ORCID Profile
0000-0003-1911-0501
Current Organisations
Australian National University
,
University of Melbourne
,
University of Queensland
,
University of California Los Angeles
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Organic Chemical Synthesis | Organic Chemistry | Quantum Chemistry | Catalysis and Mechanisms of Reactions | Theoretical and Computational Chemistry not elsewhere classified | Biomolecular Modelling and Design | Organic Chemical Synthesis | Biologically Active Molecules | Theoretical and Computational Chemistry | Physical Chemistry (Incl. Structural) | Mechanisms Of Reactions | Quantum Chemistry | Physical Organic Chemistry |
ANZSRC Socio-Economic Objective (SEO)
Expanding Knowledge in the Chemical Sciences | Human Pharmaceutical Treatments (e.g. Antibiotics) | Industrial Chemicals and Related Products not elsewhere classified | Cancer and Related Disorders | Expanding Knowledge in the Biological Sciences | Environmentally Sustainable Manufacturing not elsewhere classified | Higher education | Chemical sciences
Related Links
Publications
Phospha-Münchnones: Electronic structures and 1,3-dipolar cycloadditions
Publisher: American Chemical Society (ACS)
Date: 18-05-2010
DOI: 10.1021/JO1008383
Abstract: The reaction of imines, acid chlorides, PR(3), and base generates a new class of 1,3-dipoles: phospha-Munchnones. These 1,3-dipoles can undergo cycloadditions with alkynes followed by loss of phosphine oxides to form pyrroles. Cycloaddition reactivity is dependent upon the PR(3) employed, with PhP(catechyl) (catechyl = o-O(2)C(6)H(4)) providing the most rapid cycloadditions and optimal pyrrole yields. (1)H, (13)C, and (31)P NMR analysis and computations indicate that electron-poor catechyl-substituted phosphonites and phosphites favor a cyclic 1,3-dipolar structure, while more electron-rich phosphines instead favor the valence tautomeric acyclic ylides. X-ray crystallographic studies confirm this. Density functional theory calculations support the wide variety of P-O interactions induced by different PR(3) groups and indicate that the most efficient concerted 1,3-dipolar cycloadditions are those for dipoles whose ground-state geometry is most like the transition-state geometry. Reactions of these dipoles with monosubstituted alkynes bearing an electron-withdrawing group are calculated to occur by stepwise mechanisms. The presence of the phosphorus unit creates a large electronic bias across the 1,3-dipole, allowing for regioselective cycloadditions with substituted alkynes.
Claisen rearrangements of benzyl vinyl ethers: theoretical investigation of mechanism, substituent effects, and regioselectivity
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7OB01666B
Abstract: Theoretical calculations are reported which examine the mechanisms of Claisen rearrangements of benzyl vinyl ethers and the ways in which substituents influence reactivity and regioselectivity.
Stereoselectivity in oxyallyl-furan (4 + 3) cycloadditions: Control of intermediate conformations and dispersive stabilisation in cycloadditions involving oxazolidinone auxiliaries
Publisher: Royal Society of Chemistry (RSC)
Date: 2010
DOI: 10.1039/C0SC00280A
A Sesquiterpene Isonitrile with a New Tricyclic Skeleton from the Indo-Pacific Nudibranch Phyllidiella pustulosa: Spectroscopic and Computational Studies
Publisher: CSIRO Publishing
Date: 2020
DOI: 10.1071/CH19227
Abstract: The sesquiterpene isonitrile, 9-isocyanoneoallopupukeanane 1, has been obtained from the Indo-Pacific nudibranch Phyllidiella pustulosa. The structure of 1, which was investigated by extensive NMR experiments, molecular modelling studies, and density functional calculations, has a different arrangement of the tricyclic ring system compared with other isonitrile metabolites isolated from nudibranchs or sponges. The viability of a biosynthetic pathway leading to 1, proposed to involve a series of carbocation rearrangements, is explored in a computational study. Isonitrile 1 exhibited micromolar antimalarial activity when screened against Plasmodium falciparum infected erythrocytes.
Nonstabilised azomethine ylids from n-oxides: Unravelling the deprotonation of n-methylmorpholine n-oxide
Publisher: CSIRO Publishing
Date: 2014
DOI: 10.1071/CH14217
Abstract: Nonstabilised azomethine ylids (NAYs) are useful 1,3-dipoles, but their synthetic applications are restricted by the high temperatures often needed for their generation, and by an incomplete understanding of the effect of heteroatoms in cyclic systems. We have examined the behaviour of N-methylmorpholine N-oxide (NMO) as a NAY precursor in the Roussi reaction (low-temperature reaction of an N-oxide with strong base). The choice of base is critical to achieving cycloadduct formation. We report synthetic and computational (density functional theory) investigations of the products obtained with different bases and their mechanisms of formation.
Causation in a Cascade: The Origins of Selectivities in Intramolecular Nitrone Cycloadditions
Publisher: American Chemical Society (ACS)
Date: 12-07-2012
DOI: 10.1021/JA300002K
Radical Ring-Opening Polymerization of Phosphorus Heterocycles: Computational Design of Suitable Phosphetane Monomers
Publisher: CSIRO Publishing
Date: 2007
DOI: 10.1071/CH07121
Abstract: High-level ab initio calculations have been used to determine the propensities of various phosphetanes towards radical ring-opening polymerization. At the G3(MP2)-RAD level of theory, the propagation rate constants of 1-methylphosphetane (7.5 × 104 L mol–1 s–1), 1-phenylphosphetane (4.6 × 105 L mol–1 s–1), cis,cis-2,4-dichloro-1-phenylphosphetane (3.8 × 107 L mol–1 s–1), cis,cis-2,4-difluoro-1-phenylphosphetane (3.0 × 107 L mol–1 s–1), and 1-phenyl-3-oxaphosphetane (4.0 × 106 L mol–1 s–1) are very high, rendering them unsuitable for copolymerization with common alkenes. In contrast, the propagation rate constants of 1-tert-butylphosphetane (1.7 × 103 L mol–1 s–1) and cis,cis-2,4-dimethyl-1-phenylphosphetane (9.2 × 102 L mol–1 s–1) indicate that either incorporation of a t-butyl substituent at phosphorus or alkylation at the 2- and/or 4-positions will produce monomers with more compatible reactivities for copolymerization with alkenes. In the case of 1-tert-butylphosphetane, however, homolytic substitution of the propagating radical with the t-butyl substituent at P will be competitive with the propagation step and could affect the microstructure of the polymer. The borane adduct and the oxide of 1-phenylphosphetane were both found to be unreactive towards radical ring-opening. The calculations suggest that, for chiral phosphetanes, the ring-opening reaction is enantioselective at phosphorus and the resulting polymer will be isotactic.
Chemoselective and Diastereoselective Intramolecular (3+2) Cycloadditions of Epoxy and Aziridinyl Enolsilanes.
Publisher: Wiley
Date: 23-03-2022
Abstract: Epoxy and aziridinyl enolsilanes react as oxyallylic cation equivalents in highly chemo- and diastereoselective intramolecular (3+2) cycloadditions with a range of dienes and olefins. With acyclic dienes, the (3+2) cycloaddition outcompetes the (4+3) pathway traditionally observed in this kind of system almost exclusively. With both conjugated dienes and isolated olefins, excellent diastereoselectivities are observed, and cycloadducts can be obtained in optically-enriched forms. Computational studies indicate that the stepwise (3+2) cycloaddition involves an activated epoxy/aziridinyl intermediate and the conformational flexibility of the intermediate determines the preference for (3+2) cycloadduct formation. Further transformations of the (3+2) cycloadducts produce densely functionalized trans-hydrindane scaffolds.
Glycosylations of Simple Acceptors with 2‐O‐Acyl l ‐Idose or l ‐Iduronic Acid Donors Reveal Only a Minor Role for Neighbouring‐Group Participation
Publisher: Wiley
Date: 17-05-2018
Aromatic Claisen Rearrangements of Benzyl Ketene Acetals: Conversion of Benzylic Alcohols to (ortho‐Tolyl)acetates
Publisher: Wiley
Date: 12-12-2016
Origin of stereoselectivity in the (4 + 3) cycloadditions of chiral alkoxy siloxyallyl cations with furan
Publisher: American Chemical Society (ACS)
Date: 11-01-2010
DOI: 10.1021/OL902591K
Abstract: The mechanisms and stereoselectivities of (4 + 3) cycloadditions between chiral alkoxy siloxyallyl cations and furan are examined using density functional theory calculations. These cycloadditions are predicted to take place via stepwise mechanisms. The stereoselectivities of cycloadditions involving siloxyallyl cations derived from chiral alpha-methyl benzylic alcohols are controlled by two effects: minimization of steric repulsion between the alpha-Me group and the allyl group and attractive CH-pi interactions between the furan and the aryl group.
Towards the Synthesis of Dihydrooxepino[4,3-b]pyrrole-Containing Natural Products via Cope Rearrangement of Vinyl Pyrrole Epoxides
Publisher: American Chemical Society (ACS)
Date: 02-12-2015
DOI: 10.1021/ACS.ORGLETT.5B02965
Abstract: An approach to the dihydrooxepino[4,3-b]pyrrole core of diketopiperazine natural products which utilizes a vinyl pyrrole epoxide Cope rearrangement was investigated. It was found that an ester substituent on the epoxide was essential for the [3,3]-rearrangement to occur. Density functional calculations with M06-2X provided explanations for the effects of the pyrrole and ester groups on these rearrangements.
