Download The Magic Methyl Effect

Demystifying the Magic Methyl Effect
Patricia Zhang
MacMillan Group Meeting
June 11, 2015
Demystifying the Magic Methyl Effect
Demystifying the Magic Methyl Effect
■ When is the Magic Methyl Effect in play?
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
~a large emphasis on the drastic change in conformation, hence, binding affinity
HO
Me
O
O
O
Me
H
O
H
HO
Me
O
O
O
Me
Me
H
O
H
Me
Me
Me
Me
O
O
O
O
Me
mevastatin
IC 50 HMG-CoAR = 5.6 nM
HO
H
Me
Me
lovastatin
IC 50 HMG-CoAR = 2.2 nM
simvastatin
IC 50 HMG-CoAR = 0.9 nM
"The methyl group, so often considered as chemically inert, is able to alter deeply
the pharmacological properties of a molecule."
Bazzini, P.; Wermuth, C. G. In The Practice of Medicinal Chemistry; Academic Press: San Diego, 2008; pp 431-418.
"In comparison to its importance to the pharmaceutical industry, the methyl group is,
in our opinion, underrepresented in recent synthetic chemistry.
Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
Demystifying the Magic Methyl Effect
■ The Benign Methyl Group - DNA vs RNA
O
O
base
Me
NH
N
H
NH
HO
O
O
H
thymine
O
O
P
N
H
H
H/OH
uracil
O-
O-
DNA
N
N
H
RNA
NH 2
O
N
guanine
NH 2
N
N
NH
NH 2
N
H
O
O
cytosine
N
H
N
N
adenine
■ 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)
Nishio, M.; Umezawa, Y.; Hirota, M.; Takeuchi, Y. Tetrahedron 1995, 51, 8665.
Umezawa, Y.; Nishio, M. Nucleic Acids Res. 2002, 30, 2183.
Demystifying the Magic Methyl Effect
■ The Benign Methyl Group - DNA vs RNA
O
O
base
Me
NH
N
H
NH
HO
O
O
H
thymine
O
O
P
O-
■ yellow = adenine
O-
DNA
N
H
H
H/OH
■ gray = thymine
O
uracil
RNA
■ red = CH/π-interaction
NH 2
O
N
N
H
guanine
N
N
NH
N
NH 2
NH 2
N
H
O
cytosine
N
H
N
N
adenine
■ 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)
Nishio, M.; Umezawa, Y.; Hirota, M.; Takeuchi, Y. Tetrahedron 1995, 51, 8665.
Umezawa, Y.; Nishio, M. Nucleic Acids Res. 2002, 30, 2183.
Demystifying the Magic Methyl Effect
■ The Benign Methyl Group - CH/π-interactions
CH/π-interactions
H
H
C
H
π(donor)
σ∗(acceptor)
H
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
Nishio, M.; Umezawa, Y.; Hirota, M.; Takeuchi, Y. Tetrahedron 1995, 51, 8665.
Umezawa, Y.; Nishio, M. Nucleic Acids Res. 2002, 30, 2183.
Demystifying the Magic Methyl Effect
■ Modes of Action
a combination of......
Solubility
Conformation
Binding Interactions
Metabolism
later......
Current Synthetic Methods
Demystifying the Magic Methyl Effect
■ Modes of Action
a combination of......
Solubility
Conformation
Binding Interactions
Metabolism
later......
Current Synthetic Methods
Demystifying the Magic Methyl Effect
■ Solubility
General solubility for increased bioavailability
Lipophilicity
Hydrophilic Effect
"lipid loving", hydrophobic
benzene
Me
Me
toluene
OH
Me
Me
n-butanol
8.2g/100g H 2O
Log P = 2.13
Me
Me
Me
isobutanol
5g/100g H 2O
OH
tert-butanol
miscible
Log P = 2.69
Log P is logarithm of the partition
coefficient between n-octanol and water
Me
■ important for crossing biomembranes to
get to target tissues and for transport
through bloodstream
Me
Me
OH
Me
Me
Me
Me
= H 2O
OH
n-pentanol
2.4g/100g H 2O
Me
Me
Me
Me
Me
OH
2-pentanol
4.9g/100g H 2O
Me
OH
neopentanol
12.2g/100g H 2O
■ fewer water molecules needed to be
organized, entropic gain with "globular"
+ 3
shape
■ more negative ΔG desolvation when
transitioning from aqueous to membrane
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.
