Demystifying the Magic Methyl Effect - Princeton...
Transcript of Demystifying the Magic Methyl Effect - Princeton...
![Page 1: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/1.jpg)
Demystifying the Magic Methyl Effect
Patricia ZhangMacMillan Group Meeting
June 11, 2015
![Page 2: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/2.jpg)
Demystifying the Magic Methyl Effect
![Page 3: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/3.jpg)
Demystifying the Magic Methyl Effect
"In comparison to its importance to the pharmaceutical industry, the methyl group is,in our opinion, underrepresented in recent synthetic chemistry.
The so-called Magic Methyl Effect: (a general definition)
"a rare but welcome phenomenon" where installation of a methyl group on a drug candidate leds to an increase in potency
"The methyl group, so often considered as chemically inert, is able to alter deeply the pharmacological properties of a molecule."
~a large emphasis on the drastic change in conformation, hence, binding affinity
Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
■ When is the Magic Methyl Effect in play?
Me
O
OHO
HO
OMe
Me H Me
O
OHO
HO
OMe
Me H Me
O
OHO
HO
OMe
Me Me
Me
mevastatinIC50 HMG-CoAR = 5.6 nM
lovastatinIC50 HMG-CoAR = 2.2 nM
Me
simvastatinIC50 HMG-CoAR = 0.9 nM
Bazzini, P.; Wermuth, C. G. In The Practice of Medicinal Chemistry; Academic Press: San Diego, 2008; pp 431-418.
![Page 4: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/4.jpg)
Demystifying the Magic Methyl Effect
■ The Benign Methyl Group - DNA vs RNA
NH
NH
NH
NHMe
O
O
O
O
thymine uracil
NH
N
NH2
ON
NHN
NH NH2
O
N
NN
NH
NH2
■ CH/π-interaction has been studied for Me and purine oligonucleotides to show appreciable change in DNA strand stiffness (important for enzyme recognition of DNA)
Umezawa, Y.; Nishio, M. Nucleic Acids Res. 2002, 30, 2183.
base
O
H/OHO HH
POO-
HO
O-
Nishio, M.; Umezawa, Y.; Hirota, M.; Takeuchi, Y. Tetrahedron 1995, 51, 8665.
DNA RNA
cytosineguanine adenine
![Page 5: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/5.jpg)
Demystifying the Magic Methyl Effect
■ The Benign Methyl Group - DNA vs RNA
NH
NH
NH
NHMe
O
O
O
O
thymine uracil
NH
N
NH2
ON
NHN
NH NH2
O
N
NN
NH
NH2
■ CH/π-interaction has been studied for Me and purine oligonucleotides to show appreciable change in DNA strand stiffness (important for enzyme recognition of DNA)
Umezawa, Y.; Nishio, M. Nucleic Acids Res. 2002, 30, 2183.
base
O
H/OHO HH
POO-
HO
O-
Nishio, M.; Umezawa, Y.; Hirota, M.; Takeuchi, Y. Tetrahedron 1995, 51, 8665.
DNA RNA
cytosineguanine adenine
■ yellow = adenine■ gray = thymine■ red = CH/π-interaction
![Page 6: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/6.jpg)
Demystifying the Magic Methyl Effect
■ The Benign Methyl Group - CH/π-interactions
Umezawa, Y.; Nishio, M. Nucleic Acids Res. 2002, 30, 2183.Nishio, M.; Umezawa, Y.; Hirota, M.; Takeuchi, Y. Tetrahedron 1995, 51, 8665.
Via CH/π-interactions: methyl groups have a greater chance to be involved in an interaction compared to OH due to:
■ more (three) hydrogens
■ multiple simultaneous interactions possible
■ additive free energy effects
CH
HHH
π(donor) σ∗(acceptor)
CH/π-interactions
![Page 7: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/7.jpg)
Demystifying the Magic Methyl Effect
■ Modes of Action
Solubility Conformation
Binding Interactions Metabolism
Current Synthetic Methods
a combination of......
later......
![Page 8: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/8.jpg)
Demystifying the Magic Methyl Effect
■ Modes of Action
Solubility Conformation
Binding Interactions Metabolism
Current Synthetic Methods
a combination of......
later......