Examining the Role of Aryldiazonium Salts in Surface Electroinitiated Polymerization
Publisher: American Chemical Society (ACS)
Date: 13-04-2022
DOI: 10.1021/ACS.LANGMUIR.2C00396
Abstract: Historically, the irreversible reduction of aryldiazonium salts has provided a reliable method to modify surfaces, demonstrating a catalogue of suitable diazonium salts for targeted applications. This work expands the knowledge of diazonium salt chemistry to participate in surface electroinitiated emulsion polymerization (SEEP). The influence of concentration, electronic effects, and steric hindrance/regiochemistry of the diazonium salt initiator on the production of polymeric films is examined. The objective of this work is to determine if a polymer film can be tailored, controlling the thickness, density, and surface homogeneity using specific diazonium chemistry. The data presented herein demonstrate a significant difference in polymer films that can be achieved when selecting a variety of diazonium salts and vinylic monomers. A clear trend aligns with the electron-rich diazonium salt substitution providing the thickest films (up to 70.9 ± 17.8 nm) with increasing diazonium concentration and electron-withdrawing substitution achieving optimal homogeneity for the surface of the film at a 5 mM diazonium concentration.
Rho GTPase Signaling in Platelet Regulation and Implication for Antiplatelet Therapies
Publisher: MDPI AG
Date: 28-01-2023
DOI: 10.3390/IJMS24032519
Abstract: Platelets play a vital role in regulating hemostasis and thrombosis. Rho GTPases are well known as molecular switches that control various cellular functions via a balanced GTP-binding/GTP-hydrolysis cycle and signaling cascade through downstream effectors. In platelets, Rho GTPases function as critical regulators by mediating signal transduction that drives platelet activation and aggregation. Mostly by gene targeting and pharmacological inhibition approaches, Rho GTPase family members RhoA, Rac1, and Cdc42 have been shown to be indispensable in regulating the actin cytoskeleton dynamics in platelets, affecting platelet shape change, spreading, secretion, and aggregation, leading to thrombus formation. Additionally, studies of Rho GTPase function using platelets as a non-transformed model due to their anucleated nature have revealed valuable information on cell signaling principles. This review provides an updated summary of recent advances in Rho GTPase signaling in platelet regulation. We also highlight pharmacological approaches that effectively inhibited platelet activation to explore their possible development into future antiplatelet therapies.
pi-ligand exchange on phosphenium ions: Reversible exchange between free and coordinated alkynes in phosphirenium salts
Publisher: American Chemical Society (ACS)
Date: 16-12-2004
DOI: 10.1021/OM030607Z
A Substituent‐Directed Strategy for the Selective Synthesis of L‐Hexoses: An Expeditious Route to L‐Idose
Publisher: Wiley
Date: 25-02-2021
Computational studies of RAFT polymerization-mechanistic insights and practical applications
Publisher: Wiley
Date: 13-03-2006
EBC‐342: A Novel Tetrahydrofuran Moiety Containing Casbane from the Australian Rainforest
Publisher: Wiley
Date: 10-02-2020
Abstract: The Australian rainforest plant, Croton insularis , has provided a further casbane diterpene family member in the form of EBC‐342, which contains a novel tetrahydrofuran ring. A combination of DP4 and TD‐DFT CD methods were required to confirm both structure and absolute stereochemistry.
Why do silanes reduce electron-rich phosphine oxides faster than electron-poor phosphine oxides?
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/C9CC08718D
Abstract: DFT calculations explain the counterintuitive phenomenon that silanes reduce electron-rich (alkyl) phosphine oxides faster than electron-poor (aryl) phosphine oxides.
Synthesis, Magnetic Properties, and Catalytic Properties of a Nickel(II)-Dependent Biomimetic of Metallohydrolases
Publisher: Frontiers Media SA
Date: 25-09-2018
How does cross-conjugation influence thiol additions to enones? A computational study of thiol trapping by the naturally occurring divinyl ketones zerumbone and α-santonin
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/C9OB02709B
Abstract: DFT calculations show how the kinetics and thermodynamics of thiol additions to enones are affected by incorporation of the enone into a cross-conjugated inyl ketone moiety.
AlCl3-Catalyzed Ring Expansion Cascades of Bicyclic Cyclobutenamides Involving Highly Strained Cis,Trans-Cycloheptadienone Intermediates
Publisher: American Chemical Society (ACS)
Date: 20-04-2015
DOI: 10.1021/JACS.5B02561
Why a proximity-induced Diels-Alder reaction is so fast
Publisher: American Chemical Society (ACS)
Date: 25-05-2012
DOI: 10.1021/OL301083Q
Multistereocenter-Containing Cyclopentanoids from Ynamides via Oxazolidinone-Controlled Nazarov Cyclization
Publisher: American Chemical Society (ACS)
Date: 13-06-2017
Abstract: Achieving ready-enantioselective access to multistereocenter-containing cyclopentyl rings is an area of great significance to organic synthesis. In this work, we describe a general protocol for accessing multistereocenter-containing cyclopentanoids from simple N-alkynyloxazolidinones (Ox-ynamides). This protocol involves conversion of Ox-ynamides into Ox-activated inyl and aryl vinyl ketones that undergo facile Nazarov cyclization with excellent chemo-, regio-, and stereocontrol. The Ox auxiliary directs all aspects of reactivity and selectivity, both in the electrocyclization and in the subsequent transformations of the resulting oxyallyl intermediate. Stereoinduction in the electrocyclization results from a "coupled-torque" mechanism in which rotation of the Ox group, driven by increasing orbital overlap of the nitrogen lone pair with the incipient oxyallyl cation, is coupled with the rotation of the termini of the pentadienyl cation, favoring a particular direction of conrotatory ring closure (torquoselectivity). The associated lone-pair stabilization of the transition state by Ox promotes cyclization of traditionally resistant substrates, broadening the scope of this asymmetric Nazarov cyclization. The Ox group also facilitates the stereo- and regioselective incorporation of nucleophiles (Nu) and dienes, giving more complex, multistereocenter containing cyclopentanoids. Finally, the Ox group is readily removed and recovered or can be converted into other amine functionalities.
Influence of Base and Structure in the Reversible Covalent Conjugate Addition of Thiol to Polycyclic Enone Scaffolds
Publisher: American Chemical Society (ACS)
Date: 13-02-2013
DOI: 10.1021/OL400094K
Abstract: The energetics of thiol addition and elimination reactions to bicyclic enones derived from an indole core structure were explored using (1)H NMR and density functional theory (DFT) calculations. The agreement between experiment and theory is excellent, and the combined results reveal that even minor changes in the conformation of the enone, substituents on the scaffold, and the use of different bases have a signficant influence on product distribution. A potential application of these principles is in the rational design of new reversible covalent enzyme inhibitors.
Does nature click? Theoretical prediction of an enzyme-catalyzed transannular 1,3-dipolar cycloaddition in the biosynthesis of lycojaponicumins A and B
Publisher: American Chemical Society (ACS)
Date: 06-11-2013
DOI: 10.1021/JA409928Z
Abstract: Biosynthetic 1,3-dipolar cycloadditions are rare. No enzymes have yet been identified whose function is to catalyze this class of reactions. Recently, however, a 1,3-dipolar cycloaddition was proposed as a key step in the biosynthesis of two Lycopodium alkaloids, lycojaponicumins A and B. The lycojaponicumins' fused bicyclic tetrahydroisoxazole ring system was proposed to originate from a transannular 1,3-dipolar cycloaddition between a nitrone and an enone in a nine-membered macrocycle. We have used quantum mechanical calculations to predict whether this cycloaddition could constitute a feasible step in a biosynthetic pathway. Our calculations define a general computational approach for analyzing whether a putative biosynthetic reaction is likely to be enzyme-catalyzed. The quantum mechanically predicted rate of the uncatalyzed reaction in water is compared with the rate enhancement theoretically achievable when the reaction is catalyzed by a theozyme (theoretical enzyme). Density functional theory calculations (M06-2X) predict that the uncatalyzed transannular 1,3-dipolar cycloaddition of the putative lycojaponicumin precursor in water is moderately facile (ΔG(++) = 21.5 kcal/mol, k = 10(-3) s(-1)) and that an enzyme could accelerate the cycloaddition by placing hydrogen bond donors around the enone while maintaining an otherwise nonpolar active site. The theoretical enzyme-catalyzed process has ΔG(++) ≈ 17 kcal/mol, corresponding to a 2000-fold rate enhancement, and the predicted kcat (2 s(-1)) is similar to those of known enzymes involved in secondary metabolic pathways. Thus, theory predicts that the proposed transannular 1,3-dipolar cycloaddition is a plausible step in a biosynthetic pathway leading to the lycojaponicumins and suggests that dipolar cycloadditions can be accelerated by enzyme catalysis.
Reassignments and Corroborations of Oxo‐Bridged Natural Products Directed by OSE and DU8+ NMR Computation
Publisher: Wiley
Date: 24-04-2019
Abstract: Structural misassignments of natural products are prevalent in the literature. Developing methods and theoretical concepts to assist those undertaking structural elucidation is therefore of paramount importance, such that biologists and synthetic chemists avoid pursuing phantom chemical entities. Herein described is a strategy for predicting the isolabilities of oxygen-substituted bridgehead natural products based on calculations of olefin strain energies, NMR chemical shifts and coupling constants (DU8+). This approach provides corroborating evidence for the structures of certain bridgehead alkene natural products while leading to the reassignment of several other structures.
