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