![Page 9: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/9.jpg)
Demystifying the Magic Methyl Effect
■ Solubility
Lipophilicity"lipid loving", hydrophobic
General solubility for increased bioavailability
■ important for crossing biomembranes to get to target tissues and for transport through bloodstream
Log P is logarithm of the partitioncoefficient between n-octanol and water
Me
Log P = 2.13 Log P = 2.69
Hydrophilic Effect
Me OHMe
MeOH
Me
MeMe
MeOH
Me
Me
OHMe
OH
Me
Me
Me Me MeMe
MeMe Me
= H2O
+ 3
OH
n-butanol8.2g/100g H2O
n-pentanol2.4g/100g H2O
2-pentanol4.9g/100g H2O
neopentanol12.2g/100g H2O
isobutanol5g/100g H2O
tert-butanolmiscible
■ fewer water molecules needed to be organized, entropic gain with "globular" shape
■ more negative ΔGdesolvation when transitioning from aqueous to membrane
benzene toluene
Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
![Page 10: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/10.jpg)
Demystifying the Magic Methyl Effect
■ Lipophilicity to increase bioavailability
Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
HO
HO
O
HN
Me
morphinestructure elucidated by Sir Robert Robinson
HO
HO
O
HNH
normorphine6-fold reduction in in vivo
analgesic activity
■ dominant ionic interactions for drug catalytic site still maintained
■ more polar nitrogen moiety, harder to pass through blood-brain barrier
codeine3-fold reduction in in vivo
analgesic activity, 200-fold reduction in receptor affinity
O
HO
O
HN
Me
Me
Placement of methyl groups is important:
![Page 11: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/11.jpg)
Demystifying the Magic Methyl Effect
■ Lipophilicity to increase bioavailability
Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
O
OH
O
H
NMe
Placement of methyl groups is important:
N
HN
H-bond donor
HisVI-17TM-VI
O
O H
TM III
AspIII-08
HN
TM VTrpV-10
PheV-13
TM = transmembrane domain
■ ionic interaction with aminiumcation and carboxylate
■ H-bond interaction
■ van der Waals interactions
H
![Page 12: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/12.jpg)
Demystifying the Magic Methyl Effect
■ Lipophilicity to increase bioavailability
Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
O
OH
O
H
NMe
Me
Placement of methyl groups is important:
N
N
weak H-bond acceptor
H
HisVI-17TM-VI
O
O H
TM III
AspIII-08
HN
TM VTrpV-10
PheV-13
TM = transmembrane domain
■ dominant ionic interactions for drug catalytic site still maintained
■ weaker H-bond interaction causes 200-fold reduction inreceptor binding
■ codeine gets metabolized tomorphine
![Page 13: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/13.jpg)
Demystifying the Magic Methyl Effect
■ Lipophilicity to increase bioavailability
Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
O
O
O
H
NMe
Placement of methyl groups is important:
N
HN
H-bond donor
HisVI-17TM-VI
O
O H
TM III
AspIII-08
HN
TM VTrpV-10
PheV-13
TM = transmembrane domain
■ heterocodeine has a 2-fold increase in in vivo activity
■ H-bond interaction
■ methyl allyic ether aids in solubility, hence, passage through central nervous system
H
Me
![Page 14: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/14.jpg)
Demystifying the Magic Methyl Effect
■ Free energy of desolvation
■ more -CH3 groups leads to more spontaneous transfer from aqueous to protein layer
Nemethy, G. Angew. Chem. Int. Ed. 1967, 6, 195-206.Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
O
HONH2
O
HONH2
Me
O
HONH2
Me Me
O
HONH2
O
HONH2
Me
glycine alanine valine leucine isoleucine
■ ΔΔGtransfer of C-H to C-CH3 = 0.8 kcal/mol
■ theoretical ~3.5 fold boost in potency from methylation
MeMe
MeMe
MeMe
Me
Me Me
increasing methyls, decreasing ΔGdesolvation
ΔGtransfer kcal/mol= -1.3 (-0.73) -1.9 (-1.69) -1.9 (-2.42) -1.9 (-2.97)( ) = side chain contribution moving from water to ethanol
Me
Me
Me
Andrews, P. R.; Craik, D. J.; Martin, J. L. J. Med. Chem. 1984, 27, 1648-1657.
