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Breaking Symmetry: Engineering Single-Chain Dimeric Streptavidin as Host for Artificial Metalloenzymes

The biotin-streptavidin technology has been extensively exploited to engineer artificial metalloenzymes (ArMs) that catalyze a dozen different reactions. Despite its versatility, the homotetrameric nature of streptavidin (Sav) and the noncooperative binding of biotinylated cofactors impose two limitations on the genetic optimization of ArMs: (i) point mutations are reflected in all four subunits of Sav, and (ii) the noncooperative binding of biotinylated cofactors to Sav may lead to an erosion in the catalytic performance, depending on the cofactor:biotin-binding site ratio. To address these challenges, we report on our efforts to engineer a (monovalent) single-chain dimeric streptavidin (scdSav) as scaffold for Sav-based ArMs. The versatility of scdSav as host protein is highlighted for the asymmetric transfer hydrogenation of prochiral imines using [Cp*Ir(biot-p-L)Cl] as cofactor. By capitalizing on a more precise genetic fine-tuning of the biotin-binding vestibule, unrivaled levels of activity and selectivity were achieved for the reduction of challenging prochiral imines. Comparison of the saturation kinetic data and X-ray structures of [Cp*Ir(biot-p-L)Cl]¡¤scdSav with a structurally related [Cp*Ir(biot-p-L)Cl]¡¤monovalent scdSav highlights the advantages of the presence of a single biotinylated cofactor precisely localized within the biotin-binding vestibule of the monovalent scdSav. The practicality of scdSav-based ArMs was illustrated for the reduction of the salsolidine precursor (500 mM) to afford (R)-salsolidine in 90% ee and >17 ?000 TONs. Monovalent scdSav thus provides a versatile scaffold to evolve more efficient ArMs for in vivo catalysis and large-scale applications.

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SOLIFENACIN COMPOSITIONS

Compositions and/or formulations comprising solifenacin or a salt thereof and processes for preparing the same. Certain compositions and formulations contain a stable amorphous form of solifenacin succinate.

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The role of the aromatic ligand in the asymmetric transfer hydrogenation of the CN bond on Noyori’s chiral Ru catalysts

Only four types of dimeric precursors [RuCl2(eta6-arene)]2 for the synthesis of Noyori’s half sandwich diamine catalysts [RuCl(TsDPEN)(eta6-arene)] are commercially available, yet so far no study has tried to systematically evaluate how these systems perform during the asymmetric transfer hydrogenation of various 3,4-dihydroisoquinolines (i.e., the typical substrates for Noyori asymmetric transfer hydrogenation benchmarking). Experiments combined with molecular modeling allowed us to assess their properties and formulate a hypothesis clarifying the difference in enantioselectivity of these systems.

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Development of an R-selective amine oxidase with broad substrate specificity and high enantioselectivity

Amine oxidases are useful bio-catalysts for the synthesis of enantiomerically pure 1, 2 and 3 chiral amines. Enzymes in this class (e.g., MAO-N from Aspergillus niger) reported previously have been shown to be highly S selective. Herein we report the development of an enantiocomplementary R-selective amine oxidase based on 6-hydroxy-D-nicotine oxidase (6-HDNO) with broadened substrate scope and high enantioselectivity. The engineered 6-HDNO enzyme has been applied to the preparative deracemisation of a range of racemic amines to yield S-configured products, for example, (S)-nicotine, in high ee. Nicotine rush: An R-selective amine oxidase based on 6-hydroxy-D-nicotine oxidase (6-HDNO) with broadened substrate scope and high enantioselectivity has been developed. The engineered 6-HDNO enzyme is applied to the preparative deracemization of a range of racemic amines to yield S-configured products, for example, (S)-nicotine, in high ee.