Demystifying the Magic Methyl Effect
■ Lipophilicity to increase bioavailability
Placement of methyl groups is important:
Me
HO
HO
O
N
Me
O
morphine
structure elucidated by
Sir Robert Robinson
O
NH
H
HO
O
N
H
HO
normorphine
6-fold reduction in in vivo
analgesic activity
Me
H
HO
codeine
3-fold reduction in in vivo
analgesic activity, 200-fold
reduction in receptor affinity
■ dominant ionic interactions for drug catalytic
site still maintained
■ more polar nitrogen moiety, harder to pass
through blood-brain barrier
Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
Demystifying the Magic Methyl Effect
■ Lipophilicity to increase bioavailability
Placement of methyl groups is important:
TM = transmembrane domain
HisVI-17
TM-VI
H
N
N
OH
TM III
O
H
■ H-bond interaction
O
AspIII-08
■ van der Waals interactions
H
O
H
O
■ ionic interaction with aminium
cation and carboxylate
N
H-bond donor
Me
H
N
TM V
TrpV-10
PheV-13
Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
Demystifying the Magic Methyl Effect
■ Lipophilicity to increase bioavailability
Placement of methyl groups is important:
TM = transmembrane domain
TM-VI
HisVI-17
N
N
OH
■ dominant ionic interactions for
drug catalytic site still maintained
H
TM III
O
O
AspIII-08
H
O
H
O
N
■ weaker H-bond interaction
causes 200-fold reduction in
receptor binding
Me
weak H-bond acceptor
Me
H
N
TM V
■ codeine gets metabolized to
morphine
TrpV-10
PheV-13
Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
Demystifying the Magic Methyl Effect
■ Lipophilicity to increase bioavailability
Placement of methyl groups is important:
TM = transmembrane domain
HisVI-17
TM-VI
H
N
Me
N
O
TM III
O
H
■ H-bond interaction
O
AspIII-08
H
O
H
O
N
H-bond donor
Me
■ heterocodeine has a 2-fold
increase in in vivo activity
■ methyl allyic ether aids in solubility,
hence, passage through central nervous
system
H
N
TM V
TrpV-10
PheV-13
Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
Demystifying the Magic Methyl Effect
■ Free energy of desolvation
■ more -CH3 groups leads to more spontaneous transfer from aqueous to protein layer
Me
Me
Me
HO
NH 2
HO
NH 2
O
glycine
ΔG transfer kcal/mol=
Me
HO
O
NH 2
Me
Me
Me
HO
NH 2
HO
NH 2
O
O
alanine
valine
leucine
isoleucine
-1.3 (-0.73)
-1.9 (-1.69)
-1.9 (-2.42)
-1.9 (-2.97)
( ) = side chain
contribution moving
from water to ethanol
O
increasing methyls, decreasing ΔGdesolvation
Me
Me
Me
Me
Me
Me
Me
Me
Me
■ ΔΔG transfer of C-H to C-CH3 = 0.8 kcal/mol
■ theoretical ~3.5 fold boost in potency from methylation
Andrews, P. R.; Craik, D. J.; Martin, J. L. J. Med. Chem. 1984, 27, 1648-1657.
Nemethy, G. Angew. Chem. Int. Ed. 1967, 6, 195-206.
Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
Demystifying the Magic Methyl Effect
■ The bigger picture of methylation and potency improvements
■ 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%
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.
Demystifying the Magic Methyl Effect
■ The bigger picture of methylation and potency improvements
■ methylation just as likely to decrease binding affinity as it is to increase
Methyl
Effect
free energy
fromthan 3 kcal/mol (4 cases,
■ rare for addition of MeMagic
group
to give
free- energy
gaingain
greater
Me addition is or above what is predicted
0.0019%
■ 10 fold boost (1.36 kcal/mol) - 8%
■ 100 fold boost (2.7 kcal/mol) - 0.4%
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.