![Page 15: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/15.jpg)
Demystifying the Magic Methyl Effect
■ The bigger picture of methylation and potency improvements
Leung, C. S.; Leung, S. S. F.; Tirado-Rives, J.; Jorgensen, W. L. J. Med. Chem. 2012, 55, 4489-4500.Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
■ methylation just as likely to decrease binding affinity as it is to increase
■ rare for addition of Me group to give free energy gain greater than 3 kcal/mol (4 cases, 0.0019%■ 10 fold boost (1.36 kcal/mol) - 8% ■ 100 fold boost (2.7 kcal/mol) - 0.4%
![Page 16: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/16.jpg)
Demystifying the Magic Methyl Effect
■ The bigger picture of methylation and potency improvements
Leung, C. S.; Leung, S. S. F.; Tirado-Rives, J.; Jorgensen, W. L. J. Med. Chem. 2012, 55, 4489-4500.Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
■ methylation just as likely to decrease binding affinity as it is to increase
■ rare for addition of Me group to give free energy gain greater than 3 kcal/mol (4 cases, 0.0019%■ 10 fold boost (1.36 kcal/mol) - 8% ■ 100 fold boost (2.7 kcal/mol) - 0.4%
Magic Methyl Effect - free energy gain from Me addition is or above what is predicted
![Page 17: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/17.jpg)
Demystifying the Magic Methyl Effect
■ How do you invoke the Magic Methyl Effect?
Solubility Conformation
Binding Interactions Metabolism
a combination of......
![Page 18: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/18.jpg)
Demystifying the Magic Methyl Effect
■ How do you invoke the Magic Methyl Effect?
Solubility Conformation
Binding Interactions Metabolism
a combination of......
![Page 19: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/19.jpg)
Demystifying the Magic Methyl Effect
■ Conformational preorganization leads to ~200-fold boost
Leung, C. S.; Leung, S. S. F.; Tirado-Rives, J.; Jorgensen, W. L. J. Med. Chem. 2012, 55, 4489-4500.Angell, R. et al. Bioorg. Med. Chem. Lett. 2008, 18 , 4428-4432.
R
O NH
NH
biphenyl amide inhibitors of p38α kinase
R Ki (nM)
H
Me
Cl
F
OMe
>2500
12
25
460
520
IC50
>16,000
75
160
2900
3300
(inhibitor constant, nM needed to achieve 1/2 max inhibition)
O
O NH
NH
O
O NH
NH
O
Me
rotation out of plane
planarfree rotation
![Page 20: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/20.jpg)
Demystifying the Magic Methyl Effect
■ Conformational preorganization leads to ~200-fold boost
Leung, C. S.; Leung, S. S. F.; Tirado-Rives, J.; Jorgensen, W. L. J. Med. Chem. 2012, 55, 4489-4500.Angell, R. et al. Bioorg. Med. Chem. Lett. 2008, 18 , 4428-4432.
■ methyl in lipophilic pocket - larger groups do not fit■ several hydrophobic interactions with biphenyl■ dihedral angle of o-Me-biphenyl free drug matches the bound conformer best
![Page 21: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/21.jpg)
Demystifying the Magic Methyl Effect
■ Conformational preorganization leads to ~200-fold boost
Leung, C. S.; Leung, S. S. F.; Tirado-Rives, J.; Jorgensen, W. L. J. Med. Chem. 2012, 55, 4489-4500.Angell, R. et al. Bioorg. Med. Chem. Lett. 2008, 18 , 4428-4432.
■ methyl in lipophilic pocket - larger groups do not fit■ several hydrophobic interactions with biphenyl■ dihedral angle of o-Me-biphenyl free drug matches the bound conformer best
![Page 22: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/22.jpg)
Demystifying the Magic Methyl Effect
■ Conformational preorganization leads to 480-fold boost
Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
N
ONN N
Me
H
ON
F
96 nM
α-methylationN
Me
OO
NN
N
N
F
Meπ-stacking
U-shape confirmed by NMR,minimize 1,3-diaxial strain
0.2 nM
under development at Merck for insomina,dual antagonist of orexin-1 and -2 receptors
If α-substituent is
F
CF3
larger alkyl groups
unstable next to heteroatom, not as much steric influence, change in stereoelectronics
risk of violating Lipinski's rules: CF3: ΔMW= 68 g/mol, ΔclogP~0.9, Me: ΔMW= 14 g/mol, ΔclogP~0.5)
too lipophilic, not a good track record of becoming drugs
"In terms of value, a methyl group that leads to a profound improvement in potency is hard to beat."