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ALKYLATION OF THE ISOQUINOLINE SKELETON IN THE 1-POSITION: LITHIATED 2-PIVALOYL- AND 2-BIS(DIMETHYLAMINO)-PHOSPHINOYL-1,2,3,4-TETRAHYDROISOQUINOLINES

Nucleophilic reactivity in the 1-position of 1,2,3,4-tetrahydroisoquinoline is generated by lithiation of the N-pivaloyl- (16a) and N-phosphinoyl-derivatives (17a).The organolithium compounds (16b, 17b) thus obtained are highly nucleophilic and can be alkylated even with poor alkylating reagents such as secondary halides, neopentyl bromide and cyclopentanone.Hydrolysis of the phosphorylamide products with hydrochloric acid leads to 1-substituted tetrahydroisoquinolines in excellent yields (Table 2).

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Catalytic kinetic resolution of cyclic secondary amines

The catalytic resolution of racemic cyclic amines has been achieved by an enantioselective amidation reaction featuring an achiral N-heterocyclic carbene catalyst and a new chiral hydroxamic acid cocatalyst working in concert. The reactions proceed at room temperature, do not generate nonvolatile byproducts, and provide enantioenriched amines by aqueous extraction.

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Reactions of 1,2,3,4-Tetrahydroisoquinoline Derivatives with Sulfur

1,2,3,4-Tetrahydroisoquinolines react with sulfur in pyridine to give two different types of products, depending on the structure of the starting compounds. 1-Substituted derivatives 1 undergo partial dehydrogenation with formation of the corresponding 3,4-dihydroisoquinolines 3. 1,2,3,4-Tetrahydroisoquinolines 5 bearing no substituent in 1-position yield the 3,4-dihydro-1(2H)isoquinolinethiones 6, comprising a new and simple synthesis of compounds 6.

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Iron-Catalyzed Anti-Markovnikov Hydroamination and Hydroamidation of Allylic Alcohols

Hydroamination allows for the direct access to synthetically important amines. Controlling the selectivity of the reaction with efficient, widely applicable, and economic catalysts remains challenging, however. This paper reports an iron-catalyzed formal anti-Markovnikov hydroamination and hydroamidation of allylic alcohols, which yields gamma-amino and gamma-amido alcohols, respectively. Homoallylic alcohol is also feasible. The catalytic system, consisting of a pincer Fe-PNP complex (1-4 mol %), a weak base, and a nonpolar solvent, features exclusive anti-Markovnikov selectivity, broad substrate scope (>70 examples), and good functional group tolerance. The reaction could be performed at gram scale and applied to the synthesis of drug molecules and heterocyclic compounds. When chiral substrates are used, the stereochemistry and enantiomeric excess are retained. Further application of the chemistry is seen in the functionalization of amino acids, natural products, and existing drugs. Mechanistic studies suggest that the reaction proceeds via two cooperating catalytic cycles, with the iron complex catalyzing a dehydrogenation/hydrogenation process while the amine substrate acts as an organocatalyst for the Michael addition step.

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Tetrahydroisoquinoline – Wikipedia,
1,2,3,4-Tetrahydroisoquinoline | C9H11N – PubChem

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A highly efficient synthesis of 1-methyl-, 1-benzyl-, and 1-phenyl-1,2,3,4-tetrahydroisoquinolines by a modified pummerer reaction

(¡À)-1-Methyl- (13b), (¡À)-1-benzyl- (13c), and (¡À)-1-phenyl- (13d)-1,2,3,4-tetrahydroisoquinolines, which are supposed to participate in the pathogenesis of Parkinson’s disease, were prepared by using a modified Pummerer reaction as a key step in excellent overall yields from the commercially available ketones (4b-c).

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Experimental and Theoretical Observations on the Intramolecular Nucleophilic Addition of alpha-Amino Carbanions to Arynes: Synthesis of 1-Aryl-1,2,3,4-tetrahydroisoquinolines

1-Aryl-1,2,3,4-tetrahydroisoquinolines (THIQ) are key intermediates and products in the pharmaceutical industry. A new method involving intramolecular nucleophilic addition of alpha-amino carbanions to in-situ-generated arynes in N-Boc-protected (Boc = tert-butoxycarbonyl) amine substrates is presented for the synthesis of these compounds. Surprisingly, a similar reaction in Lewis-acid-complexed tertiary amines failed. These results have been analysed using quantum chemical calculations on the intermediates involved in the reactions.

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