boxing clever with comfa · boxing clever with comfa james melville. overview • stability – box...
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Boxing Clever with CoMFA
James Melville
Overview
• Stability– Box versus smooth
• Application– Catalyst design
Smooth cut-off
24
26
28
30
0 0.02 0.04 0.06
r / Å
Eele
c /
kca
l m
ol-1
AbruptSmooth
Box cutoff
2/3
Aldosterone
Comparison - steric
-1
7.5
16
24.5
33
-12 -5.5 1 7.5 14r / Å
Evd
w /
kcal
mol
-1
smoothbox
Comparison - electrostatic
-9
-2.5
4
-14 -7.5 -1 5.5 12
r / Å
Ees
p / k
cal m
ol-1
smoothbox
Stability Analysis
• 31 CoMFA steroids
• 38 D2 antagonists– Boström et al. 2003
• 34 polychlorinated dibenzofurans– Lukacova and Balaz 2003
Parameters
• 2Å lattice
• 27 displacements of 0.1Å
• Look at mean LOO q2
• AM1 partial charges
q2 – Steric only
0.73 ± 0.020.71 ± 0.01Dibenzofurans
0.76 ± 0.020.74 ± 0.02D2 antagonists
0.68 ± 0.010.71 ± 0.01Steroids
BoxSmooth
q2 – Electrostatic only No column dropping, 1/r
0.65 ± 0.010.30 ± 0.48Dibenzofurans
0.47 ± 0.160.20 ± 0.13D2 antagonists
0.64 ± 0.060.53 ± 0.11Steroids
BoxSmooth
q2 – Electrostatic only Column dropping, 1/r
0.73 ± 0.000.75 ± 0.01Dibenzofurans
0.81 ± 0.010.80 ± 0.02D2 antagonists
0.71 ± 0.010.69 ± 0.01Steroids
BoxSmooth
q2 – Steric and Electrostatic Column dropping, 1/r
0.74 ± 0.000.74 ± 0.01Dibenzofurans
0.79 ± 0.000.79 ± 0.01D2 antagonists
0.72 ± 0.010.72 ± 0.01Steroids
BoxSmooth
Conclusions
• Standard parameters are stable
• Column dropping increases stability
• Box method can also help
• Number of components less predictable
• Much smaller differences at 1Å
Ph2C=N CO2tBu
Ph2C=N
Br
CO2tBu
Ph2C=N
Br
CO2tBu
(S)
(R)
Application: Asymmetric Catalysis
Catalyst Core
N
O
NH Br+
R2 R1
Substituents – R1
I F3C
FF
F FF
F
Substituents – R2
BrI
F3C FF
F FF
F
O
O
OO
Experimental observations
• 13 different substituents
• 88 catalysts
• ee range: 16%-93%
• y = ln(%S/%R)
Parameters
• MMFF94 optimisation
• Least squares atom fit
• Gasteiger-Hückel atomic charges
• 2Å lattice - ~1200 descriptors
• LOO cross-validation
Results – steric and electrostatic
• 1/r, column-dropping, smooth:
q2 = 0.73
• 1, no column-dropping, box:
q2 = 0.72
But…
Results
• 1/r, column-dropping, smooth:
No. Components = 6
• 1, no column-dropping, box:
No. Components = 4
Acknowledgements
• Jonathan Hirst
• EPSRC
• Gatsby Foundation
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