Ionic and Neutral Mechanisms for C–H Bond Silylation of Aromatic Heterocycles Catalyzed by Potassium tert-Butoxide
Publisher: American Chemical Society (ACS)
Date: 12-05-2017
DOI: 10.1021/JACS.6B13032
Abstract: Exploiting C-H bond activation is difficult, although some success has been achieved using precious metal catalysts. Recently, it was reported that C-H bonds in aromatic heterocycles were converted to C-Si bonds by reaction with hydrosilanes under the catalytic action of potassium tert-butoxide alone. The use of Earth-abundant potassium cation as a catalyst for C-H bond functionalization seems to be without precedent, and no mechanism for the process was established. Using ambient ionization mass spectrometry, we are able to identify crucial ionic intermediates present during the C-H silylation reaction. We propose a plausible catalytic cycle, which involves a pentacoordinate silicon intermediate consisting of silane reagent, substrate, and the tert-butoxide catalyst. Heterolysis of the Si-H bond, deprotonation of the heteroarene, addition of the heteroarene carbanion to the silyl ether, and dissociation of tert-butoxide from silicon lead to the silylated heteroarene product. The steps of the silylation mechanism may follow either an ionic route involving K
Quantum chemical mapping of initialization processes in RAFT polymerization
Publisher: Wiley
Date: 03-07-2006
Diels–Alder Reactions of Chiral Sulfinylquinones: From Sterically Directed to CH–π Directed Stereoselectivity
Publisher: CSIRO Publishing
Date: 2020
DOI: 10.1071/CH19525
Heteroatom-Interchanged Isomers of Lissoclinamide 5: Copper(II) Complexation, Halide Binding, and Biological Activity
Publisher: Wiley
Date: 25-03-2018
Stereoselectivities and regioselectivities of (4 + 3) cycloadditions between allenamide-derived chiral oxazolidinone-stabilized oxyallyls and furans: Experiment and theory
Publisher: American Chemical Society (ACS)
Date: 18-08-2011
DOI: 10.1021/JA205700P
Steric and Solvation Effects in Ionic SN2 Reactions
Publisher: American Chemical Society (ACS)
Date: 20-10-2009
DOI: 10.1021/JA9053459
Abstract: This paper explores the contribution of solvation to the overall steric effects of S(N)2 reactions observed in solution. The reactions of chloride ion with a series of alkyl chloronitriles, RCH(CN)Cl (R = methyl, ethyl, isopropyl, tert-butyl) were investigated both experimentally and theoretically. These reactions serve as a model system for the parent reactions, Cl(-) + RCH(2)Cl, which are too slow to measure. Each additional substitution at the beta-carbon lowers the reactivity, clearly demonstrating a steric hindrance effect. The magnitude of the steric effect, however, is not significantly different in the gas phase and in solution. We conclude that the solvation energies of the corresponding S(N)2 transition states must be similar regardless of size of the substituent. This lack of size dependence in the current system is in sharp contrast with many other ionic systems such as ionization of simple alkyl alcohols, where solvation depends strongly on size. We propose that the weak size dependence results from the compensation between a direct shielding effect of the substituent and an indirect ionic solvation effect, which arises from the geometric perturbations introduced by the substitution. The conclusion is further supported by calculations using polarizable continuum models and QM/MM simulations.
Rhodium catalyzed template-assisted distal para-C–H olefination
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C9SC01824G
Abstract: We report first ex le of template assisted rhodium catalyzed para -C–H alkenylation.
Synthesis of spirocyclic orthoesters by ‘anomalous’ rhodium(ii )-catalysed intramolecular C–H insertions
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C7OB02123B
Abstract: Spirocyclic orthoesters are synthesised by ‘anomalous’ Rh( ii )-catalysed intramolecular C–H insertion reactions.
The Oxidation of Oxygen and Sulfur‐Containing Heterocycles by Cytochrome P450 Enzymes
Publisher: Wiley
Date: 02-08-2023
Abstract: The cytochrome P450 (CYP) superfamily of monooxygenase enzymes play important roles in the metabolism of molecules which contain heterocyclic, aromatic functional groups. Here we study how oxygen‐ and sulfur‐containing heterocyclic groups interact with and are oxidized using the bacterial enzyme CYP199A4. This enzyme oxidized both 4‐(thiophen‐2‐yl)benzoic acid and 4‐(thiophen‐3‐yl)benzoic acid almost exclusively via sulfoxidation. The thiophene oxides produced were activated towards Diels‐Alder dimerization after sulfoxidation, forming dimeric metabolites. Despite X‐ray crystal structures demonstrating that the aromatic carbon atoms of the thiophene ring were located closer to the heme than the sulfur, sulfoxidation was still favoured with 4‐(thiophen‐3‐yl)benzoic acid. These results highlight a preference of this cytochrome P450 enzyme for sulfoxidation over aromatic hydroxylation. Calculations predict a strong preference for homodimerization of the enantiomers of the thiophene oxides and the formation of a single major product, in broad agreement with the experimental data. 4‐(Furan‐2‐yl)benzoic acid was oxidized to 4‐(4′‐hydroxybutanoyl)benzoic acid using a whole‐cell system. This reaction proceeded via a γ‐keto‐α,β‐unsaturated aldehyde species which could be trapped in vitro using semicarbazide to generate a pyridazine species. The combination of the enzyme structures, the biochemical data and theoretical calculations provides detailed insight into the formation of the metabolites formed from these heterocyclic compounds.
Endo Selectivity in the (4 + 3) Cycloaddition of Oxidopyridinium Ions
Publisher: American Chemical Society (ACS)
Date: 12-10-2021
DOI: 10.1021/ACS.ORGLETT.1C03028
Abstract: The (4 + 3) cycloaddition of 2-trialkylsilyl-4-alkylbutadienes with an
Rearrangement-Free Hydroxylation of Methylcubanes by a Cytochrome P450: The Case for Dynamical Coupling of C–H Abstraction and Rebound
Publisher: American Chemical Society (ACS)
Date: 19-11-2019
DOI: 10.1021/JACS.9B08064
Abstract: The highly strained cubylmethyl radical undergoes one of the fastest radical rearrangements known (reported
Direct Observation of an Oxepin from a Bacterial Cytochrome P450-Catalyzed Oxidation.
Publisher: Wiley
Date: 16-02-2016
Abstract: The cytochromes P450 are hemoproteins that catalyze a range of oxidative C-H functionalization reactions, including aliphatic and aromatic hydroxylation. These transformations are important in a range of biological contexts, including biosynthesis and xenobiotic biodegradation. Much work has been carried out on the mechanism of aliphatic hydroxylation, implicating hydrogen atom abstraction, but aromatic hydroxylation is postulated to proceed differently. One mechanism invokes as the key intermediate an arene oxide (and/or its oxepin tautomer). Conclusive isolation of this intermediate has remained elusive and, currently, direct formation of phenols from a Meisenheimer intermediate is believed to be favored. We report here the identification of a P450 [P450cam (CYP101A1) and P450cin (CYP176A1)]-generated arene oxide as a product of in vitro oxidation of tert-butylbenzene. Computations (CBS-QB3) predict that the arene oxide and oxepin have similar stabilities to other arene oxides/oxepins implicated (but not detected) in P450-mediated transformations, suggesting that arene oxides can be unstable terminal products of P450-catalyzed aromatic oxidation that can explain the origin of some observed metabolites.
(4+3) Cycloaddition Reactions of N-Alkyl Oxidopyridinium Ions.
Publisher: Wiley
Date: 16-10-2017
Abstract: N-Methylation of methyl 5-hydroxynicotinate followed by reaction with a diene in the presence of triethylamine afforded (4+3) cycloadducts in good to excellent yields. High regioselectivity was observed with 1-substituted and 1,2-disubstituted butadienes. Density functional theory calculations indicate that the cycloaddition involves concerted addition of the diene onto the oxidopyridinium ion. The process provides rapid access to bicyclic nitrogenous structures resembling natural alkaloids.
Regioselectivities of (4 + 3) cycloadditions between furans and oxazolidinone-substituted oxyallyls
Publisher: American Chemical Society (ACS)
Date: 04-11-2010
DOI: 10.1021/OL1023745
Tris(trimethylsilyl)methane is not an effective mediator of radical reactions
Publisher: Elsevier BV
Date: 08-2007
Computational analysis of the stereochemical outcome in the imidazolidinone-catalyzed enantioselective (4 + 3)-cycloaddition reaction
Publisher: American Chemical Society (ACS)
Date: 19-12-2015
DOI: 10.1021/JO501906M
Abstract: Computations show why the catalytic, asymmetric (4 + 3)-cycloaddition reaction developed in the Harmata laboratories proceeds with facial selectivity opposite to that for models proposed for related catalyzed Diels-Alder reactions. Computations with M06-2X/6-311+G(d,p)//B3LYP/6-31G(d) show that iminium ions derived from MacMillan's chiral 2-tert-butyl-5-benzylimidazolidinone and siloxypentadienals undergo (4 + 3)-cycloadditions with furans preferentially on the more crowded face. Conformational reorganization of the benzyl group, to avoid intramolecular interaction with the silyl group, is responsible for differentiating the activation barriers of top- and bottom-face attack.
Reassignments and Corroborations of Oxo‐Bridged Natural Products Directed by OSE and DU8+ NMR Computation
Publisher: Wiley
Date: 24-04-2019
Synthesis, characterization and computational investigation of the phosphatase activity of a dinuclear Zinc(II) complex containing a new heptadentate asymmetric ligand
Publisher: Elsevier BV
Date: 02-2023
DOI: 10.1016/J.JINORGBIO.2022.112064
Abstract: We report the synthesis of a new asymmetric heptadentate ligand based on the 1,3-diaminopropan-2-ol backbone. The ligand 3-[[3-(bis-pyridin-2-ylmethyl-amino)-2-hydroxy-propyl]-(2-carbamoyl-ethyl)-amino]-propionamide (HL1) contains two amide and two pyridine groups attached to the 1,3-diaminopropan-2-ol core. Reaction between HL1 and Zn(ClO
Anionic ring‐opening polymerization of small phosphorus heterocycles and their borane adducts: An ab initio investigation
Publisher: Wiley
Date: 03-2007
DOI: 10.1002/HC.20323
Torquoselective Ring Opening of Fused Cyclobutenamides: Evidence for a Cis,Trans-Cyclooctadienone Intermediate
Publisher: American Chemical Society (ACS)
Date: 03-07-2014
DOI: 10.1021/JA502252T
Five-coordinate transition metal complexes and the value of τ5: observations and caveats
Publisher: Royal Society of Chemistry (RSC)
Date: 2020
DOI: 10.1039/D0DT02985H
Abstract: The τ 5 parameter is not limited to values between 0 and 1 in five-coordinate transition metal complexes.