![Page 23: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/23.jpg)
Demystifying the Magic Methyl Effect
■ Use of methyl group to decrease binding affinity
Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
O
OH
NHClCl
diclofenacKi (µM) COX-1 = 0.01Ki (µM) COX-2 = 0.01
NHClCl
O OO
HNH
OTyr355 N
NH2
HN
Arg120
O
NH
OH
Ser353
NSAID
![Page 24: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/24.jpg)
Demystifying the Magic Methyl Effect
■ Use of methyl group to decrease binding affinity
Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
O
OH
NHClCl
O
OH
NHFCl
Me
diclofenac
lumiracoxib
Ki (µM) COX-1 = 0.01Ki (µM) COX-2 = 0.01
Ki (µM) COX-1 = 3.2Ki (µM) COX-2 = 0.06
NHFCl
O O
OHHN
OTyr355 H2N
NH2
HNArg120
O
NH
OH
Ser353
NSAID, but taken off market due to liver damage
NSAID
Me
no H-bonds
![Page 25: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/25.jpg)
Demystifying the Magic Methyl Effect
■ Methyl group installation around freely rotating bonds
Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
"rationally developed" - combichem-HTS drug discovery tactic
N
NHN
N
Me
HN O
NN
Me
imatinib - Novartistreats chronic myelogenous leukemia
by inhibiting Bcr-Abl kinase
Capdeville, R.; Buchdunger, E.; Zimmermann, J.; Matter, A. Nature Rev. Drug Discovery 2002, 1 , 493.
■ Patients live up to 5 years longer
■ very minimal side effects
■ Bcr-Abl kinase responsible for cell growth of cancer cells
■ first tyrosine-kinase inhibitor on market
![Page 26: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/26.jpg)
Demystifying the Magic Methyl Effect
■ Methyl group installation around freely rotating bonds
Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
N
NHN
N
HN
O
Ar
PKA, TK and Bcr-Ablk inhibitor
N
NHN
N
HN
O
Ar
Me
Bcr-Ablk selectivity over PKCHTS to get scaffold
N
NHN
N
HN
O
Ar
Me N
NHN
N
Me
HN O
Ar
confirmed by X-ray diffraction
Capdeville, R.; Buchdunger, E.; Zimmermann, J.; Matter, A. Nature Rev. Drug Discovery 2002, 1 , 493.
Conformers:
methylation
steric clash
![Page 27: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/27.jpg)
Demystifying the Magic Methyl Effect
■ A change in conformation isn't everything
antihistamines tend to be rigid
Bazzini, P.; Wermuth, C. G. In The Practice of Medicinal Chemistry; Academic Press: San Diego, 2008; pp 431-418.Harms, A. F.; Nauta, W. Th. J. Med. Chem. 1959, 2, 57-77.
ON
Me
Me
diphenhydramine
ON
Me
Me
Orphenadrine
Benadryl
Me
ON
Me
Me
Me rotation out of plane
ON
Me
Me
diphenhydramineToladryl
Me
5-fold reduction in activity
3.7-fold increase in activity2.5-fold decrease in anticholine activity
2.1-fold increase in anticholine activity
![Page 28: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/28.jpg)
Demystifying the Magic Methyl Effect
■ A change in conformation isn't everything
antihistamines tend to be rigid
Bazzini, P.; Wermuth, C. G. In The Practice of Medicinal Chemistry; Academic Press: San Diego, 2008; pp 431-418.Harms, A. F.; Nauta, W. Th. J. Med. Chem. 1959, 2, 57-77.
ON
Me
Me
diphenhydramine
ON
Me
Me
Orphenadrine
Benadryl
Me
ON
Me
Me
Me rotation out of plane
ON
Me
Me
diphenhydramineToladryl
Me
5-fold reduction in activity
3.7-fold increase in activity2.5-fold decrease in anticholine activity
2.1-fold increase in anticholine activity
![Page 29: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/29.jpg)
Demystifying the Magic Methyl Effect
■ Overview of where to place Me groups for most impact
Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
ortho substitution on substituted alkyl rings around two freely rotatable bonds
NNN
Me
Me
159-fold boost
N
N
NN
NH
Me
Me
NH
MeO MeMe
1333-fold boost
NO
N
Me MeMe
F
FMe
HO
Me
97-fold boost
O MeMeMe Me
OMe
598-fold boost
NNMe
OCl
Cl
Me
480-fold boost
Me
Me
O
NH
O
OH
Me
NH
Me
ClCl
2135-fold boost
![Page 30: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/30.jpg)
Demystifying the Magic Methyl Effect
■ How do you invoke the Magic Methyl Effect?
Solubility Conformation
Binding Interactions Metabolism
a combination of......
