科研成果

2018
Wang S, Rodríguez-Escrich C, Fan X, Pericàs MA. A site isolation-enabled organocatalytic approach to enantiopure γ-amino alcohol drugs. TetrahedronTetrahedron. 2018;74:3943-3946.Abstract
Solid support-enabled site isolation has previously allowed to use paraldehyde as an acetaldehyde surrogate in aldol reactions. However, only electron-poor aldehydes were tolerated by the system. Herein, we show that the temporary conversion of benzaldehyde into η6-benzaldehyde Cr(CO)3 circumvents this limitation. Asymmetric synthesis of (R)-Phenoperidine, as well as formal syntheses of (R)-Fluoxetine and (R)-Atomoxetine, illustrate the benefits of this strategy.
Li M, Berritt S, Wang C, Yang X, Liu Y, Sha S-C, Wang B, Wang R, Gao X, Li Z, et al. Sulfenate anions as organocatalysts for benzylic chloromethyl coupling polymerization via C=C bond formation. Nature CommunicationsNature Communications. 2018;9:1754.Abstract
Organocatalytic polymerization reactions have a number of advantages over their metal-catalyzed counterparts, including environmental friendliness, ease of catalyst synthesis and storage, and alternative reaction pathways. Here we introduce an organocatalytic polymerization method called benzylic chloromethyl-coupling polymerization (BCCP). BCCP is catalyzed by organocatalysts not previously employed in polymerization processes (sulfenate anions), which are generated from bench-stable sulfoxide precatalysts. The sulfenate anion promotes an umpolung polycondensation via step-growth propagation cycles involving sulfoxide intermediates. BCCP represents an example of an organocatalyst that links monomers by C=C double bond formation and offers transition metal-free access to a wide variety of polymers that cannot be synthesized by traditional precursor routes.
Wang R, Ma M, Gong X, Panetti GB, Fan* X, Walsh PJ *. Visible-Light-Mediated Umpolung Reactivity of Imines: Ketimine Reductions with Cy2NMe and Water. Organic LettersOrganic Letters. 2018;20:2433-2436.
Liu L, Liu Y, Zhang G, Ge Y, Fan X, Lin F, Wang J, Zheng H, Xie X, Zeng X, et al. Genetically Encoded Chemical Decaging in Living Bacteria. Biochemistry. 2018;57:446-450.
2017
Fan X, Walsh PJ. Chelation-Controlled Additions to Chiral α- and β-Silyloxy, α-Halo, and β-Vinyl Carbonyl Compounds. Accounts of Chemical ResearchAccounts of Chemical Research. 2017;50:2389-2400.
Liu Y, Li Z, Xie Y, He P, Qiao J, Fan X, Du Y. Efficient One-Pot Synthesis of 2,4-Disubstituted Thiazoles and Dimeric Thiazoles Directly from Acyl Chlorides and β-Azido Disulfides. SynthesisSynthesis. 2017;49:4876-4886.
Fan X, Li J, Chen PR. Bioorthogonal chemistry in living animals. National Science ReviewNational Science Review. 2017;4:300-302.
2016
Zhang G, Li J, Xie R, Fan X, Liu Y, Zheng S, Ge Y, Chen PR. Bioorthogonal Chemical Activation of Kinases in Living Systems. ACS Central ScienceACS Central Science. 2016;2:325-331.
Ge Y, Fan X, Chen PR. A genetically encoded multifunctional unnatural amino acid for versatile protein manipulations in living cells. Chemical ScienceChemical Science. 2016;7:7055-7060.Abstract
The genetic code expansion strategy allowed incorporation of unnatural amino acids (UAAs) bearing diverse functional groups into proteins, providing a powerful toolkit for protein manipulation in living cells. We report a multifunctional UAA, Nε-p-azidobenzyloxycarbonyl lysine (PABK), that possesses a panel of unique properties capable of fulfilling various protein manipulation purposes. In addition to being used as a bioorthogonal ligation handle, an infrared probe and a photo-affinity reagent, PABK was shown to be chemically decaged by trans-cyclooctenols via a strain-promoted 1,3-dipolar cycloaddition, which provides a new bioorthogonal cleavage strategy for intracellular protein activation. The biocompatibility and efficiency of this method were demonstrated by decaging of a PABK-caged firefly luciferase under living conditions. We further extended this method to chemically rescue a bacterial toxin OspF inside mammalian host cells.
Fan X, Ge Y, Lin F, Yang Y, Zhang G, Ngai WSC, Lin Z, Zheng S, Wang J, Zhao J, et al. Optimized Tetrazine Derivatives for Rapid Bioorthogonal Decaging in Living Cells. Angewandte Chemie International EditionAngewandte Chemie International Edition. 2016;55:14046-14050.