Cibalackrot Dendrimers for Hyperfluorescent Organic Light‐Emitting Diodes
Publisher: Wiley
Date: 12-04-2022
Abstract: Hyperfluorescent organic light‐emitting diodes (HF‐OLEDs) enable a cascading Förster resonance energy transfer (FRET) from a suitable thermally activated delayed fluorescent (TADF) assistant host to a fluorescent end‐emitter to give efficient OLEDs with relatively narrowed electroluminescence compared to TADF‐OLEDs. Efficient HF‐OLEDs require optimal FRET with minimum triplet diffusion via Dexter‐type energy transfer (DET) from the TADF assistant host to the fluorescent end‐emitter. To hinder DET, steric protection of the end‐emitters has been proposed to disrupt triplet energy transfer. In this work, the first HF‐OLEDs based on structurally well‐defined macromolecules, dendrimers is reported. The dendrimers contain new highly twisted dendrons attached to a Cibalackrot core, resulting in high solubility in organic solvents. HF‐OLEDs based on dendrimer blend films are fabricated to show external quantum efficiencies of % at 100 cd m −2 . Importantly, dendronization with the bulky dendrons is found to have no negative impact to the FRET efficiency, indicating the excellent potential of the dendritic macromolecular motifs for HF‐OLEDs. To fully prevent the undesired triplet diffusion, Cibalackrot dendrimers HF‐OLEDs are expected to be further improved by adding additional dendrons to the Cibalackrot core and / or increasing dendrimer generations.
Biosynthetic insights provided by unusual sesterterpenes from the medicinal herb Aletris farinosa
Publisher: Royal Society of Chemistry (RSC)
Date: 2015
DOI: 10.1039/C5SC02056E
Abstract: Configuration of a single stereocenter determines if a key carbocation in sesterterpene biosynthesis undergoes simple elimination or a cascade of seven 1,2-methyl and hydride migrations.
EBC-219: a new diterpene skeleton, crotinsulidane, from the Australian rainforest containing a bridgehead double bond.
Publisher: Wiley
Date: 05-05-2014
Abstract: EBC-219 (4), isolated from Croton insularis (Baill), was established by spectroscopic and DFT methods as the first member of a new diterpene skeletal class, uniquely defined by the presence of a bicyclo[10.2.1] bridgehead olefin. The proposed biogenetic pathway to 4 from the co-isolated natural products EBC-131 (1), EBC-180 (2) and EBC-181 (3) is highly likely. EBC-180 (2) and EBC-181 (3) showed moderate to strong cytotoxic activity against various cancer cell lines.
Opposing Auxiliary Conformations Produce the Same Torquoselectivity in an Oxazolidinone-Directed Nazarov Cyclization
Publisher: American Chemical Society (ACS)
Date: 11-06-2013
DOI: 10.1021/JA4036434
Abstract: Most applications of chiral oxazolidinone auxiliaries in asymmetric synthesis operate through a common set of stereocontrol principles. That is, the oxazolidinone is made to adopt a specific, coplanar conformation with respect to the prochiral substrate, and reaction occurs preferentially at whichever stereoheterotopic face is not blocked by the substituents on the oxazolidinone. In contrast to these principles, we report here the discovery of an alternative mechanism of oxazolidinone-based stereocontrol that does not require coplanarity and is driven instead by allylic strain. This pathway has been uncovered through computational studies of an asymmetric Nazarov cyclization. Chiral oxazolidinone auxiliaries provide essentially complete control over the torquoselectivity of ring closure and the regioselectivity of subsequent deprotonation. Density functional theory calculations (M06-2X//B3LYP) reveal that in the transition state of 4π electrocyclic ring closure, the oxazolidinone ring and the cyclizing pentadienyl cation are distorted from coplanarity in a manner that gives two transition state conformations of similar energy. These two conformers are distinguished by a 180° flip in the auxiliary orientation such that in one conformer the oxazolidinone carbonyl is oriented toward the OH of the pentadienyl cation (syn-conformer) and in the other it is oriented away from this OH (anti-conformer). Surprisingly, both conformations induce the same sense of torquoselectivity, with a 3-5 kcal/mol preference for the C5-β epimer of the ring-closed cation. In both conformations, the conrotatory mode that leads to the C5-α epimer is disfavored due to higher levels of allylic strain between the oxazolidinone substituent and adjacent groups on the pentadienyl cation (R(4) and OH). The excellent torquoselectivities obtained in the oxazolidinone-directed Nazarov cyclization suggest that the allylic strain-driven stereoinduction pathway represents a viable alternative mechanism of stereocontrol for reactions of sterically congested substrates that lie outside of the traditional coplanar (N-acyloxazolidinone) paradigm.
Theoretical investigation of the mechanisms and stereoselectivities of reductions of acyclic phosphine oxides and sulfides by chlorosilanes
Publisher: American Chemical Society (ACS)
Date: 12-04-2012
DOI: 10.1021/JO300346G
Abstract: Computational studies were performed to explain the highly varied stereoselectivities obtained in the reductions of acyclic phosphine oxides and sulfides by different chlorosilanes. The reductions of phosphine oxides by HSiCl(3), HSiCl(3)/Et(3)N, and Si(2)Cl(6) and the reductions of phosphine sulfides by Si(2)Cl(6) (all in benzene) were explored by means of B3LYP, B3LYP-D, and SCS-MP2 calculations. For the reductions of phosphine oxides by HSiCl(3), the calculations support the mechanism proposed by Horner in which a hydride is transferred from silicon to phosphorus through a four-centered, frontside transition state. This mechanism leads to retention of stereochemistry at phosphorus. For the other three reductions, two classes of mechanisms were explored. Phosphorane-based mechanisms that were previously proposed by Mislow and involve SiCl(3)(-) were compared with novel alternative mechanisms that involve nonionic rearrangement processes. In one of these, donor-stabilized SiCl(2) is formed as an intermediate. The calculations support a phosphorane-based mechanism for the reductions of phosphine oxides by HSiCl(3)/Et(3)N and Si(2)Cl(6) (which proceed with inversion) but favor the rearrangement pathways for the reductions of phosphine sulfides by Si(2)Cl(6) (which proceed with retention).
Origins of stereoselectivity in uncatalyzed and ZnBr2-catalyzed Diels–Alder reactions of a chiral sulfinylquinone
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C9OB01756A
Abstract: DFT calculations show how a chiral sulfinyl group differentiates the diastereotopic faces of an adjacent CC bond in quinone Diels–Alder reactions.
Deep‐Red Lasing and Amplified Spontaneous Emission from Nature Inspired Bay‐Annulated Indigo Derivatives
Publisher: Wiley
Date: 14-11-2019
Different Geometric Requirements for Cytochrome P450-Catalyzed Aliphatic Versus Aromatic Hydroxylation Results in Chemoselective Oxidation
Publisher: American Chemical Society (ACS)
Date: 06-01-2022
Understanding condensation domain selectivity in non-ribosomal peptide biosynthesis: structural characterization of the acceptor bound state
Publisher: Research Square Platform LLC
Date: 06-01-2021
DOI: 10.21203/RS.3.RS-125509/V1
Abstract: Non-ribosomal peptide synthetases are important enzymes for the assembly of complex peptide natural products. Within these multi-modular assembly lines, condensation domains perform the central function of chain assembly, typically by forming a peptide bond between two peptidyl carrier protein (PCP)-bound substrates. In this work, we report the first structural snapshots of a condensation domain in complex with an aminoacyl-PCP acceptor substrate. These structures allow the identification of a mechanism that controls access of acceptor substrates to the active site in condensation domains. The structures of this previously uncharacterized complex also allow us to demonstrate that condensation domain active sites do not contain a distinct pocket to select the side chain of the acceptor substrate during peptide assembly but that residues within the active site motif can instead serve to tune the selectivity of these central biosynthetic domains.
Mechanistic Studies on the Base-Promoted Ring Opening of Glycal-Derived
Publisher: American Chemical Society (ACS)
Date: 21-12-2022
Abstract: In the presence of a nucleophilic base, ring-fused
Mapping the Interactions of I2, I., I−, and I+with Alkynes and Their Roles in Iodocyclizations
Publisher: Wiley
Date: 03-06-2015
Abstract: A combination of experiment and theory has been used to explore the mechanisms by which molecular iodine (I2 ) and iodonium ions (I(+) ) activate alkynes towards iodocyclization. Also included in the analysis are the roles of atomic iodine (I(.) ) and iodide ion (I(-) ) in mediating the competing addition of I2 to the alkyne. These studies show that I2 forms a bridged I2 -alkyne complex, in which both alkyne carbons are activated towards nucleophilic attack, even for quite polarized alkynes. By contrast, I(+) gives unsymmetrical, open iodovinyl cations, in which only one carbon is activated toward nucleophilic attack, especially for polarized alkynes. Addition of I2 to alkynes competes with iodocyclization, but is reversible. This fact, together with the capacity of I2 to activate both alkyne carbons towards nucleophilic attack, makes I2 the reagent of choice (superior to iodonium reagents) for iodocyclizations of resistant substrates. The differences in the nature of the activated intermediate formed with I2 versus I(+) can also be exploited to accomplish reagent-controlled 5-exo/6-endo- ergent iodocyclizations.