Demystifying the Magic Methyl Effect
■ How do you invoke the Magic Methyl Effect?
a combination of......
Solubility
Conformation
Binding Interactions
Metabolism
Demystifying the Magic Methyl Effect
■ How do you invoke the Magic Methyl Effect?
a combination of......
Solubility
Conformation
Binding Interactions
Metabolism
Demystifying the Magic Methyl Effect
■ Conformational preorganization leads to ~200-fold boost
O
O
N
H
R
N
H
O
NH
planar
free rotation
O
NH
biphenyl amide inhibitors of p38α kinase
R
K i (nM)
IC 50
H
>2500
>16,000
Me
12
75
Cl
25
160
F
460
2900
OMe
520
3300
O
N
H
Me
rotation out of plane
O
NH
(inhibitor constant, nM needed to
achieve 1/2 max inhibition)
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.
Demystifying the Magic Methyl Effect
■ Conformational preorganization leads to ~200-fold boost
■ 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
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.
Demystifying the Magic Methyl Effect
■ Conformational preorganization leads to ~200-fold boost
■ 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
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.
Demystifying the Magic Methyl Effect
■ Conformational preorganization leads to 480-fold boost
F
Me
Me
N
N
O
N
α-methylation
N
N
N
N
H
N
F
π-stacking
O
O
U-shape confirmed by NMR,
minimize 1,3-diaxial strain
N
O
N
96 nM
under development at Merck for insomina,
dual antagonist of orexin-1 and -2 receptors
Me
0.2 nM
"In terms of value, a methyl group that leads to a profound improvement in potency is hard to beat."
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
Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
Demystifying the Magic Methyl Effect
■ Use of methyl group to decrease binding affinity
OH
NH
O
Cl
Cl
H
N
O
Tyr355
diclofenac
K i (µM) COX-1 = 0.01
K i (µM) COX-2 = 0.01
N
H
N
H
Arg120
NH 2
O
O
NSAID
O
O
N
H
NH
OH
Cl
Cl
Ser353
Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
Demystifying the Magic Methyl Effect
■ Use of methyl group to decrease binding affinity
OH
NH
O
Cl
Cl
HN
O
Tyr355
diclofenac
K i (µM) COX-1 = 0.01
K i (µM) COX-2 = 0.01
H 2N
HN
H
Arg120
NH 2
O
no H-bonds
NSAID
Me
O
O
N
H
OH
O
NH
Me
O
Cl
OH
Ser353
F
NH
Cl
F
lumiracoxib
K i (µM) COX-1 = 3.2
K i (µM) COX-2 = 0.06
NSAID, but taken off market
due to liver damage
Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
Demystifying the Magic Methyl Effect
■ Methyl group installation around freely rotating bonds
"rationally developed" combichem-HTS drug discovery tactic
H
N
N
Me
■ Patients live up to 5 years longer
N
HN
N
O
■ very minimal side effects
■ Bcr-Abl kinase responsible for
cell growth of cancer cells
N
Me
■ first tyrosine-kinase inhibitor on market
N
imatinib - Novartis
treats chronic myelogenous leukemia
by inhibiting Bcr-Abl kinase
Capdeville, R.; Buchdunger, E.; Zimmermann, J.; Matter, A. Nature Rev. Drug Discovery 2002, 1 , 493.
Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
Demystifying the Magic Methyl Effect
■ Methyl group installation around freely rotating bonds
H
N
N
H
N
N
Ar
H
N
N
O
methylation
N
H
N
N
Me
Ar
O
N
PKA, TK and Bcr-Ablk inhibitor
HTS to get scaffold
Bcr-Ablk selectivity over PKC
Conformers:
N
H
N
H
N
N
Me
N
Ar
H
N
N
O
Me
N
steric clash
N
HN
O
Ar
confirmed by X-ray diffraction
Capdeville, R.; Buchdunger, E.; Zimmermann, J.; Matter, A. Nature Rev. Drug Discovery 2002, 1 , 493.
Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
Demystifying the Magic Methyl Effect
■ A change in conformation isn't everything
Me
O
N
O
Me
diphenhydramine
diphenhydramine
Toladryl
Benadryl
antihistamines tend to be rigid
Me
3.7-fold increase in activity
2.5-fold decrease in anticholine activity
Me
N
Me
Orphenadrine
Me
Me
Me
O
N
Me
rotation out of plane
O
N
Me
Me
5-fold reduction in activity
2.1-fold increase in anticholine activity
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.
Demystifying the Magic Methyl Effect
■ A change in conformation isn't everything
Me
O
N
O
Me
diphenhydramine
diphenhydramine
Toladryl
Benadryl
antihistamines tend to be rigid
Me
3.7-fold increase in activity
2.5-fold decrease in anticholine activity
Me
N
Me
Orphenadrine
Me
Me
Me
O
N
Me
rotation out of plane
O
N
Me
Me
5-fold reduction in activity
2.1-fold increase in anticholine activity
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.
Demystifying the Magic Methyl Effect
■ Overview of where to place Me groups for most impact
ortho substitution
MeO
on substituted alkyl rings
F
Me
O
HO
Me
Me
Cl
Me
Me
N
Me
N
N
N
H
F
Me
N
N
N
H
Me
Me
O
Me
Me
O
Me
NH
Me
Me
97-fold boost
Me
Cl
Me
O
N
H
OH
N
1333-fold boost
N
around two freely rotatable bonds
2135-fold boost
Me
Me
Me
N
N
N
OMe
O
N
Cl
Cl
Me
Me
159-fold boost
598-fold boost
480-fold boost
Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
Demystifying the Magic Methyl Effect
■ How do you invoke the Magic Methyl Effect?
a combination of......
Solubility
Conformation
Binding Interactions
Metabolism
Demystifying the Magic Methyl Effect
■ Prevention and enhancement of drug metabolism
Methyl Groups as Protecting group
Protection of adjacent functional group:
HO
O
prevention of hydrolysis
Me
Me
Me
H 2N
Me
H
N
O
O
O
plasmatic amidases
cleavage blocked
N
O
H
Me
Me
Me
Me
procainamide
Me
O
N
H
N
Me
lidocaine
Me
simvastatin
OH
S
O
O
N
O
meloxicam
N
N
H
Methyl Groups as a Metabolic Soft Spot
Change in half-life:
Me
S
Me
Me
heterocycle susceptible
to oxidation
R
R
Me
Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
Demystifying the Magic Methyl Effect
■ Prevention and enhancement of drug metabolism
OH
S
O
O
N
N
N
H
OH
[O]
O
S
CYP2C9
S
Me
O
O
N
S
N
H
OH
O
NH 2
Me
S
O
O
sudoxicam
N
S
N
H
N
Me
Me
O
meloxicam
■ Mechanism of metabolization of thiazole derivatives
R1
N
R
S
R1
[O]
N
R
O
S
hydrolysis
NH 2
R
S
O
R1
O
H
+
Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
Demystifying the Magic Methyl Effect
■ Prevention and enhancement of drug metabolism
OH
S
O
O
N
N
OH
[O]
O
S
N
H
CYP2C9
S
Me
O
O
N
S
N
H
OH
O
N
NH 2
Me
S
O
O
sudoxicam
N
Me
S
N
H
Me
O
meloxicam
■ Alternative oxidation
OH
S
O
O
N
O
N
N
H
Me
S
OH
O
[O]
Me
S
O
N
OH
N
N
H
S
Me
O
Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
Demystifying the Magic Methyl Effect
■ Oxidation of benzylic methyl groups
Me
F
N
CF3
methylation to decrease
half-life
N
N
H 2NO 2S
CF3
N
MeO 2S
long half-life leads to accumulation
of drug and possible side effects
celecoxib
anti-inflammatory drug
OH
O
HO
[O]
N
MeO 2S
CF3
N
N
CF3
N
MeO 2S
Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
Demystifying the Magic Methyl Effect
■ Prodrug example
OH
S
O2N
increase potency
H
N
N
H
HO
Me
Me
O
N
N
H
Me
Me
hycanthone
oxaminiquine
antihelmintic drug
in vivo
S
Me
O
N
H
S
Me
[P]O
N
Me
Me
O
N
H
N
Me
more lipophilic,
better bioavailability
Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111 , 5215-5246.