2014
Robinson JR, Fan XY, Yadav J, Carroll PJ, Wooten AJ, Pericas MA, Schelter EJ, Walsh PJ. Air- and Water-Tolerant Rare Earth Guanidinium BINOLate Complexes as Practical Precatalysts in Multifunctional Asymmetric Catalysis. Journal of the American Chemical SocietyJournal of the American Chemical SocietyJournal of the American Chemical Society. 2014;136:8034-8041.Abstract
Shibasaki's REMB catalysts (REMB; RE = Sc, Y, La-Lu; M = Li, Na, K; B = 1,1'-bi-2-naphtholate; RE/M/B = 1/3/3) are among the most enantioselective asymmetric catalysts across a broad range of mechanistically diverse reactions. However, their widespread use has been hampered by the challenges associated with their synthesis and manipulation. We report here the self-assembly of novel hydrogen-bonded rare earth metal BINOLate complexes that serve as bench-stable precatalysts for Shibasaki's REMB catalysts. Incorporation of hydrogen-bonded guanidinium cations in the secondary coordination sphere leads to unique properties, most notably, improved stability toward moisture in solution and in the solid state. We have exploited these properties to develop straightforward, high-yielding, and scalable open-air syntheses that provide rapid access to crystalline, nonhygroscopic complexes from inexpensive hydrated RE starting materials. These compounds can be used as precatalysts for Shibasaki's REMB frameworks, where we have demonstrated that our system performs with comparable or improved levels of stereoselectivity in several mechanistically diverse reactions including Michael additions, aza-Michael additions, and direct Aldol reactions.
Yadav J, Stanton GR, Fan XY, Robinson JR, Schelter EJ, Walsh PJ, Pericas MA. Asymmetric Allylation of Ketones and Subsequent Tandem Reactions Catalyzed by a Novel Polymer-Supported Titanium-BINOLate Complex. Chemistry-a European JournalChemistry-a European Journal. 2014;20:7122-7127.Abstract
By using a novel, simple, and convenient synthetic route, enantiopure 6-ethynyl-BINOL (BINOL=1,1-binaphthol) was synthesized and anchored to an azidomethylpolystyrene resin through a copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction. The polystyrene (PS)-supported BINOL ligand was converted into its diisopropoxytitanium derivative in situ and used as a heterogeneous catalyst in the asymmetric allylation of ketones. The catalyst showed good activity and excellent enantioselectivity, typically matching the results obtained in the corresponding homogeneous reaction. The allylation reaction mixture could be submitted to epoxidation by simple treatment with tert-butyl hydroperoxide (TBHP), and the tandem asymmetric allylation epoxidation process led to a highly enantioenriched epoxy alcohol with two adjacent quaternary centers as a single diastereomer. A tandem asymmetric allylation/Pauson-Khand reaction was also performed, involving simple treatment of the allylation reaction mixture with Co2(CO)8/N-methyl morpholine N-oxide. This cascade process resulted in the formation of two diastereomeric tricyclic enones in high yields and enantioselectivities.
Robinson JR, Yadav J, Fan XY, Stanton GR, Schelter EJ, Pericas MA, Walsh PJ. Non-Covalent Immobilization of Rare Earth Heterobimetallic Frameworks and their Reactivity in an Asymmetric Michael Addition. Advanced Synthesis & CatalysisAdvanced Synthesis & Catalysis. 2014;356:1243-1254.Abstract
Heterobimetallic Lewis acid catalysts are broadly useful and methods to recycle them have immediate applications. However, their immobilization through covalent binding can be challenging. Non-covalent immobilization of supported asymmetric catalysts is attractive due to ease of preparation and potential for reversible binding. We report a novel non-covalent binding strategy for Shibasaki's REMB framework {RE=rare earth metal; M=Li, Na, K; B=BINOL; RE:M:B=1:3:3, [M-3(sol)(n)][(BINOLate)(3)RE]} and explore the reactivity of the supported catalyst.
Fan X, Rodríguez-Escrich C, Wang S, Sayalero S, Pericàs MA. Highly Enantioselective Cross-Aldol Reactions of Acetaldehyde Mediated by a Dual Catalytic System Operating under Site Isolation. Chemistry – A European Journal. 2014;20:13089-13093.Abstract
Abstract Polystyrene-supported (PS) diarylprolinol catalysts 1?a (Ar=phenyl) and 1?b (Ar=3,5-bis(trifluoromethyl)phenyl) have been developed. Operating under site-isolation conditions, PS-1?a/1?b worked compatibly with PS-bound sulfonic acid catalyst 2 to promote deoligomerization of paraldehyde and subsequent cross-aldol reactions of the resulting acetaldehyde in one pot, affording aldol products in high yields with excellent enantioselectivities. The effect of water on the performance of the catalytic system has been studied and its optimal amount (0.5?equiv) has been determined. The dual catalytic system (1/2) allows repeated recycling and reuse (10 cycles). The potential of this methodology is demonstrated by a two-step synthesis of a phenoperidine analogue (68?% overall yield; 98?%?ee) and by the preparation of highly enantioenriched 1,3-diols 4 and 3-methylamino-1-arylpropanols 5, key intermediates in the synthesis of a variety of druglike structures.