Origins of stereoselectivity in the α-alkylation of chiral hydrazones
Publisher: American Chemical Society (ACS)
Date: 11-11-2010
DOI: 10.1021/JO1019877
The stereoselectivities of tributyltin hydride-mediated reductions of 5-bromo-d-glucuronides to l-iduronides are dependent on the anomeric substituent: Syntheses and DFT calculations
Publisher: Royal Society of Chemistry (RSC)
Date: 2016
DOI: 10.1039/C6OB00283H
Abstract: Reduction of a 5- C -bromo- d -glucuronyl β-fluoride with tributyltin hydride gives exclusively the l -ido product. The selectivity is traced to a transition state gauche effect and an Sn–F interaction.
Front cover: developing cyclic peptide heteroatom interchange: synthesis and DFT modelling of a HI-ascidiacyclamide isomer (Eur. J. Org. Chem. /2018)
Publisher: Wiley
Date: 19-06-2018
(4+3) Cycloaddition Reactions of N‐Alkyl Oxidopyridinium Ions
Publisher: Wiley
Date: 16-10-2017
Safety of administering biologics to IBD patients at an outpatient infusion center In New York City during the COVID-19 pandemic: Sars-CoV-2 seroprevalence and clinical and social characteristics
Publisher: Cold Spring Harbor Laboratory
Date: 17-03-2021
DOI: 10.1101/2021.03.15.21253615
Abstract: Patients with immune-mediated inflammatory diseases (IMIDs) and acquired and genetic immunodeficiencies receiving therapeutic infusions are considered high risk for SARS-CoV-2 infection. However, the seroprevalance in this group and the safety of routine administrations at outpatient infusion centers are unknown. To determine the infection rate and clinical-social factors related to SARS-CoV-2 in asymptomatic patients with IMIDs and immunodeficiencies receiving routine non-cancer therapeutic infusions, we conducted a seroprevalence study at our outpatient infusion center. We report the first prospective SARS-CoV-2 sero-surveillance of 444 IBD/IMID, immunodeficiency, and immune competent patients at an outpatient infusion center in the U.S. showing lower seroprevalence in patients compared with the general population and provide clinical and social characteristics associated with seroprevalence in this group. These data suggest that patients can safely continue infusions at outpatient centers.
Aromatic interactions in asymmetric catalysis: Control of enantioselectivity in Diels-Alder reactions catalysed by camphor-derived hydrazides
Publisher: Royal Society of Chemistry (RSC)
Date: 2013
DOI: 10.1039/C3OB40850G
Abstract: Density functional theory calculations (M06-2X//B3LYP) have been performed to determine the factors responsible for enantioselectivity in Diels–Alder reactions catalysed by two series of c hor-derived amines. Hydrazides 2 and sulfonylhydrazides 3 catalyze the reaction of cyclopentadiene with cinnamaldehyde to give the same enantiomer of cycloadduct. The calculations reveal that the two classes of catalysts control enantioselectivity by opposite mechanisms. Hydrazides 2 favour addition to the bottom face of a trans iminium cation, while sulfonylhydrazides 3 favour addition to the top face of a cis iminium ion. In the transition state for cycloadditions catalysed by 2, a stabilising CH–π interaction between the diene and a benzyl substituent α to the iminium nitrogen accelerates the reaction and enhances the enantioselectivity. The facial selectivity can be reinforced by appending onto the benzyl side-arm an α-methyl group that sterically hinders addition to the top face.
The mechanism of cleavage of Evans chiral auxiliaries by LiOOH: origins of the different regioselectivities obtained with LiOH, LiOOH, LiOBn and LiSBn
Publisher: CSIRO Publishing
Date: 2023
DOI: 10.1071/CH23086
Asymmetric synthesis of multiple quaternary stereocentre-containing cyclopentyls by oxazolidinone-promoted Nazarov cyclizations
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C8SC00031J
Abstract: Ox -activated inyl ketones undergo torquoselective Nazarov cyclization to give cyclopentanoids containing up to three new contiguous quaternary (4°) stereocentres.
An unprecedented stereoselective base-induced trimerization of an α-bromovinylsulfone
Publisher: Royal Society of Chemistry (RSC)
Date: 2017
DOI: 10.1039/C7OB01121K
Abstract: A unprecedented base-induced trimerization of bromovinylsulfone 1 afforded the cyclohexene 6 as a single diastereoisomer.
Mechanism of SH 2 reactions of disulfides: Frontside vs backside, stepwise vs concerted
Publisher: American Chemical Society (ACS)
Date: 23-06-2009
DOI: 10.1021/JO900834M
Abstract: Density functional theory calculations indicate that the S(H)2 reactions of disulfides with alkyl or aryl radicals take place via concerted backside displacement. The activation energies for reactions of Me* with RSSR (R = Me, Et, (i)Pr, (t)Bu) increase with the size of R, since larger R groups prevent the formation of an ideal geometry for SOMO-LUMO overlap. Frontside transition states can also be located, but these lie at least 11 kcal mol(-1) above the corresponding backside transition states.
Mechanisms of Carbonyl Activation by BINOL N-Triflylphosphoramides: Enantioselective Nazarov Cyclizations
Publisher: American Chemical Society (ACS)
Date: 17-04-2017
Transition states and energetics of nucleophilic additions of thiols to substituted α,β-unsaturated ketones: Substituent effects involve enone stabilization, product branching, and solvation
Publisher: American Chemical Society (ACS)
Date: 16-05-2011
DOI: 10.1021/JO200761W
Abstract: CBS-QB3 enthalpies of reaction have been computed for the conjugate additions of MeSH to six α,β-unsaturated ketones. Compared with addition to methyl vinyl ketone, the reaction becomes 1-3 kcal mol(-1) less exothermic when an α-Me, β-Me, or β-Ph substituent is present on the C=C bond. The lower exothermicity for the substituted enones occurs because the substituted reactant is stabilized more by hyperconjugation or conjugation than the product is stabilized by branching. Substituent effects on the activation energies for the rate-determining step of the thiol addition (reaction of the enone with MeS(-)) were also computed. Loss of reactant stabilization, and not steric hindrance, is the main factor responsible for controlling the relative activation energies in the gas phase. The substituent effects are further magnified in solution in water (simulated by CPCM calculations), the addition of MeS(-) to an enone is disfavored by 2-6 kcal mol(-1) when one or two methyl groups are present on the C=C bond (ΔΔG(‡)). The use of CBS-QB3 gas-phase energies in conjunction with CPCM solvation corrections provides kinetic data in good agreement with experimental substituent effects. When the energetics of the thiol additions were calculated with several popular density functional theory and ab initio methods (B3LYP, MPW1PW91, B1B95, PBE0, B2PLYP, and MP2), some substantial inaccuracies were noted. However, M06-2X (with a large basis set), B2PLYP-D, and SCS-MP2 gave results within 1 kcal mol(-1) of the CBS-QB3 benchmark values.
Synthesis, Characterization and Complexation Studies of a Cage Ligand Bearing a Tris(bipyridyl)iron(II) Capping Group
Publisher: CSIRO Publishing
Date: 2002
DOI: 10.1071/CH02144
Abstract: Reaction between 5-(4-amino-2-thiabutyl)-5-methyl-3,7-dithianonane-1,9-diamine (N3S3) and 5-methyl-2,2-bipyridine-5-carbaldehyde and subsequent reduction of the resulting imine with sodium borohydride results in a potentially ditopic ligand (L). Treatment of L with one equivalent of an iron(II) salt led to the monoprotonated complex [Fe(HL)]3+, isolated as the hexafluorophosphate salt. The presence of characteristic bands for the tris(bipyridyl)iron(II) chromophore in the UV/vis spectrum indicated that the iron(II) atom is coordinated octahedrally by the three bipyridyl (bipy) groups. The [Fe(bipy)3] moiety encloses a cavity composed of the N3S3 portion of the ditopic ligand. The mononuclear and monomeric nature of the complex [Fe(HL)]3+ has been established also by accurate mass analysis. [Fe(HL)]3+ displays reduced stability to base compared with the complex [Fe(bipy)3]2+. In aqueous solution [Fe(HL)]3+ exhibits irreversible electrochemical behaviour with an oxidation wave ca. 60 mV to more positive potential than [Fe(bipy)3]2+. Investigations of the interaction of [Fe(L)]2+ with copper(II), iron(II), and mercury(II) using mass spectroscopic and potentiometric methods suggested that where complexation occurred, fewer than six of the N3S3 cavity donors were involved. The high affinity of the complex [Fe(L)]2+ for protons is one reason suggested to contribute to the reluctance to coordinate a second metal ion.
Reductions of phosphine oxides and sulfides by perchlorosilanes: Evidence for the involvement of donor-stabilized dichlorosilylene
Publisher: American Chemical Society (ACS)
Date: 08-12-2012
DOI: 10.1021/JO202370X
Abstract: Hexachlorodisilane reduces phosphine oxides and sulfides to the corresponding phosphines with opposite stereoselectivities. Through quantum mechanical calculations, a new mechanistic picture is reported that explains these stereoselectivities. Phosphine oxides are shown to react via conventional phosphorane intermediates, but phosphine sulfides follow a dramatically different mechanism involving donor-stabilized SiCl(2).
Entropy versus tether strain effects on rates of intramolecular 1,3-dipolar cycloadditions of N-alkenylnitrones
Publisher: Elsevier BV
Date: 04-2011
Nazarov Cyclizations Catalyzed by BINOL Phosphoric Acid Derivatives: Quantum Chemistry Struggles To Predict the Enantioselectivity
Publisher: American Chemical Society (ACS)
Date: 11-10-2021
Abstract: Quantum chemical calculations have successfully predicted the stereoselectivities of many BINOL phosphoric acid catalyzed reactions over the past 10-15 years. Herein we report a contrasting ex le: a reaction for which standard quantum chemistry techniques have proven unexpectedly ineffective at explaining the stereoselectivity. The Nazarov cyclizations of a inyl ketone catalyzed by a BINOL phosphoric acid or H
Low Amplified Spontaneous Emission and Lasing Thresholds from Hybrids of Fluorenes and Vinylphenylcarbazole
Publisher: Wiley
Date: 26-08-2020
Lasing Operation under Long‐Pulse Excitation in Solution‐Processed Organic Gain Medium: Toward CW Lasing in Organic Semiconductors
Publisher: Wiley
Date: 09-09-2020
The fate of copper catalysts in atom transfer radical chemistry
Publisher: Royal Society of Chemistry (RSC)
Date: 2019
DOI: 10.1039/C8PY01688G
Abstract: The pathway of atom transfer radical polymerisation (ATRP) is influenced by the nature of the alkyl bromide initiator (RBr) to the extent that reactions between the radical R˙ and the original copper( i ) catalyst can ert the reaction toward different products.
