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Paton Research Group Computational Organic Chemistry
http://paton.chem.ox.ac.uk [email protected]
Chemistry Research Laboratory, office 11 (first floor) 01865 275428
Introduction
Theory has played a major role in shaping our understanding of chemistry. More than ever before, computational and theoretical approaches are in widespread use to gain insight into chemical structure, reactivity and selectivity.
The group's research interests focus on solving problems in organic and bio-organic chemistry using theoretical and computational methods. In particular, our research is concerned with prediction and design: we test these designs working in close collaboration with synthetic and crystallographic groups based in Oxford, the UK and the USA. We are supported by state-of-the-art facilities in the Chemistry Research Laboratory and the Oxford Supercomputer Centre.
We are looking to recruit talented and committed scientists interested in the underlying principles of reactivity, mechanism and selectivity.
Designer Catalysts
Predictive Models for Regio- and Stereoselectivity We use high-level calculations to gain insight into the factors that control selectivity in synthesis. In collaboration with the Garg group at UCLA we have developed a new way to understand regioselective nucleophilic addition to substituted benzynes. We were able to predict poor selectivity of 5,6-indolynes and the high selectivity of 6,7-indolynes prior to experiment, and we are now using calculations to design temporary directing groups which can later be removed.
Our predistortion model is a rapid and reliable way to predict the regiochemical outcome of nucleophilic addition to substituted benzynes.
References: a) J. Am. Chem. Soc. 2010, 132, 9335 ; b) J. Am. Chem. Soc. 2010, in press
Catalysis, whether by transition metals or small organic molecules, is of vast importance in synthesis. However, the discovery of new catalysts has traditionally depended on many man-hours of trial-and-error screening. We are interested in using computational predictions for the rational design of new catalysts. Collaborations are in place with the Houk group (UCLA) and experimentalists based in the UK, Germany and the USA to develop computational protocols for the de novo design of catalysts. These methods will be used to screen for stereoselective catalysts which will be subject to experimental verification.
“What I cannot create, I do not understand.” We will study the catalytic mechanism of organocatalysts, design and make predictions and test them in experiment.
An area of current interest is the screening and design of a unnatural enzymes, capable of catalyzing chemical reactions for which there are no naturally-occurring catalysts. We begin by computing the transition state for our desired reaction and then find the ideal positions and orientations of catalytic groups that stabilize the transition state. A large number of known protein folds are screened to see which can incorporate the catalytic groups and substrate in the desired geometry. The best designs are then tested in experiment.
Computational design of an unnatural enzyme to catalyze isoxazole ring-opening.
NO2
N OH
NO2
COHN
X'
X
X'
X
Nuc
NucX'
Increased Ring Distortion
Decreased Ring Distortion
NucX
X'
XNuc
H
X'
XH
Nucpre-distorted aryne
!+!-
124
129
135
125
143
117
110
124
130
127109
109
133
121
124
110129
111120
125143
Unravelling Mechanisms
Calculations are used to shed light on mechanism: to assess the viability of a proposed mechanism we compute the energies of all intermediates and transition states that connect reactant to product. The rearrangement of 5-dialkylamino-2,4-pentadienals to Z-α,β,γ,δ-unsaturated amides occurs upon heating, and was presumed to proceed via a series of pericyclic rearrangements. State-of-the-art calculations performed in collaboration with experimentalists in the Vanderwal group (UC Irvine) were used to discount a number of possible mechanisms leaving only one plausible pathway.
Our proposed mechanism of Zincke aldehyde thermal rearrangement.
Gold catalyzes a number of additions to π-bonds. In collaboration with the experimentalists in the USA, we used oxygen isotopic labelling and calculations to show that the rearrangement of alkynyl-esters follows an unprecedented 4+2 mechanism following Au-catalyzed oxygen addition to the alkyne. Work is now underway to predict which substrates will undergo similar rearrangements.
Labelling and computational studies show the 4+2, and not the 2+2 mechanism occurs in gold catalyzed intramolecular oxygen transfer.