Demystifying the Magic Methyl Effect
■ How are methyl groups typically installed?
HN
De Novo Synthesis
O
N
N
H
O
S
N
O
N
Me
Me
Me
GSK2210875
40 nM, >754-fold boost
Suzuki coupling
O
S
N
NH
N
N
OH
R
R
Callfor
forC-H
C-HtotoC-Me
C-Metransformations
transformations
AACall
O
H
N
N
S
NH
+
O
R
µWave
R
X
selective reduction
S
N
N
N
O
R
R
Pilla, M. et al. Bioorg. Med. Chem. Lett. 2010, 20, 7521-7524.
Demystifying the Magic Methyl Effect
■ How are methyl groups typically installed?
A
A Call
Call for
for C-H
C-H to
to C-Me
C-Me transformations
transformations
i) Boc 2O
ii) RuO 2, NaIO 4
iii) MeMgBr
Me
Me
NH
NH
iv) TFA then NaOH
v) Pd(OH) 2/C, H 2
Me
41%
■ 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
Cui, L.; Peng, Y.; Zhang, L. J. Am. Chem. Soc. 2009, 131 , 8394-8395.
Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
Demystifying the Magic Methyl Effect
■ Modes of Action
a combination of......
Solubility
Conformation
Binding Interactions
Metabolism
later......
Current Synthetic Methods
Demystifying the Magic Methyl Effect
■ Methylation of C(sp2)-H Bonds
■ Most acidic C-H via induction or ortho-direction
Direct deprotonation via inductive effects:
OMOM
tBuLi, THF
OMOM
OMOM
MeI
Li
Me
-78 °C
Limitations: need base stable functional groups
Li-halogen exchange requires de novo synthesis
■ directed C-H activation with transition metal
First report of complementary acidic methodology:
Me
O
Me
NH
1.5 equiv Pd(OAc) 2
AcOH, 10 equiv MeI, 60 °C
HN
O
O
PdIIL n
MeI
Me
NH
Me
via PdIV
81% yld
Snieckus, V. Chem. Rev. 1990, 90, 879-933.
Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
Tremont, S. J.; Rahman, H. U. J. Am Chem. Soc. 1984, 106 , 5759-5760.
Demystifying the Magic Methyl Effect
■ Methylation of C(sp2)-H Bonds
■ Improvements with Pd(OAc) 2 and MeI
catalytic Pd(OAc) 2:
O
MeO
O
3 equiv MeI, 5 mol% Pd(OAc) 2
N
H
N
MeO
O2, NaOTf, K 2CO3
tAmOH, 125 °C, 36 hr
N
H
N
Me
90%
Ambient temperatures:
MeO
H
N
Me
O
2 equiv MeI, 5 mol% Pd(OAc) 2
H
N
MeO
AgOAc, Cu(OTf)2
TFA, CH2Cl2, 25 °C, 11 hr
Me
Me
O
86%
Jang, M. J.; Youn, S. W. Bull. Korean Chem. Soc. 2011, 32, 2865-2866.
Zhao, Z.; Chen, G. Org. Lett. 2011, 13 , 4850-4853.
Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
Demystifying the Magic Methyl Effect
■ Methylation of C(sp2)-H Bonds
■ Transmetalation reagents can be used
various oxidants needed for metal turnover:
Me
O
Me
S
O
Me
N
Me
O
Me
Me
Me
86%
Me
Me
N
N
Me
O
75%
62%
SnMe4
OH
83%
MeBF 3K
MeB(OH) 2
10 mol% Pd(OAc) 2,
BQ, Cu(OAc)2
MeCN, 100 °C, 40 h
10 mol% Pd(OAc) 2,
MnF 3, AcOH
TFE/H2O, 40 °C, 3h
10 mol% Pd(OAc) 2,
air, BQ, AgOAc
tAMOH, 100 °C, 20 h
O
H
N
Me
Me
MeMgCl
Me
N
10 mol% Co(acac)2
DMPU, THF, rt, 12 h
Me
68%
Me
76%
MeCOOH
2.5 mol% [{Rh(CO)2Cl}2],
Boc 2O, toluene,
140 °C, 24 hr
Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
Demystifying the Magic Methyl Effect
■ Methylation of C(sp2)-H Bonds
■ Transmetalation reagents can be used
various oxidants needed for metal turnover:
Me
O
Me
S
O
Me
N
Me
Me
Me
Me
86%
OH
Me
Me
N
N
Me
O
75%
62%
SnMe4
MeBF 3K
10 mol% Pd(OAc) 2,
MnF 3, AcOH
TFE/H2O, 40 °C, 3h
10 mol% Pd(OAc) 2,
air, BQ, AgOAc
tAMOH, 100 °C, 20 h
O
Me
Ph
O
O
H
N
Me Me
Me
Ph
10 mol% Co(acac)2 Me Me
DMPU, THF, rt, 12 h
peroxides as transmetallating
reagents
68%
Me
83%
MeB(OH) 2
10 mol% Pd(OAc) 2,
BQ, Cu(OAc)2
MeCN, 100 °C, 40 h
MeMgCl
O
10Me
mol% Pd(OAc)N2,
neat,
140 °C, 12 h
Me
β-methyl elimination
76%
MeCOOH
N
2.5 mol% [{Rh(CO)
54% 2Cl}2],
Me
Boc 2O, toluene,
140 °C, 24 hr
Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
Demystifying the Magic Methyl Effect
■ Methylation of C(sp2)-H Bonds
■ Application of Minisci reaction
Et
O
N
+
N
EtCHO
FeSO 4•7H 2O
H 2O2, H 2SO 4
O
N
N
O
O
Et
OH
77%
O
Et
OH
O
easy installation of Me for SAR:
N
Me
N
O
N
O
O
N
O
via AcOH
Et
Et
OH
O
Irinotecan-Pfizer
Topoisomerase I inhibitor,
cancer treatment
O
N
N
O
Et
OH
O
Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
Duncton, M. A. J. Med. Chem. Comm. 2011, 2, 1135-1161.
Demystifying the Magic Methyl Effect
■ Methylation of C(sp2)-H Bonds
■ Me radical generation known to functionalize arenes
O
Me
OH
O
O
O
Me
Me
S
HO
S
Me
Me
O
O
O
Me
HO
S
+
Me
Me
Fenton's Reagent with DMSO
FeSO 4•7H2O, H 2O2, DMSO
diacyl peroxides
heat or hν
Me
Minisci with Fe 2+
Minisci with Ag+
AgNO2, (NH 4)2S2O8, H 2SO 4
FeSO 4•7H2O, tBuO 2H, H 2SO 4
tBuO 2H + Fe 2+
O
+ Fe 3+
Me
OH
carboxylic acid
Fe 3+ + tBuO
+
2 Ag+ + S2O82-
OH
-H+
-CO2
+
+
Me
Me
2 SO 42-
-H+
O
Fe 2+
2 Ag2+ +
OH
Ag2+
-CO2
Ag+
+
Me
carboxylic acid
Giordano, C.; Minisci, F.; Tortelli, V.; Vismara, E. J. Chem. Soc., Perkin Trans. 2 1984, 293.
Levy, M.; Szwarc, M. J. Am. Chem. Soc. 1955, 77, 1949.
Demystifying the Magic Methyl Effect
■ Methylation of C(sp2)-H Bonds
■ Me radical generation known to functionalize arenes
O
Me
OH
O
O
O
Me
Me
S
HO
S
Me
Me
O
O
O
Me
HO
S
+
Me
Me
Fenton's Reagent with DMSO
FeSO 4•7H2O, H 2O2, DMSO
diacyl peroxides
heat or hν
Me
Minisci with Fe 2+
Minisci with Ag+
AgNO2, (NH 4)2S2O8, H 2SO 4
FeSO 4•7H2O, tBuO 2H, H 2SO 4
tBuO 2H + Fe 2+
O
or decomposition:
3+
+
O
Me Fe
Me
OH
Me
carboxylicMe
acid
Fe 3+ + tBuO
+
2 Ag+ + S2O82-
OH
-H+
-CO2 O
Me
Me
+
Me
2 SO 42-
-H+
O
Fe 2+ + Me
+
Me
2 Ag2+ +
OH
Ag2+
-CO2
Ag+
+
Me
carboxylic acid
Giordano, C.; Minisci, F.; Tortelli, V.; Vismara, E. J. Chem. Soc., Perkin Trans. 2 1984, 293.