Concerted Ring Opening and Cycloaddition of Chiral Epoxy Enolsilanes with Dienes
Publisher: Wiley
Date: 07-05-2015
Catalytic wittig reactions of semi- and nonstabilized ylides enabled by ylide tuning
Publisher: Wiley
Date: 22-09-2014
Abstract: The first ex les of catalytic Wittig reactions with semistabilized and nonstabilized ylides are reported. These reactions were enabled by utilization of a masked base, sodium tert-butyl carbonate, and/or ylide tuning. The acidity of the ylide-forming proton was tuned by varying the electron density at the phosphorus center in the precatalyst, thus facilitating the use of relatively mild bases. Steric modification of the precatalyst structure resulted in significant enhancement of E selectivity up to >95:5, E/Z.
Chemoselective and Diastereoselective Intramolecular (3+2) Cycloadditions of Epoxy and Aziridinyl Enolsilanes
Publisher: Wiley
Date: 23-03-2022
Abstract: Epoxy and aziridinyl enolsilanes react as oxyallylic cation equivalents in highly chemo‐ and diastereoselective intramolecular (3+2) cycloadditions with a range of dienes and olefins. With acyclic dienes, the (3+2) cycloaddition outcompetes the (4+3) pathway traditionally observed in this kind of system almost exclusively. With both conjugated dienes and isolated olefins, excellent diastereoselectivities are observed, and cycloadducts can be obtained in optically‐enriched forms. Computational studies indicate that the stepwise (3+2) cycloaddition involves an activated epoxy/aziridinyl intermediate and the conformational flexibility of the intermediate determines the preference for (3+2) cycloadduct formation. Further transformations of the (3+2) cycloadducts produce densely functionalized trans ‐hydrindane scaffolds.
Modular Mesoionics: Understanding and Controlling Regioselectivity in 1,3-Dipolar Cycloadditions of Munchnone Derivatives
Publisher: American Chemical Society (ACS)
Date: 07-11-2013
DOI: 10.1021/JA406833Q
Abstract: 1,3-Dipolar cycloadditions of mesoionic 1,3-dipoles (Münchnones, imino-Münchnones, and phospha-Münchnones) with alkynes offer versatile, modular synthetic routes to pyrroles. Reactivity and regioselectivity differ markedly for different members of this series, and we report here the first general rationale for differences in reactivity by means of a systematic investigation of 1,3-dipolar cycloadditions involving electron-poor and electron-rich alkynes. Competition kinetic measurements indicate that Münchnones and phospha-Münchnones are nucleophilic 1,3-dipoles that react most rapidly with electron-poor alkynes. However, the regioselectivities of cycloadditions are found to undergo an inversion as a function of alkyne ionization potential. The exact point at which this occurs is different for the two dipoles, allowing rational control of the pyrrole formed. The origins of these reactivities and regioselectivities are examined computationally. Frontier molecular orbital predictions are found not to be accurate for these reactions, but transition state calculations give correct predictions of reactivity and selectivity, the origins of which can be analyzed using the distortion/interaction model of reactivity. Cycloadditions with electron-poor alkynes are shown to favor the regioisomer that has either the most favorable TS interaction energy (Münchnones or imino-Münchnones) or the smallest TS distortion energy (phospha-Münchnones). Cycloadditions with more electron-rich aryl-substituted alkynes, on the other hand, generally favor the regioisomer that has the smaller TS distortion energy. These insights delineate the synthetically important distinctions between Münchnones and phospha-Münchnones: phospha-Münchnones undergo highly regioselective cycloadditions with electron-poor alkynes that do not react selectively with Münchnones, and the reverse is true for cycloadditions of Münchnones with electron-rich alkynes.
Catalytic Asymmetric Staudinger–aza-Wittig Reaction for the Synthesis of Heterocyclic Amines
Publisher: American Chemical Society (ACS)
Date: 04-06-2019
DOI: 10.1021/JACS.9B04803
Asymmetric synthesis of a tertiary arsine by nucleophilic addition to a chiral phosphine-stabilized arsenium salt
Publisher: American Chemical Society (ACS)
Date: 05-09-2008
DOI: 10.1021/OM8006272
Mechanistic aspects of thiol additions to Michael acceptors: Insights from computations
Publisher: Wiley
Date: 21-09-2023
DOI: 10.1002/WCMS.1636
Abstract: Computational studies have delivered valuable mechanistic insights into thiol Michael additions, which are important CS bond‐forming reactions used in biological and materials chemistry. The field has delivered a wealth of understanding about the ways in which substituents, catalysts, and the local environment influence the addition pathway. Several mechanistic scenarios are now recognized, differing with respect to the energies and timing of the bond‐forming processes. While technical challenges still exist, the field has advanced to such an extent that full‐scale simulations of the additions of Michael acceptors to protein thiol groups are now possible. This article is categorized under: Structure and Mechanism Reaction Mechanisms and Catalysis
EBC‐232 and 323: A Structural Conundrum Necessitating Unification of Five In Silico Prediction and Elucidation Methods**
Publisher: Wiley
Date: 30-08-2020
Abstract: Structurally unique halimanes EBC‐232 and EBC‐323, isolated from the Australian rainforest plant Croton insularis , proved considerably difficult to elucidate. The two diastereomers, which consist an unusual oxo‐6,7‐spiro ring system fused to a dihydrofuran, were solved by unification and consultation of five in silico NMR elucidation and prediction methods [i.e., ACDLabs, olefin strain energy (OSE), DP4, DU8+ and TD DFT CD]. Structure elucidation challenges of this nature are prime test case ex les for empowering future AI learning in structure elucidation.
Should Contemporary Density Functional Theory Methods Be Used to Study the Thermodynamics of Radical Reactions?
Publisher: American Chemical Society (ACS)
Date: 22-09-2007
DOI: 10.1021/JP075837W
Abstract: The performance of a variety of DFT functionals (BLYP, PBE, B3LYP, B3P86, KMLYP, B1B95, MPWPW91, MPW1B95, BB1K, MPW1K, MPWB1K, and BMK), together with the ab initio methods RHF, RMP2, and G3(MP2)-RAD, and with ONIOM methods based on combinations of these procedures, is examined for calculating the enthalpies of a range of radical reactions. The systems studied include the bond dissociation energies (BDEs) of R-X (R = CH3, CH2F, CH2OH, CH2CN, CH2Ph, CH(CH3)Ph, C(CH3)2Ph X = H, CH3, OCH3, OH, F), RCH(Ph)-X (R = CH3, CH3CH2, CH(CH3)2, C(CH3)3, CH2F, CH2OH, CH2CN X = H, F), R-TEMPO (R = CH3, CH2CH3, CH(CH3)2, C(CH3)3, CH2CH2CH3, CH2F, CH2OH, CH2CN, CH(CN)CH3, CH(Cl)CH3 TEMPO = 2,2,6,6,-tetramethylpiperidin-1-yloxyl) and HM1M2-X (M1, M2 = CH2CH(CH3), CH2CH(COOCH3), CH2C(CH3)(COOCH3) X = Cl, Br), the beta-scission energies of RXCH2* and RCH2CHPh* (R = CH3, CH2CH3, CH(CH3)2, C(CH3)3 X = O, S, CH2), and the enthalpies of several radical addition, ring-opening, and hydrogen- and chlorine-transfer reactions. All of the DFT methods examined failed to provide an accurate description of the energetics of the radical reactions when compared with benchmark G3(MP2)-RAD values, with all methods tested showing unpredictable deviations of up to 40 kJ mol-1 or more in some cases. RMP2 also shows large deviations from G3(MP2)-RAD in the absolute values of the enthalpies of some types of reaction and, although it fares somewhat better than the DFT methods in modeling the relative values, it fails for substituents capable of strongly interacting with the unpaired electron. However, it is possible to obtain cost-effective accurate calculations for radical reactions using ONIOM-based procedures in which a high-level method, such as G3(MP2)-RAD, is only used to model the core reaction (which should contain all substituents alpha to the reaction center), and the full system is modeled using a lower-cost procedure such as RMP2.
Investigation of the identity of the nucleophile initiating the hydrolysis of phosphate esters catalyzed by dinuclear mimics of metallohydrolases
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.JINORGBIO.2016.02.008
Abstract: di-Zinc(II) complexes of the ligands 2,6-bis((bis(2-methoxyethyl)amino)methyl)-4-methylphenol (HL1), 2,6-bis(bis(hydroxyethyl)aminomethyl)-4-methylphenol (HL2) and 2,6-bis((hydroxyethyl)(methoxyethyl)-aminomethyl)-4-methylphenol (HL3) have been prepared and characterized. The three ligands differ in their donor types, having ether donors (HL1), alkoxido donors (HL2) and both ether and alkoxido donors (HL3). These differences allowed an investigation into the role of the potential nucleophiles in the hydrolysis reaction with the phosphodiester substrate bis(2,4-dinitrophenyl)phosphate (BDNPP). In addition, the di-Mg(II) complex of ligand HL2 was prepared in order to examine the potential for Mg(II) to replace Zn(II) in these biomimetic systems. Kinetically relevant pK
Mechanistic Studies on the Base-Promoted Conversion of Alkoxy-Substituted, Ring-Fused gem-Dihalocyclopropanes into Furans: Evidence for a Process Involving Electrocyclic Ring Closure of a Carbonyl Ylide Intermediate
Publisher: American Chemical Society (ACS)
Date: 03-10-2018
Abstract: The mechanism associated with the base-promoted conversion of alkoxy-substituted and ring-fused gem-dihalocyclopropanes such as 40 into annulated furans has been explored. Treatment of compound 40 with potassium tert-butoxide affords a mixture of furans 23/27 and 41, an outcome that suggests the intermediacy of the slowly interconverting carbonyl ylides 42 and 43 that undergo rapid [1,5]-electrocyclizations and subsequent dehydrohalogenation to afford the observed products. This proposal is supported by ab initio MO and DFT calculations that also suggest a vinylcarbene insertion pathway is less likely to be operative.