![Page 31: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/31.jpg)
Demystifying the Magic Methyl Effect
■ Prevention and enhancement of drug metabolism
Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
Protection of adjacent functional group:
Change in half-life:
Methyl Groups as a Metabolic Soft Spot
MeMe
RR
Methyl Groups as Protecting group
Me
O
OHO
HO
OMe
Me Me
Me
simvastatin
O
HN N
Me
procainamide
NH
N
Me
Me
lidocaine
Me
MeMeO
plasmatic amidasescleavage blocked
SN
OH O
NH
S
N
MeO O
Me
meloxicamheterocycle susceptible
to oxidation
H2Nprevention of hydrolysis
![Page 32: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/32.jpg)
Demystifying the Magic Methyl Effect
■ Prevention and enhancement of drug metabolism
Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
■ Mechanism of metabolization of thiazole derivatives
SN
OH O
NH
S
N
MeO O
sudoxicam
SN
OH O
NH
S
N
MeO O
Me
meloxicam
SN
OH O
NH
MeO O
S
NH2
[O]
N
SR
R1N
SR
R1
ONH2
SR
O
O H
R1
CYP2C9
[O] hydrolysis+
![Page 33: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/33.jpg)
Demystifying the Magic Methyl Effect
■ Prevention and enhancement of drug metabolism
Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
■ Alternative oxidation
SN
OH O
NH
S
N
MeO O
sudoxicam
SN
OH O
NH
S
N
MeO O
Me
meloxicam
SN
OH O
NH
MeO O
S
NH2
[O]
CYP2C9
SN
OH O
NH
S
N
MeO O
Me
SN
OH O
NH
S
N
MeO O
OH
[O]
![Page 34: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/34.jpg)
Demystifying the Magic Methyl Effect
■ Oxidation of benzylic methyl groups
Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
F
N NCF3
MeO2S
Me
N NCF3
H2NO2S
N NCF3
MeO2S
OH
celecoxib long half-life leads to accumulation of drug and possible side effects
anti-inflammatory drug
methylation to decreasehalf-life
N NCF3
MeO2S
O
HO
[O]
![Page 35: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/35.jpg)
Demystifying the Magic Methyl Effect
■ Prodrug example
Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
oxaminiquineantihelmintic drug
increase potency
NH
HN
Me
Me
OH
O2NNH
N
Me
S
OMe
HO
hycanthone
NH
N
Me
S
OMe
[P]ONH
N
Me
MeS
OMe
more lipophilic, better bioavailability
in vivo
![Page 36: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/36.jpg)
Demystifying the Magic Methyl Effect
■ How are methyl groups typically installed?
Pilla, M. et al. Bioorg. Med. Chem. Lett. 2010, 20, 7521-7524.
A Call for C-H to C-Me transformations
De Novo Synthesis
Suzuki couplingO NH
Me
O
NH
N
SN
N
OO
HN
MeMe
40 nM, >754-fold boost
N NH
HN S
O
R
O
RX
N
SN
N
OH
RR
GSK2210875
+µWave
selective reduction
N
SN
N
O
RR
A Call for C-H to C-Me transformations
![Page 37: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/37.jpg)
Demystifying the Magic Methyl Effect
■ How are methyl groups typically installed?
Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
A Call for C-H to C-Me transformations
■ Direct methylation will come in handy during fine-tuning stages of drug development
■ Many cases where methylation of advanced intermediate only possible via de novo
■ Payoff is unknown
■ Need to explore methylated chemical space
■ Recent advances made for CF3, CHF2, monofluorination - leaving Me behind
NH
Me
NH
Me
Me
i) Boc2Oii) RuO2, NaIO4iii) MeMgBr
iv) TFA then NaOHv) Pd(OH)2/C, H2
41%
Cui, L.; Peng, Y.; Zhang, L. J. Am. Chem. Soc. 2009, 131 , 8394-8395.
A Call for C-H to C-Me transformationsA Call for C-H to C-Me transformations
![Page 38: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/38.jpg)
Demystifying the Magic Methyl Effect
■ Modes of Action
Solubility Conformation
Binding Interactions Metabolism
Current Synthetic Methods
a combination of......
later......
![Page 39: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/39.jpg)
Demystifying the Magic Methyl Effect
■ Methylation of C(sp2)-H Bonds
Tremont, S. J.; Rahman, H. U. J. Am Chem. Soc. 1984, 106 , 5759-5760.
