GNA do not significantly cross-pair with each other, either in a parallel or antiparallel fashion. GNA discriminates strongly in favor of the Watson-Crick base-pairing scheme, with only slightly lower fidelity than DNA. Two (S)-GNA homoduplex structures recently determined by X-ray crystallography, one a brominated 6-mer duplex and the other an 8-mer duplex containing two copper(II) ions, reveal that the overall GNA double helix is distinct from canonical A- and B-form nucleic acids. The structure is perhaps best described as a helical ribbon loosely wrapped around the helix axis. Within the backbone, the propylene glycol nucleotides adopt two different conformations, gauche and anti, with respect to the torsional angles between the vicinal C3'-O and C2'-O bonds. A strikingly large backbone-base inclination results in extensive zipper-like interstrand and reduced intrastrand base-base interactions. This strong backbone-base inclination might explain the observation that neither the R- nor S-enantiomer of GNA cross-pairs with DNA, whereas (S)-GNA can interact with RNA strands that are devoid of G:C base pairs. Given the combination of structural simplicity, straightforward synthetic accessibility, and high duplex stability of GNA duplexes, GNA affords a promising nucleic acid scaffold for biotechnology and nanotechnology. Along these lines, we describe the functionalization of GNA duplexes through the incorporation of metal-ion-mediated base pairs. Finally, the properties of GNA discussed here reinforce its candidacy as one of the initial genetic molecules formed during the origins of life on Earth.

Incorporation of porphyrin acetylides into duplexes of the simplified nucleic acid GNA.

A porphyrin-acetylide-modified GNA (glycol nucleic acid) phosphoramidite building block was synthesized in an economical fashion starting from (S)-glycidyl-4,4'- dimethoxytrityl ether in just 4 steps with an overall yield of 48%. The porphyrin acetylide nucleotide was incorporated into GNA duplexes opposite ethylene glycol abasic sites and the duplexes were analyzed by UV-melting, UV-vis, fluorescence spectroscopy, and circular dichroism. The modified GNA duplexes display lower thermal stabilities, however, the stabilities of the duplexes can be modulated by the incorporation of Zn(2+) (further destabilization) or Ni(2+) (stabilization relative to the uncomplexed porphyrin). Uncomplexed as well as Ni(2+)-coordinated porphyrins intercalate into the GNA duplex whereas Zn(2+)-coordinated porphyrins are most likely located outside the base stack. Adjacent porphyrins in opposite strands of GNA duplexes show an electronic interaction with each other which might be exploited in the future for the design of photoelectrical devices.

The release of exosomes in the medial prefrontal cortex and nucleus accumbens brain regions of chronic constriction injury (CCI) model mice could elevate the pain sensation.

BACKGROUND: Brain function relies on the capacity of neurons to locally modulate each other at the level of synapses. Therefore, the exosomal pathway may constitute a well-designed mechanism for local and systemic interneuronal transfer of information within functional brain networks. Exosomes bind to and are endocytosed by neurons of different brain regions to play a definite role. The medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) brain regions are known to involve in pain modulation. Our study observes the roles of exosomal activity in these two dominant regions of the pain-related pathway, and there influence on the analgesic effects in CCI mice. METHODS: We induced pain exosomes in the mPFC and NAc in the mice of chronic constriction injury of the sciatic nerve model to produce neuropathic pain, and assessed changes that might affect analgesic behaviors. These changes were measured through a combination of behavioral, surgical, and other cellular testings. RESULTS: Our study found that pain expression was elevated in mice given exogenous exosomes isolated from CCI mice, especially at the 2 h and 4 h time interval, in mice given exosomes at the mPFC and NAc, respectively. We also found that inhibiting formation of pain exosomes through GW4869 within the mPFC and NAc can elevate the pain threshold. CONCLUSION: Results from our study supported the idea that the release of mPFC and NAc exosomes of CCI model has elevated the pain sensations in the subjected mice. This study will further help in designing new clinical trials, and will revolutionize the drug-induced anesthetic responses.

Pyrene acetylide nucleotides in GNA: probing duplex formation and sensing of copper(II) ions.

The synthesis and evaluation of GNA duplexes containing fluorescent pyrene and pyrene acetylide nucleotides is reported. Interestingly, only the pyrene acetylides, but not the related plain pyrene nucleotides, form strong excimers upon stacking in glycol nucleic acid (GNA) duplexes. The ability of the large pyrene acetylide nucleotide to be accommodated in GNA duplexes opposite an abasic site was investigated by molecular modeling. The interstrand pyrene acetylide excimer formation was used to monitor GNA duplex formation and was applied to the design of a copper(II)-selective "turn-on" fluorescence sensor.

Metal-mediated base pairing within the simplified nucleic acid GNA.

Hydroxypyridone and pyridopurine homo- and hetero-base pairs have been investigated in the context of duplex GNA (glycol nucleic acid). Phosphoramidites for automated GNA solid phase synthesis were synthesized economically in a few steps starting from commercially available enantiopure glycidol. Similar to their behavior in DNA, the hydroxypyridone and pyridopurine homo-base pairs display a metal-dependent base pairing, with the hydroxypyridone base pair exhibiting a preference for copper(II) ions and the pyridopurine a preference for nickel(II) ions. However, these metallo-base pairs show modulated properties in GNA with respect to metal-dependent pairing stabilities and metal selectivities. Most interestingly, the hydroxypyridone homo-base pair and hydroxypyridone-pyridopurine hetero-base pair are particularly well accommodated in the GNA duplex and form copper(II)-dependent base pairs that are more stable compared to a Watson-Crick A:T base pair at the same position by nearly 20 degrees C and 24 degrees C, respectively. The structure of the copper(II)-hydroxypyridone homo-base pair is discussed based on a recent metallo-GNA duplex crystal structure.

Stereogenic-Only-at-Metal Asymmetric Catalysts.

Chirality is an essential feature of asymmetric catalysts. This review summarizes asymmetric catalysts that derive their chirality exclusively from stereogenic metal centers. Reported chiral-at-metal catalysts can be divided into two classes, namely, inert metal complexes, in which the metal fulfills a purely structural role, so catalysis is mediated entirely through the ligand sphere, and reactive metal complexes. The latter are particularly appealing because structural simplicity (only achiral ligands) is combined with the prospect of particularly effective asymmetric induction (direct contact of the substrate with the chiral metal center). Challenges and solutions for the design of such reactive stereogenic-only-at-metal asymmetric catalysts are discussed.

Ruthenium complexes as protein kinase inhibitors.

[reaction: see text] Replacing complex natural products with simple metal complexes could lead to a new class of metallopharmaceuticals in which the metal center plays mainly a structural role. A strategy is introduced for the creation of ruthenium complex-based protein kinase inhibitors 1 (X = CO or CH(2)), morphed out of the class of indolocarbazole inhibitors with the alkaloid staurosporine as its most prominent member.

Synthesis and structure of a novel supramolecular Zn3Co8 assembly containing a linear Zn3 core.

Reaction of Zn(OAc)(2).2H2O (OAc = acetate) with LH2 in THF followed by reaction with Co2(CO)8 yields the novel supramolecular assembly Zn3L2(OAc)2[Co2(CO)6](4).0.5CH2Cl2, which was characterized by X-ray diffraction (LH2 = (CH2)3(N=CH-2-OH-5-C identical to CSiMe3C6H3)2 or N,N'-propylenebis(2-hydroxy-5-trimethylsilylethynl-1-aldimine).