2013
Fan XY, Rodriguez-Escrich C, Sayalero S, Pericas MA. Paraldehyde as an Acetaldehyde Precursor in Asymmetric Michael Reactions Promoted by Site-Isolated Incompatible Catalysts. Chemistry-a European JournalChemistry-a European Journal. 2013;19:10814-10817.
Du Z-X, Zhang L-Y, Fan X-Y, Wu F-C, Da C-S. Highly enantioselective biomimetic intramolecular dehydration: kinetic resolution of β-hydroxy ketones catalyzed by β-turn tetrapeptides. Tetrahedron LettersTetrahedron Letters. 2013;54:2828-2832.Abstract
Racemic β-hydroxy ketones were kinetically resoluted into the enantiopure isomers and (E)-α,β-unsaturated ketones using catalytic asymmetric intramolecular dehydration for the first time. Synthetic tetrapeptides were used to imitate fatty acid dehydratases to efficiently discriminate racemic β-hydroxy ketones, enantioselectively catalyze the intramolecular dehydration, and result in highly enantioenriched β-hydroxy and (E)-α,β-unsaturated ketones in the environmentally benign process. Mechanistically, the high discrimination of the racemic substrates and successive enantioselective dehydration are highly dependent on the cooperative catalysis of the NH2 and COOH groups of the peptide.
2012
Fan XY, Sayalero S, Pericas MA. Asymmetric alpha-Amination of Aldehydes Catalyzed by PS-Diphenylprolinol Silyl Ethers: Remediation of Catalyst Deactivation for Continuous Flow Operation. Advanced Synthesis & CatalysisAdvanced Synthesis & Catalysis. 2012;354:2971-2976.Abstract
Polystyrene (PS)-supported diphenylprolinol silyl ethers have been developed as highly active catalysts for the enantioselective a-amination of aldehydes. Understanding the mechanism of catalyst deactivation has led to the development of reaction conditions notably extending catalyst life in repeated recycling (10 cycles; accumulated TON of 480) and has allowed the implementation of a continuous flow alpha-amination process (6 min residence time, 8 h operation).
Fan XY, Alza E, Pericas MA. A highly active organocatalyst for the asymmetric alpha-aminoxylation of aldehydes and alpha-hydroxylation of ketones. RSC AdvancesRSC Advances. 2012;2:6164-6166.Abstract
Enantiopure trans-3-trifluoromethylsulfonylamino-4-silyloxypyrrolidines efficiently catalyse the asymmetric alpha-aminoxylation of aldehydes. At 1% catalyst loading (solvent-free conditions) or at 2% catalyst loading (acetonitrile solution) aldehydes are completely converted in short reaction times leading to alpha-aminoxylation products with very high (96-99%) enantioselectivity.
2011
Martin-Rapun R, Fan XY, Sayalero S, Bahramnejad M, Cuevas F, Pericas MA. Highly Active Organocatalysts for Asymmetric anti-Mannich Reactions. Chemistry-a European JournalChemistry-a European Journal. 2011;17:8780-8783.
2010
Liu Y, Da CS, Yu SL, Yin XG, Wang LR, Fan XY, Li WP, Wang R. Catalytic Highly Enantioselective Alkylation of Aldehydes with Deactivated Grignard Reagents and Synthesis of Bioactive Intermediate Secondary Arylpropanols. Journal of Organic ChemistryJournal of Organic ChemistryJournal of Organic Chemistry. 2010;75:6869-6878.Abstract
Because of the high reactivity of Grignard reagents a direct highly enantioselective Grignard reaction with aldehydes has lately been disclosed In this report. Grignard leagents were: introduced with bis[2-(N,N'-dimethylamino)ethyl) ether (BDMAEF) to effectively deactivate then reactivity thus a highly enantioselective alkylation of aldehydes with Grignard reagents resulted from catalysis by (S)-BINOL-Ti(O'Pt)(2). It is thought that BDMAEE chelates the in situ generated salts MgBt(2) from Schlenk equilibrium of RMgBr and Mg(O'Pt)Br from transmetalation of RMgBt with Ti(O'Pt). The Mg salt can actively promote the undesired background reaction to give the racemate I he chelation definitely inhibits the catalytic activity of the Mg salts suppresses the unwanted background reaction, and enables the highly enantioselective addition catalyzed by (S)-BINOL-Ti(O'Pt)(2) Consequently, the Mg salt byproducts were not removed. less Ti(O'Pt)(4) than RMgBr was used. and extremely low temperature was avoided in this catalytic asymmetric reaction in comparison with the research disclosed before Various alkyl Grignard leagents were investigated in the asymmetric addition and 'BuMgBr resulted in the highest enantioselectivity. >99% Furthermore important intermediate secondary arylpropanols for chiral drug synthesis were effectively synthesized with high enantioselectivity, up to 97%, in one step

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