OMOM
■ Most acidic C-H via induction or ortho-direction
■ directed C-H activation with transition metal
Direct deprotonation via inductive effects:
tBuLi, THF
-78 °C
OMOMLi
MeIOMOM
Me
Limitations: need base stable functional groups
First report of complementary acidic methodology:
Li-halogen exchange requires de novo synthesis
NH
O
Me 1.5 equiv Pd(OAc)2
AcOH, 10 equiv MeI, 60 °C
HN O
Me
PdIILn
NH
O
MeMeI
Me
81% yld
Snieckus, V. Chem. Rev. 1990, 90, 879-933.Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
via PdIV
![Page 40: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/40.jpg)
Demystifying the Magic Methyl Effect
■ Methylation of C(sp2)-H Bonds
Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
■ Improvements with Pd(OAc)2 and MeI
catalytic Pd(OAc)2:
MeONH
O
N
MeONH
O
NMe
90%
3 equiv MeI, 5 mol% Pd(OAc)2
O2, NaOTf, K2CO3tAmOH, 125 °C, 36 hr
Ambient temperatures:
MeO MeO
Me
86%
2 equiv MeI, 5 mol% Pd(OAc)2
AgOAc, Cu(OTf)2TFA, CH2Cl2, 25 °C, 11 hr
HN
O
MeHN
O
Me
Zhao, Z.; Chen, G. Org. Lett. 2011, 13 , 4850-4853.Jang, M. J.; Youn, S. W. Bull. Korean Chem. Soc. 2011, 32, 2865-2866.
![Page 41: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/41.jpg)
Demystifying the Magic Methyl Effect
■ Methylation of C(sp2)-H Bonds
Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
■ Transmetalation reagents can be usedvarious oxidants needed for metal turnover:
MeB(OH)2 MeBF3K
MeMgCl10 mol% Co(acac)2DMPU, THF, rt, 12 h
SnMe410 mol% Pd(OAc)2,
BQ, Cu(OAc)2MeCN, 100 °C, 40 h
10 mol% Pd(OAc)2,air, BQ, AgOAc
tAMOH, 100 °C, 20 h
10 mol% Pd(OAc)2,MnF3, AcOH
TFE/H2O, 40 °C, 3h
N
OMe Me
MeMe Me
86%
Me Me
SO
N
O OH
MeMe N
MeO
Me
OHN
MeMe
68%
NMe
Me
76%
2.5 mol% [{Rh(CO)2Cl}2],Boc2O, toluene,140 °C, 24 hr
MeCOOH
75% 83%62%
![Page 42: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/42.jpg)
Demystifying the Magic Methyl Effect
■ Methylation of C(sp2)-H Bonds
Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
■ Transmetalation reagents can be usedvarious oxidants needed for metal turnover:
MeB(OH)2 MeBF3K
MeMgCl10 mol% Co(acac)2DMPU, THF, rt, 12 h
SnMe410 mol% Pd(OAc)2,
BQ, Cu(OAc)2MeCN, 100 °C, 40 h
10 mol% Pd(OAc)2,air, BQ, AgOAc
tAMOH, 100 °C, 20 h
10 mol% Pd(OAc)2,MnF3, AcOH
TFE/H2O, 40 °C, 3h
N
OMe Me
MeMe Me
86%
Me Me
SO
N
O OH
MeMe N
MeO
Me
OHN
MeMe
68%
NMe
Me
76%
2.5 mol% [{Rh(CO)2Cl}2],Boc2O, toluene,140 °C, 24 hr
MeCOOH
75% 83%62%
OO Ph
Ph
Me Me
Me Me10 mol% Pd(OAc)2,
neat,140 °C, 12 h
N
Me 54%β-methyl elimination
peroxides as transmetallating reagents
![Page 43: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/43.jpg)
Demystifying the Magic Methyl Effect
■ Methylation of C(sp2)-H Bonds
Duncton, M. A. J. Med. Chem. Comm. 2011, 2, 1135-1161.
■ Application of Minisci reaction
Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
NN
O
O
OOHEt
EtCHO
FeSO4•7H2OH2O2, H2SO4
77%
NN
O
O
OOHEt
Et
NN
O
O
OOHEt
EtO
O
N
N
Topoisomerase I inhibitor,cancer treatment
Irinotecan-Pfizer
NN
O
O
OOHEt
Me
via AcOH
+
easy installation of Me for SAR:
![Page 44: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/44.jpg)
Demystifying the Magic Methyl Effect
■ Methylation of C(sp2)-H Bonds
Levy, M.; Szwarc, M. J. Am. Chem. Soc. 1955, 77, 1949.
