5 research outputs found
Insights into the Lactonase Mechanism of Serum Paraoxonase 1 (PON1): Experimental and Quantum Mechanics/Molecular Mechanics (QM/MM) Studies
No full textSerum paraoxonase 1 (PON1) is a versatile enzyme for the hydrolysis of various substrates (e.g., lactones, phosphotriesters) and for the formation of a promising chemical platform gamma-valerolactone. Elucidation of the PQNL-catalyzed,lactonase reaction mechanism is very important for, understanding the enzyme function and for engineering this enzyme for specific applications. Kinetic study and hybrid quantum mechanics/molecular mechanics (QM/MM) method were used to investigate the PONT-catalyzed lactonase reaction of gamma-butyrolactone (GBL) and (R)-gamma-valerolactone (GVL). The activation energies obtained from the QM/MM calculations were in good agreement with the experiments. Interestingly, the QM/MM energy barriers at MP2/3-21G(d,p) level for the lactonase of GVL and GBL were respectively 14.3-16.2 and 11.5-131 kcal/mol, consistent with the experimental values (15.57 and 14.73 kcal/mol derived from respective k(cat) values of 36.62 and 147.21 s(-1)). The QM/MM energy barriers at MP2/6-31G(4) and MP2/6-31G(d,p), levels were also in relatively good agreements with the experiments. Importantly, the difference in the QM/MM energy barriers at MP2 level with all investigated basis sets for the lactonase of GVL and GBL were in excellent agreement With the experiments (09-3.1 and 0.8 kcal/mol, respectively). A detailed mechanism for the PON1-catalyzed lactonase reaction was also proposed in this studyclos
Enantioselective Total Synthesis of Lycoposerramine‑Z Using Chiral Phosphoric Acid Catalyzed Intramolecular Michael Addition
No full textA new
enantioselective total synthesis of phlegmarine-type Lycopodium alkaloid lycoposerramine-Z (1) has
been accomplished, using one-pot chemoselective sequential additions
of two different Grignard reagents to the bis-Weinreb-amide intermediate
and an efficient construction of the fully fuctionalized cyclohexanone
intermediate with a chiral phosphoric acid catalyzed enantioselective
intramolecular Michael addition
Unified Total Synthesis of Tetracyclic Diquinane Lycopodium Alkaloids (+)-Paniculatine, (−)-Magellanine, and (+)-Magellaninone
No full textA unified route for the total synthesis
of three tetracyclic diquinane Lycopodium alkaloids (+)-paniculatine, (−)-magellanine,
and (+)-magellaninone has been accomplished in 13–14 overall
steps based on late-stage diverse transformations from an advanced
tetracyclic common intermediate. In the established synthesis, quick
formation of the two five-membered rings was efficiently achieved
by an intramolecular reductive coupling of ketone–carbonyl
and ester–carbonyl and an organocatalytic intramolecular Michael
addition of aldehyde-derived enamine to an internal enone functionality
with satisfactory redox and step economies and excellent stereoselectivities,
providing the requisite tricyclic carbo-framework possessing multiple
dense stereogenic centers, and an intramolecular reductive amination
finally furnished the essential piperidine ring
Jacobian Code Generated by Source Transformation and Vertex Elimination can be as Efficient as Hand-Coding
No full textThis article presents the first extended set of results from ELIAD, a source-
transformation implementation of the vertex-elimination Automatic
Differentiation approach to calculating the Jacobians of functions defined by
Fortran code (Griewank and Reese, Automatic Differentiation of Algorithms:
Theory, Implementation, and Application, 1991, pp. 126-135). We introduce the
necessary theory in terms of well known algorithms of numerical linear algebra
applied to the linear, extended Jacobian system that prescribes the relationship
between the derivatives of all variables in the function code. Using an example,
we highlight the potential for numerical instability in vertex-elimination. We
describe the source transformation implementation of our tool ELIAD and present
results from five test cases, four of which are taken from the MINPACK-
2 collection (Averick et al, Report ANL/MCS-TM-150, 1692) and for which hand-
coded Jacobian codes are available. On five computer/compiler platforms, we show
that the Jacobian code obtained by ELIAD is as efficient as hand-coded Jacobian
code. It is also between 2 to 20 times more efficient than that produced by
current, state of the art, Automatic Differentiation tools even when such tools
make use of sophisticated techniques such as sparse Jacobian compression. We
demonstrate the effectiveness of reverse-ordered pre-elimination from the
(successively updated) extended Jacobian system of all intermediate variables
used once. Thereafter, the monotonic forward/reverse ordered eliminations of all
other intermediates is shown to be very efficient. On only one test case were
orderings determined by the Markowitz or related VLR heuristics found superior.
A re-ordering of the statements of the Jacobian code, with the aim of reducing
reads and writes of data from cache to registers, was found to have mixed
effects but could be very beneficial
Enantioselective Total Synthesis of (+)-Sieboldine A and Analogues Thereof
No full textAn 11-step enantioselective total synthesis of (+)-sieboldine
A
(1) has been accomplished from (5R)-methylcyclohex-2-en-1-one
(16), in which an intramolecular ketone/ester reductive
coupling followed by one-pot acidic treatment to quickly construct
the unique oxa-spiroacetal and a TsOH-catalyzed displacement to directly
form the characteristic N-hydroxyazacyclononane ring
successfully served as the key methodologies. Moreover, several full-skeleton
analogues of 1 were also synthesized on the basis of
the advanced intermediates, and their inhibitory effects on electric
eel acetylcholinesterase were examined