Mechanistic Aspects of Hydrosilane/Potassium tert-Butoxide (HSiR3/KOtBu)-Mediated Reactions
Publisher: American Chemical Society (ACS)
Date: 23-03-2020
Effects of substituents on the stabilities of phosphonyl radicals and their hydroxyphosphinyl tautomers
Publisher: American Chemical Society (ACS)
Date: 28-07-2007
DOI: 10.1021/JP072358O
Abstract: High-level ab initio quantum chemical methods have been used to calculate the radical stabilization energies (RSEs) of phosphonyl radicals XYP(=O)* bearing a range of substituents X and Y. The main influences on these radicals' stabilities are sigma-effects. Due to the high positive charge on phosphorus, sigma-withdrawal is destabilizing, and sigma-donation is stabilizing. The pyramidal geometry at phosphorus minimizes the effect of stabilization by pi-delocalization, while the potentially stabilizing effect of lone-pair donation is outweighed by concomitant sigma-withdrawal. Thus, the calculated RSEs of phosphonyl radicals XHP(=O)* increase in the order X = F < Me(3)N+ < MeO < CF3 < tBu < Me(2)N < NC < H < Ph < MeS < Me(3)Si. The tautomeric hydroxyphosphinyl radicals X(OH)P. exhibit a different set of substituent effects, with RSEs increasing in the order X = CF3 < Me(2)N < Me(3)N+ < MeO < (t)Bu < H < MeS < Me(3)Si < F < NC < Ph. In these radicals, both the sigma- and pi-properties of the X substituent influence stability, in tandem with those of the OH group. A comparison of the absolute enthalpies of isomeric phosphonyl and hydroxyphosphinyl radicals indicates that the hydroxyphosphinyl radicals X(OH)P* are more stable than the phosphonyl radicals XYP(=O)*. This is not a common situation in phosphorus chemistry. It is primarily attributed to the greater phosphorus p character of the singly occupied molecular orbital (SOMO) in the hydroxyphosphinyl radicals compared with the phosphonyl tautomers. As in closed-shell phosphorus species, the magnitude of the effect is modulated by the electronegativity of the substituent X.
Aromatic Interactions as Control Elements in Stereoselective Organic Reactions
Publisher: American Chemical Society (ACS)
Date: 24-07-2013
DOI: 10.1021/AR3000794
Does H3O+ Really Act as a Ligand in the Solid State?
Publisher: American Chemical Society (ACS)
Date: 23-08-2021
Synthetic studies towards the mulberry Diels–Alder adducts: H-bond accelerated cycloadditions of chalcones
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C2OB25115A
Abstract: The methyl ether derivatives 2, 4 and 6 of the mulberry Diels-Alder adducts chalcomoracin (1) and mulberrofuran C (3) and kuwanon J (5) respectively have been synthesized by a thermal [4 + 2]-cycloaddition reaction between a chalcone and dehydroprenyl diene. A H-bonded ortho OH substituent on the chalcone was found to be essential for Diels-Alder reactivity. Density functional theory calculations show that the OH group lowers the barrier for the Diels-Alder reaction by 2-3 kcal mol(-1) compared with OMe. The acceleration by the OH group is traced to two transition-state effects: a stronger diene-chalcone interaction and better planarity of the aryl-diene unit.
Croton insularis introduces the seco-casbane class with EBC-329 and the first casbane endoperoxide EBC-324.
Publisher: Royal Society of Chemistry (RSC)
Date: 02-09-2014
DOI: 10.1039/C4CC05413J
Abstract: Investigation of Croton insularis afforded the first in class seco-casbane diterpene, EBC-329. A highly oxidised casbane, EBC-324, was also isolated. The structural motif within EBC-324, which consists of an epoxidised hemi-acetal endoperoxide, is new to the casbane family.
Control of Regioselectivity and Stereoselectivity in (4+3) Cycloadditions of Chiral Oxyallyls with Unsymmetrically Disubstituted Furans
Publisher: American Chemical Society (ACS)
Date: 31-07-2013
DOI: 10.1021/JO3011792
Outcomes of Importance to Patients in Reproductive Genetic Carrier Screening: A Qualitative Study to Inform a Core Outcome Set
Publisher: MDPI AG
Date: 12-08-2022
DOI: 10.3390/JPM12081310
Abstract: There is significant heterogeneity in the outcomes assessed across studies of reproductive genetic carrier screening (RGCS). Only a small number of studies have measured patient-reported outcomes or included patients in the selection of outcomes that are meaningful to them. This study was a cross-sectional, qualitative study of 15 patient participants conducted to inform a core outcome set. A core outcome set is an approach to facilitate standardisation in outcome reporting, allowing direct comparison of outcomes across studies to enhance understanding of impacts and potential harms. The aim of this study was to incorporate the patient perspective in the development of a core outcome set by eliciting a detailed understanding of outcomes of importance to patients. Data were collected via online, semi-structured interviews using a novel method informed by co-design and the nominal group technique. Data were analysed using reflexive thematic analysis. Outcomes elicited from patient stakeholder interviews highlighted several under-explored areas for future research. This includes the role of grief and loss in increased risk couples, the role of empowerment in conceptualising the utility of RGCS, the impact of societal context and barriers that contribute to negative experiences, and the role of genetic counselling in ensuring that information needs are met and informed choice facilitated as RGCS becomes increasingly routine. Future research should focus on incorporating outcomes that accurately reflect patient needs and experience.
Understanding the Mechanistic Requirements for Efficient and Stereoselective Alkene Epoxidation by a Cytochrome P450 Enzyme
Publisher: American Chemical Society (ACS)
Date: 02-2021
Enabling Aromatic Hydroxylation in a Cytochrome P450 Monooxygenase Enzyme through Protein Engineering.
Publisher: Wiley
Date: 06-10-2022
Abstract: The cytochrome P450 (CYP) family of heme monooxygenases catalyse the selective oxidation of C-H bonds under ambient conditions. The CYP199A4 enzyme from Rhodopseudomonas palustris catalyses aliphatic oxidation of 4-cyclohexylbenzoic acid but not the aromatic oxidation of 4-phenylbenzoic acid, due to the distinct mechanisms of aliphatic and aromatic oxidation. The aromatic substrates 4-benzyl-, 4-phenoxy- and 4-benzoyl-benzoic acid and methoxy-substituted phenylbenzoic acids were assessed to see if they could achieve an orientation more amenable to aromatic oxidation. CYP199A4 could catalyse the efficient benzylic oxidation of 4-benzylbenzoic acid. The methoxy-substituted phenylbenzoic acids were oxidatively demethylated with low activity. However, no aromatic oxidation was observed with any of these substrates. Crystal structures of CYP199A4 with 4-(3'-methoxyphenyl)benzoic acid demonstrated that the substrate binding mode was like that of 4-phenylbenzoic acid. 4-Phenoxy- and 4-benzoyl-benzoic acid bound with the ether or ketone oxygen atom hydrogen-bonded to the heme aqua ligand. We also investigated whether the substitution of phenylalanine residues in the active site could permit aromatic hydroxylation. Mutagenesis of the F298 residue to a valine did not significantly alter the substrate binding position or enable the aromatic oxidation of 4-phenylbenzoic acid however the F182L mutant was able to catalyse 4-phenylbenzoic acid oxidation generating 2'-hydroxy-, 3'-hydroxy- and 4'-hydroxy metabolites in a 83 : 9 : 8 ratio, respectively. Molecular dynamics simulations, in which the distance and angle of attack were considered, demonstrated that in the F182L variant, in contrast to the wild-type enzyme, the phenyl ring of 4-phenylbenzoic acid attained a productive geometry for aromatic oxidation to occur.
Reactivity of phosphiranes toward nucleophiles: Theoretical and experimental investigations
Publisher: Wiley
Date: 03-2008
DOI: 10.1002/HC.20405
Origins of aryl substituent effects on the stereoselectivities of additions of silyl enol ethers to a chiral oxazolinium ion
Publisher: American Chemical Society (ACS)
Date: 22-11-2011
DOI: 10.1021/OL202911V
Abstract: Density functional theory calculations are reported that reveal the role of aromatic interactions in the additions of aryl-substituted silyl enol ethers to a chiral oxazolinium ion. Aryl-substituted silyl enol ethers give the opposite diastereomer of the adduct than do aliphatic silyl enol ethers, due to a combination of attractive cation-π and CH-π interactions, reduced steric repulsion, and lower torsional strain in the more "crowded" transition state.
Computational discoveries of reaction mechanisms: recent highlights and emerging challenges
Publisher: Royal Society of Chemistry (RSC)
Date: 2022
DOI: 10.1039/D1OB02139G
Abstract: This review surveys the ways in which theoretical calculations have uncovered new insights into reaction mechanisms, illustrated by ex les from three distinct fields of organic chemistry.