■ Me radical generation known to functionalize arenes
Giordano, C.; Minisci, F.; Tortelli, V.; Vismara, E. J. Chem. Soc., Perkin Trans. 2 1984, 293.
O
OO
O
MeMe
diacyl peroxidesheat or hν
Me
Fenton's Reagent with DMSOFeSO4•7H2O, H2O2, DMSO
OS
Me MeS
Me Me
HO O OS
HO MeMe
OH
FeSO4•7H2O, tBuO2H, H2SO4
carboxylic acid
Fe3+O
OHMeFe2+ Me
-H+
AgNO2, (NH4)2S2O8, H2SO4
Ag2+O
OHMeAg+ Me
2 Ag+ S2O82- 2 Ag2+ 2 SO42-tBuO2H Fe2+ Fe3+ tBuO OH
Minisci with Fe2+ Minisci with Ag+
+ + +
+ -CO2+
+ +
carboxylic acid
+-H+
-CO2+
+
![Page 45: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/45.jpg)
Demystifying the Magic Methyl Effect
■ Methylation of C(sp2)-H Bonds
Levy, M.; Szwarc, M. J. Am. Chem. Soc. 1955, 77, 1949.
■ Me radical generation known to functionalize arenes
Giordano, C.; Minisci, F.; Tortelli, V.; Vismara, E. J. Chem. Soc., Perkin Trans. 2 1984, 293.
O
OO
O
MeMe
diacyl peroxidesheat or hν
Me
Fenton's Reagent with DMSOFeSO4•7H2O, H2O2, DMSO
OS
Me MeS
Me Me
HO O OS
HO MeMe
OH
FeSO4•7H2O, tBuO2H, H2SO4
carboxylic acid
Fe3+O
OHMeFe2+ Me
-H+
AgNO2, (NH4)2S2O8, H2SO4
Ag2+O
OHMeAg+ Me
2 Ag+ S2O82- 2 Ag2+ 2 SO42-tBuO2H Fe2+ Fe3+ tBuO OH
Minisci with Fe2+ Minisci with Ag+
+ + +
+ -CO2+
+ +
carboxylic acid
+-H+
-CO2+
+
O
MeMeMe O
MeMeMe
or decomposition:
+
![Page 46: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/46.jpg)
Demystifying the Magic Methyl Effect
■ Methylation of C(sp2)-H Bonds
DiRocco, D. A.; Dykstra, K.; Krska, S.; Vachal, P.; Conway, D. V.; Tudge, M. Angew. Chem. Int. Ed. 2014, 53, 4802-4806.
■ Various alkyl radical reagents
O
Me OO
Me
MeMe
O
Me OHO
Me
MeMe
O
Me Me Me
F F
NN
FMe
Me
HON
N
N
Voriconazoleanti-fungal
Ir(dFCF3ppy)2(dtbbpy)PF6
AcOOtBu, visible light, TFA
F F
NN
FMe
Me
HON
N
NMe
75% yld, 2.9:1F F
NN
FMe
HON
N
N
+ +
![Page 47: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/47.jpg)
Demystifying the Magic Methyl Effect
■ Methylation of C(sp2)-H Bonds
Gui,J.; Baran, P. S. et al. J. Am. Chem. Soc. 2014, 136 , 4853-4856.
■ Various alkyl radical reagents
Me
Me BF3K
Me
BF3KMe
N
Me2.5 equiv Mn(OAc)3
1 equiv TFA
AcOH:H2O 1:1,50 °C, 18 hr
N
Me
Me
Me
85%no methyl examples
Molander, G. A.; Colombel, V.; Braz, V. A. Org. Lett. 2011, 13 , 1852-1855.
S SO
OZn
O
Ph
O
1g/$205 Aldrich
N
N
O
O
Me
Me
N
NMe
N
N
O
O
Me
Me
N
NMe
SO2Ph
N
N
O
O
Me
Me
N
NMe
Me
3 equiv PSMS
5 equiv TBHPPhCF3/H2O, rt, 24 hr
PSMS 75%
A: Mg, MeOH, 50 C, 2hB: SmI2, THF/H2O, rt, 30 minC: Raney-Ni, EtOH, reflux, 2h
90%99%93%
2
![Page 48: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/48.jpg)
Demystifying the Magic Methyl Effect
■ Biocatalytic C-H methylation
Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
■ S-Adenosylmethionine (SAM)- Nature's cofactor for methylation
problems recycling cofactor
& is very costlyN
O
OHOHHH
N
N
N
SH2N
O OH
Me
NH2
SAM
O
OH
HO O O
OH
HO OMe
NovO, SAM
30 mg scale
Stecher, H.; Tengg, M.; Ueberbacher, B. J.; Remler, P.; Schwab, H.; Griengl, H.; Gruber-Khadjawi, M. Angew. Chem. Int. Ed. 2009, 48, 9546-9548.