References: Studies on pericyclic reactions a) J. Am. Chem. Soc. 2010, 132, 9335; b) J. Am. Chem. Soc. 2010, submitted. On gold catalysis a) Angew. Chem. Int. Ed. 2010, article online; b) Org. Lett. 2009, 11, 2237
Biocatalysts
The exquisite control achieved by enzymes in the biosynthesis of natural product molecules is an ongoing source of interest. The mechanism of biosynthesis of polyether natural products from their polyepoxide precursors is particularly intriguing since nature often catalyzes such transformations selectively, giving products that are not seen in the same reaction in solution. We are currently collaborating with crystallographers to understand how the enzymatic synthesis of polyethers proceeds via a six-endo process in the active site, contrary to the five-exo reaction that occurs in solution.
Calculations and X-ray crystallography will reveal how the innate preference for 5-exo epoxide opening is overturned in the enzymatic synthesis of natural products.
A number of natural products have structures that are incompletely or incorrectly assigned, and therefore present a fertile field for computational structure elucidation. In collaboration with Dr Jonathan Burton (Oxford) and Dr Jonathan Goodman (Cambridge) we are interested in using high-accuracy predictions of 1H and 13C chemical shift and coupling constants to assign the stereostructure of flexible, halogenated natural products.
Computation is used to assign the structure of natural products when many diastereoisomers have similar spectra.
Structure Elucidation of Natural Products
We publish regularly in international journals with high-impact factors. Due to the often collaborative nature of computational research, it is not unusual for PhD students to obtain five or more publications during their studies. For a highlight of recent publications see:
• Indolyne Experimental and Computational Studies: Synthetic Applications and Origins of Selectivities of Nucleophilic Additions Journal of the American Chemical Society 2010, in press • The [4+2], not [2+2], Mechanism Occurs in the Gold-Catalyzed Intramolecular Oxygen Transfer Reaction of 2-Alkynyl-1,5-Diketones Angewandte Chemie International Edition 2010, 49, 9132. • Origins of Stereoselectivity in the trans-Diels-Alder Paradigm. Journal of the American Chemical Society 2010, 132, 9335. • Indolyne and Aryne Distortions and Nucleophilic Regioselectivities Journal of the American Chemical Society 2010, 132, 1267. • Origins of Regioselectivity of Diels-Alder Reactions for the Synthesis of Bisanthraquinone Antibiotic BE-43472B Journal of Organic Chemistry 2010, 75, 922. • Gold(I)-Catalyzed Intermolecular Hydroalkoxylation of Allenes: a DFT Study Organic Letters 2009, 11, 2237. • Stereostructure Assignment of Flexible Five-Membered Rings by GIAO 13C NMR Calculations: Prediction of the Stereochemistry of Elatenyne Journal of Organic Chemistry 2008, 73, 4053.
Further Reading Me2N
O
H
Me2N
OH
E to ZMe2N O[1,5]-H 6!
N
OMeMe
H
6!
Me2N
O
O
AuR
Ph
18O
Me
18O
18O
MeMe
RO
Ph
Me
AuRMe
O
Ph18O
Me
AuRMe
O
Ph
O
AuR
Ph
18O
MeAu
R
Ph
18O
Me
O
18O
R
Me
MeO
Ph
O
R
Me
Me18O
PhAuCl
R = p-MeOC6H4
2+2 pathway
4+2 pathway
OO O O
OO HO
HO
Me
CHO
MeO
O
O
O
O
O
O
O
O
OO
HO
HH
HMeHHH
HHH
MeH Me H H
Me H H HH
Me CHO
MeO
brevetoxin B
O O OOMe
Me
Me
Me
O X
R
HO
O
O
OHH
H H
OO O
HOR
O
O
R
HO
6-endo-tet 5-exo-tetO
R H
O
R
OH OO+
H
O
R1
NO2R2 HNO2
O
R1
R2
+
aldol
Michael addition
Pro
Pro
Asp
