57 research outputs found
Aldol Reactions - Isotope Effects, Mechanism and Dynamic Effects
The mechanism of three important aldol reactions and a biomimetic
transamination is investigated using a combination of experimental kinetic isotope
effects (KIEs), standard theoretical calculations and dynamics trajectory
simulations. This powerful mechanistic probe is found to be invaluable in
understanding intricate details of the mechanism of these reactions. The successful
application of variational transition state theory including multidimensional
tunneling to theoretically predict isotope effects, described in this dissertation,
represents a significant advance in our research methodology.
The role of dynamic effects in aldol reactions is examined in great detail. The
study of the proline catalyzed aldol reaction has revealed an intriguing new dynamic
effect - quasiclassical corner cutting - where reactive trajectories cut the corner
between reactant and product valleys and avoid the saddle point. This phenomenon
affects the KIEs observed in this reaction in a way that is not predictable by
transition state theory. The study of the Roush allylboration of aldehydes presents an
example where recrossing affects experimental observations. The comparative study
of the allylboration of two electronically different aldehydes, which are predicted to have different amounts of recrossing, suggests a complex interplay of tunneling and
recrossing affecting the observed KIEs.
The Mukaiyama aldol reaction has been investigated and the results
unequivocally rule out the key carbon-carbon bond forming step as rate-limiting.
This raises several interesting mechanistic scenarios - an electron transfer
mechanism with two different rate-limiting steps for the two components, emerges
as the most probable possibility. Finally, labeling studies of the base catalyzed 1,3-
proton transfer reaction of fluorinated imines point to a stepwise process involving
an azomethine ylide intermediate. It is found that dynamic effects play a role in
determining the product ratio in this reaction
Chiral Brønsted Acid-Catalyzed Asymmetric Synthesis of N-Aryl-cis-aziridine Carboxylate Esters
We report a multi-component asymmetric Brønsted acid-catalyzed aza-Darzens reaction which is not limited to specific aromatic or heterocyclic aldehydes. Incorporating alkyl diazoacetates and, important for high ee's, ortho-tert-butoxyaniline our optimized reaction (i.e. solvent, temperature and catalyst study) affords excellent yields (61–98 %) and mostly >90 % optically active cis-aziridines. (+)-Chloramphenicol was generated in 4 steps from commercial starting materials. A tentative mechanism is outlined
Isotope Effects and Heavy-Atom Tunneling in the Roush Allylboration of Aldehydes
Intermolecular <sup>13</sup>C kinetic isotope effects (KIEs) for the Roush allylboration of <i>p-</i>anisaldehyde were determined using a novel approach. The experimental <sup>13</sup>C KIEs fit qualitatively with the expected rate-limiting cyclic transition state, but they are far higher than theoretical predictions based on conventional transition state theory. This discrepancy is attributed to a substantial contribution of heavy-atom tunneling to the reaction, and this is supported by multidimensional tunneling calculations that reproduce the observed KIEs
The catalytic mechanism of the Suzuki-Miyaura reaction
Abstract: Experimental and theoretical 13C kinetic isotope effects are utilized to obtain atomistic insight into the catalytic mechanism of the Pd(PPh3)4 catalyzed Suzuki-Miyaura reaction of aryl halides and aryl boronic acids. Under catalytic conditions, we establish that oxidative addition of aryl bromides occurs to a 12-electron monoligated palladium complex (Pd(PPh3)). For aryl iodides, the first irreversible step in the catalytic cycle precedes oxidative addition and is shown to be binding of the iodoarene to Pd(PPh3). Our results suggest that the commonly proposed oxidative addition to the 14-electron Pd(PPh3)2 complex can occur only in the presence of excess added ligand or under stoichiometric conditions. The transmetalation step, under catalytic conditions, is shown to proceed via a tetracoordinate boronate (8B4) intermediate with a Pd-O-B linkage
Isotope Effects and Mechanism of the Asymmetric BOROX Brønsted Acid Catalyzed Aziridination Reaction
The mechanism of the chiral VANOL-BOROX
Brønsted acid catalyzed
aziridination reaction of imines and ethyldiazoacetate has been studied
using a combination of experimental kinetic isotope effects and theoretical
calculations. A stepwise mechanism where reversible formation of a
diazonium ion intermediate precedes rate-limiting ring closure to
form the <i>cis-</i>aziridine is implicated. A revised model
for the origin of enantio<i>-</i> and diastereoselectivity
is proposed based on relative energies of the ring-closing transition
structures
Chiral Amino Alcohols via Catalytic Enantioselective Petasis Borono-Mannich Reactions
Chiral amino alcohols are valuable building blocks in the synthesis of drugs, natural products, and
chiral ligands used in enantioselective catalysis. The Petasis borono-Mannich reaction is a
multicomponent condensation reaction of aldehydes, amines, and boronic acids to afford chiral
amines. This report describes a practical, easily scaled, enantioselective Petasis borono-Mannich
reaction of glycolaldehyde, with primary or secondary amines, and boronates catalyzed by BINOLderived catalysts to afford chiral 1,2-amino alcohols in high yields and enantioselectivities. The
reactions are executed at room temperature in ethanol or trifluorotoluene using commercially
available reagents and leverage an inherently attractive feature of the multicomponent reaction; the
ability to use amines and boronates that possess a wide range of structural and electronic properties.