![Page 49: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/49.jpg)
Demystifying the Magic Methyl Effect
■ Methylation of C(sp3)-H Bonds
Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
■ α-Heteroatom functionalization via most acidic CH
An eye toward enantioselectivity:
NBoc
sBuLi, THF, ligand
then Me2SO4NBoc
Me 88% yield, 94% ee
NBoc
sBuLi, THF, ligand
then Me2SO4NBoc
45% yield, 28% eeMe
NN
(-)-sparteine
N NMe
NN
OO
iPr iPr
MeMeO
O
O
O
Me
Me
92% yield, 36% ee
68% yield, 36% ee
tBuLi, THF, ligand
then MeI
tBuLi, THF, ligand
then MeI
![Page 50: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/50.jpg)
Demystifying the Magic Methyl Effect
■ Methylation of C(sp3)-H Bonds
Wang, D.; Wasa, M.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130 , 7190-7191.
■ C-H activation examples - emerging interestO
OMe
MeN
O
OMe
N
Me
10 mol% Pd(OAc)2
Cu(OAc)2, BQ, O2AcOH, 100 °C
trimethylboroxine
70%
favored alkylation of primary position
Me
MeMe
Me OHN
OMe
Me
MeMe
OHN
OMe
Me
dehydroabietic acidother alkyl groups compatible with transformation
for late-stage funcationalization
10 mol% Pd(OAc)21.6 equiv MeB(OH)2, K2CO3
BQ, air, 80 °C, 48 h
40%
Chen, X.; Goodhue, C. E., Yu, J.-Q. J. Am. Chem. Soc. 2006, 128 , 12634-12635.
![Page 51: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/51.jpg)
Demystifying the Magic Methyl Effect
■ Methylation of C(sp3)-H Bonds
Zhang, S. Y.; He, G.; Nack, W. A.; Zhao, Y.; Li, Q.; Li, Chen, G. J. Am. Chem. Soc. 2013, 135 , 2124-2127.
■ C-H activation examples - emerging interest
NH
MeMe
O
N
NH
Me
O
N
Me
γ-Methylation
2-3 equiv MeI, 10 mol% Pd(OAc)220 mol% (BnO)2PO2H
Ag2CO3, NaI, Tol/tAmOH110 °C, 2-20 hr
86%
![Page 52: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/52.jpg)
Demystifying the Magic Methyl Effect
■ Methylation of C(sp3)-H Bonds
Zhang, S. Y.; He, G.; Nack, W. A.; Zhao, Y.; Li, Q.; Li, Chen, G. J. Am. Chem. Soc. 2013, 135 , 2124-2127.
■ C-H activation examples - emerging interest
NH
MeMe
O
N
NH
Me
O
N
Me
γ-Methylation
2-3 equiv MeI, 10 mol% Pd(OAc)220 mol% (BnO)2PO2H
Ag2CO3, NaI, Tol/tAmOH110 °C, 2-20 hr
86%
HN
O
NHN
O
N5 equiv MeI
Me
HN
O
N
Me
HN
O
N
Me
Me
77%
excess of MeI leads to multiple C-H activations:
![Page 53: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/53.jpg)
Demystifying the Magic Methyl Effect
■ Methylation of C(sp3)-H Bonds
Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010, 132 , 3965-3972.
■ no silver salt oxidant
5 mol% Pd(OAc)23-4 equiv MeI, K2CO3
20 mol% PivOH, tAmOH110 °C
68%
isolated palladacycle:
NHN O
Me MeMe
NHN O
MeMe
Me
Br2, CH2Cl2
-78 °C
85%
PdBr
Br
N
O Me
Me
NCNR
PdN
O Me
Me
NCNR
![Page 54: Demystifying the Magic Methyl Effect - Princeton Universitychemlabs.princeton.edu/macmillan/wp-content/uploads/... · 2016-12-24 · Demystifying the Magic Methyl Effect "In comparison](https://reader030.fdocuments.in/reader030/viewer/2022040820/5e6918c39ade462d8c796748/html5/thumbnails/54.jpg)
Me
"You sort of start thinking anything's possible if you've got enough nerve."