Non-classical MHC class I molecules regulating natural killer cell function
Publisher: Informa UK Limited
Date: 03-2013
DOI: 10.4161/ONCI.23336
Kinetics and Thermodynamics of Reversible Thiol Additions to Mono- and Diactivated Michael Acceptors: Implications for the Design of Drugs That Bind Covalently to Cysteines
Publisher: American Chemical Society (ACS)
Date: 08-11-2016
Abstract: Additions of cysteine thiols to Michael acceptors underpin the mechanism of action of several covalent drugs (e.g., afatinib, osimertinib, ibrutinib, neratinib, and CC-292). Reversible Michael acceptors have been reported in which an additional electron-withdrawing group was added at the α-carbon of a Michael acceptor. We have performed density functional theory calculations to determine why thiol additions to these Michael acceptors are reversible. The α-EWG group stabilizes the anionic transition state and intermediate of the Michael addition, but less intuitively, it destabilizes the neutral adduct. This makes the reverse reaction (elimination) both faster and more thermodynamically favorable. For thiol addition to be reversible, the Michael acceptor must also contain a suitable substituent on the β-carbon, such as an aryl or branched alkyl group. Computations explain how these structural elements contribute to reversibility and the ability to tune the binding affinities and the residence times of covalent inhibitors.
Intramolecular oxyallyl-carbonyl (3 + 2) cycloadditions
Publisher: American Chemical Society (ACS)
Date: 04-2013
DOI: 10.1021/JA312459B
Do anti-Bredt natural products exist? Olefin strain energy as a predictor of isolability
Publisher: Wiley
Date: 29-07-2015
Abstract: Bredt's rule holds a special place in the realm of physical organic chemistry, but its application to natural products chemistry—the field in which the rule was originally formulated—is not well defined. Herein, the use of olefin strain (OS) energy as a readily calculated predictor of the stability of natural products containing a bridgehead alkene is introduced. Schleyer first used OS energies to classify parent bridgehead alkenes into "isolable", "observable", and "unstable" classes. OS calculations on natural products, using contemporary forcefield methods, unequivocally predict all structurally verified bridgehead alkene natural products to be "isolable". Thus, when one assigns the structure of a putative bridgehead alkene natural product, an OS in the "observable" or "unstable" ranges is a red flag for error.
Quantum-chemical studies of RAFT polymerization: methodology, structure-reactivity correlations and kinetic implications
Publisher: Wiley
Date: 23-01-2008
Structures of a non-ribosomal peptide synthetase condensation domain suggest the basis of substrate selectivity
Publisher: Springer Science and Business Media LLC
Date: 04-05-2021
DOI: 10.1038/S41467-021-22623-0
Abstract: Non-ribosomal peptide synthetases are important enzymes for the assembly of complex peptide natural products. Within these multi-modular assembly lines, condensation domains perform the central function of chain assembly, typically by forming a peptide bond between two peptidyl carrier protein (PCP)-bound substrates. In this work, we report structural snapshots of a condensation domain in complex with an aminoacyl-PCP acceptor substrate. These structures allow the identification of a mechanism that controls access of acceptor substrates to the active site in condensation domains. The structures of this complex also allow us to demonstrate that condensation domain active sites do not contain a distinct pocket to select the side chain of the acceptor substrate during peptide assembly but that residues within the active site motif can instead serve to tune the selectivity of these central biosynthetic domains.
Structural Integration of Carbazole and Tetraphenylethylene: Ultrafast Excited‐State Relaxation Dynamics and Efficient Electroluminescence
Publisher: Wiley
Date: 25-02-2021
Developing Cyclic Peptide Heteroatom Interchange: Synthesis and DFT Modelling of a HI‐Ascidiacyclamide Isomer
Publisher: Wiley
Date: 15-06-2018
Cyclic 1,3-dipoles or acyclic phosphonium ylides? Electronic characterization of Montréalones
Publisher: American Chemical Society (ACS)
Date: 11-07-2008
DOI: 10.1021/JA802646F
Abstract: The structural features of a recently introduced class of 1,3-dipolar reagents have been computed by density functional theory and ab initio methods. The reagents are formally derived from Münchnones by replacement of the C O group with a PR3 unit. The parent species (PR3 = PH3) shows a long P...O interaction (2.55 A at the B3LYP/6-31+G(d) level), together with a nonplanar ring, and is best described as a weakly chelated acylamino-phosphonium ylide. The corresponding acyclic form, in which the P...O interaction is absent, is predicted to be 2-3 kcal mol-1 higher in enthalpy. Variation of the phosphorus substituents exerts a marked effect on the P...O distance, with electron-withdrawing groups favoring a covalent interaction [P...O 1.97 A for PR3 = PPh(catechyl)] and electron-donating groups favoring a weak interaction [P...O 3.92 A for PR3 = PPh3]. However, this variation has little effect on the relative energies of the cyclic and acyclic forms. The barriers for concerted cycloadditions with ethylene are 22.8 kcal mol-1 (PH3), 31.7 kcal mol-1 (PPh3), and 16.2 kcal mol-1 [PPh(catechyl) with axial O], which correspond with experimental observations and follow the same trend as the energies required to distort the dipole to the TS geometry.
A comparison of orbital interactions in the additions of phosphonyl and acyl radicals to double bonds
Publisher: Royal Society of Chemistry (RSC)
Date: 2008
DOI: 10.1039/B714597G
Abstract: Calculation of the barriers for addition of the H2P(=O) and HC(=O) radicals to alkenes, at the CCSD(T)/aug-cc-pVDZ//BHandHLYP/6-311G** level, indicates that both radicals display ambiphilic behaviour. For the HC(=O) radical this behaviour occurs because a secondary orbital interaction of the type pi*(C=O)<--HOMO acts in conjunction with the primary SOMO LUMO interaction. For the H2P(=O) radical, on the other hand, the much higher-lying LUMO (the sigma*P-O orbital) allows for only minimal secondary interaction, and this radical's ambiphilic behaviour is therefore reflective of a balance between SOMO-->LUMO and SOMO<--HOMO interactions.
Claisen Rearrangements of Benzyl Vinyl Ethers and Heterobenzyl Vinyl Ethers
Publisher: Georg Thieme Verlag KG
Date: 07-03-2018
Abstract: The Claisen rearrangement of benzylic substrates (benzyl vinyl ethers) has received considerably less attention than its well-known aliphatic and normal aromatic variants. Here, we review the rearrangement of both benzylic and heterobenzylic substrates, with ex les of the reaction’s use in the synthesis of natural products and drug-like molecules. 1 Introduction 2 Early Attempts at the Benzyl-Claisen Rearrangement 3 Successful Benzylic Ex les 4 Heterobenzylic Ex les 5 Conclusion
C-5 Epimerisation of d-Mannopyranosyl Fluorides: The Influence of Anomeric Configuration on Radical Reactivity
Publisher: Georg Thieme Verlag KG
Date: 07-08-2023
DOI: 10.1055/A-2149-4586
Abstract: The fluorine-directing effect has so far been exploited to provide short and efficient synthetic routes to rare L-ido sugars. However, the importance of anomeric configuration to its success has remained experimentally unverified. We now report on the synthesis of α- and β-configured per-O-benzoylated mannopyranosyl fluorides and initially show that their reactivity towards photo-bromination is strongly dependent on the anomeric configuration. The stereochemical basis of the fluorine-directing effect is then validated by revealing the striking difference in stereoselectivity observed for the free radical reductions of the isolated 5-C-bromo sugars. This work importantly provides a synthetic route to a donor-functionalised derivative of L-gulose and reveals new insights into the behaviour of glycosyl radicals.
Experimental and theoretical insights into the mechanisms of sulfate and sulfamate ester hydrolysis and the end products of type i sulfatase inactivation by aryl sulfamates
Publisher: American Chemical Society (ACS)
Date: 20-02-2014
DOI: 10.1021/JO4026513
Abstract: Type I sulfatases catalyze the hydrolysis of sulfate esters through S-O bond cleavage and possess a catalytically essential formylglycine (FGly) active-site residue that is post-translationally derived from either cysteine or serine. Type I sulfatases are inactivated by aryl sulfamates in a time-dependent, irreversible, and active-site directed manner consistent with covalent modification of the active site. We report a theoretical (SCS-MP2//B3LYP) and experimental study of the uncatalyzed and enzyme-catalyzed hydrolysis of aryl sulfates and sulfamates. In solution, aryl sulfate monoanions undergo hydrolysis by an S(N)2 mechanism whereas aryl sulfamate monoanions follow an S(N)1 pathway with SO2NH as an intermediate theory traces this difference to the markedly greater stability of SO2NH versus SO3. For Pseudomonas aeruginosa arylsulfatase-catalyzed aryl sulfate hydrolysis, Brønsted analysis (log(V(max)/K(M)) versus leaving group pK(a) value) reveals β(LG) = -0.86 ± 0.23, consistent with an S(N)2 at sulfur reaction but substantially smaller than that reported for uncatalyzed hydrolysis (β(LG) = -1.81). Common to all proposed mechanisms of sulfatase catalysis is a sulfated FGly intermediate. Theory indicates a ≥26 kcal/mol preference for the intermediate to release HSO4(-) by an E2 mechanism, rather than alkaline phosphatase-like S(N)2 substitution by water. An evaluation of the stabilities of various proposed end-products of sulfamate-induced sulfatase inactivation highlights that an imine N-sulfate derived from FGly is the most likely irreversible adduct.
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University Of California Los Angeles
Location: United States of America
Related Funding Activities
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Amount: $355,100.00
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View Funded ActivityDiscovery Projects - Grant ID: DP180103047
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Amount: $185,540.00
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View Funded ActivityDiscovery Projects - Grant ID: DP0985623
Start Date: 10-2009
End Date: 10-2012
Amount: $244,591.00
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View Funded ActivityARC Future Fellowships - Grant ID: FT120100632
Start Date: 12-2012
End Date: 12-2017
Amount: $622,868.00
Funder: Australian Research Council
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