Computational modeling of the diastereomeric transition states using DFT calculations identified a
non-conventional CH…O interaction as a key feature that selectively stabilizes the transition state
leading to the major enantiomer. The enantioselective catalytic reaction exemplifies a truly practical
multicomponent condensation to afford 1,2-amino alcohols in highly enantioenriched form
Transition-state analysis of Trypanosoma cruzi uridine phosphorylase-catalyzed arsenolysis of uridine
Uridine phosphorylase catalyzes the reversible phosphorolysis of uridine and 2′-deoxyuridine to generate uracil and (2-deoxy)ribose 1-phosphate, an important step in the pyrimidine salvage pathway. The coding sequence annotated as a putative nucleoside phosphorylase in the Trypanosoma cruzi genome was overexpressed in Escherichia coli, purified to homogeneity, and shown to be a homodimeric uridine phosphorylase, with similar specificity for uridine and 2′-deoxyuridine, and undetectable activity towards thymidine and purine nucleosides. Competitive kinetic isotope effects (KIEs) were measured and corrected for a forward commitment factor using arsenate as the nucleophile. The intrinsic KIEs are: 1′-(14)C = 1.103, 1,3-(15)N(2) = 1.034, 3-(15)N = 1.004, 1-(15)N = 1.030, 1′-(3)H = 1.132, 2′-(2)H = 1.086 and 5′-(3)H(2) = 1.041 for this reaction. Density functional theory was employed to quantitatively interpret the KIEs in terms of transition state structure and geometry. Matching of experimental KIEs to proposed transition state structures suggests an almost synchronous, S(N)2-like transition state model, in which the ribosyl moiety possesses significant bond order to both nucleophile and leaving group. Natural bond orbital analysis allowed a comparison of the charge distribution pattern between the ground state and the transition state model
Recycling Nicotinamide. The Transition-State Structure of Human Nicotinamide Phosphoribosyltransferase
Human
nicotinamide phosphoribosyltransferase (NAMPT) replenishes
the NAD pool and controls the activities of sirtuins, mono- and poly-(ADP-ribose)
polymerases, and NAD nucleosidase. The nature of the enzymatic transition-state
(TS) is central to understanding the function of NAMPT. We determined
the TS structure for pyrophosphorolysis of nicotinamide mononucleotide
(NMN) from kinetic isotope effects (KIEs). With the natural substrates,
NMN and pyrophosphate (PPi), the intrinsic KIEs of [1′-<sup>14</sup>C], [1-<sup>15</sup>N], [1′-<sup>3</sup>H], and [2′-<sup>3</sup>H] are 1.047, 1.029, 1.154, and 1.093, respectively. A unique
quantum computational approach was used for TS analysis that included
structural elements of the catalytic site. Without constraints (e.g.,
imposed torsion angles), the theoretical and experimental data are
in good agreement. The quantum-mechanical calculations incorporated
a crucial catalytic site residue (D313), two magnesium atoms, and
coordinated water molecules. The TS model predicts primary <sup>14</sup>C, α-secondary <sup>3</sup>H, β-secondary <sup>3</sup>H, and primary <sup>15</sup>N KIEs close to the experimental values.
The analysis reveals significant ribocation character at the TS. The
attacking PPi nucleophile is weakly interacting (<i>r</i><sub>C–O</sub> = 2.60 Å), and the <i>N</i>-ribosidic
C1′–N bond is highly elongated at the TS (<i>r</i><sub>C–N</sub> = 2.35 Å), consistent with an A<sub>N</sub>D<sub>N</sub> mechanism. Together with the crystal structure of the
NMN·PPi·Mg<sub>2</sub>·enzyme complex, the reaction
coordinate is defined. The enzyme holds the nucleophile and leaving
group in relatively fixed positions to create a reaction coordinate
with C1′-anomeric migration from NAM to the PPi. The TS is
reached by a 0.85 Å migration of C1′
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