Levy, M.; Szwarc, M. J. Am. Chem. Soc. 1955, 77, 1949.
Demystifying the Magic Methyl Effect
■ Methylation of C(sp2)-H Bonds
■ Various alkyl radical reagents
O
Me
O
O
O
Me
Me
Me
Me
OH
+
O
O
Me
Me
Me
Me
Me
+
Me
N
N
N
N
N
HO
N
N
N
HO
F
N
F
Me
N
F
Me
Ir(dFCF 3ppy) 2(dtbbpy)PF 6
F
F
Me
F
75% yld, 2.9:1
AcOOtBu, visible light, TFA
N
Me
N
Voriconazole
anti-fungal
N
N
HO
N
Me
F
F
Me
F
DiRocco, D. A.; Dykstra, K.; Krska, S.; Vachal, P.; Conway, D. V.; Tudge, M. Angew. Chem. Int. Ed. 2014, 53, 4802-4806.
Demystifying the Magic Methyl Effect
■ Methylation of C(sp2)-H Bonds
■ Various alkyl radical reagents
Me
Me
Me
2.5 equiv Mn(OAc) 3
1 equiv TFA
BF 3K
Me
Me
N
O
S
O
O
S
O
Me
Zn
2
N
N
O
1g/$205 Aldrich
PSMS
Me
N
N
Me
85%
O
3 equiv PSMS
5 equiv TBHP
PhCF 3/H2O, rt, 24 hr
Me
O
Me
O
Me
O
Me
N
Me
N
N
N
N
Me
75%
SO2Ph
Me
N
N
Me
N
AcOH:H2O 1:1,
50 °C, 18 hr
no methyl examples
BF 3K
O
Ph
Me
N
A: Mg, MeOH, 50 C, 2h
B: SmI2, THF/H2O, rt, 30 min
C: Raney-Ni, EtOH, reflux, 2h
90%
99%
93%
Me
Molander, G. A.; Colombel, V.; Braz, V. A. Org. Lett. 2011, 13 , 1852-1855.
Gui,J.; Baran, P. S. et al. J. Am. Chem. Soc. 2014, 136 , 4853-4856.
Demystifying the Magic Methyl Effect
■ Biocatalytic C-H methylation
■ S-Adenosylmethionine (SAM)- Nature's cofactor for methylation
NH 2
N
Me
H 2N
S
N
O
O
OH
H
OH
N
problems recycling cofactor
N
& is very costly
H
OH
SAM
OH
OH
NovO, SAM
30 mg scale
HO
O
O
HO
O
O
Me
Stecher, H.; Tengg, M.; Ueberbacher, B. J.; Remler, P.; Schwab, H.; Griengl, H.; Gruber-Khadjawi, M. Angew. Chem. Int. Ed. 2009, 48, 9546-9548.
Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
Demystifying the Magic Methyl Effect
■ Methylation of C(sp3)-H Bonds
■ α-Heteroatom functionalization via most acidic CH
An eye toward enantioselectivity:
sBuLi, THF, ligand
N
then Me 2SO 4
Boc
Me
N
then Me 2SO 4
Boc
(-)-sparteine
N
Me
45% yield, 28% ee
N
Boc
N
Me
tBuLi, THF, ligand
O
O
then MeI
88% yield, 94% ee
Boc
sBuLi, THF, ligand
N
92% yield, 36% ee
Me
Me
O
O
Me
N
tBuLi, THF, ligand
O
O
N
N
68% yield, 36% ee
iPr
N
iPr
then MeI
Me
Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52, 12256-12267.
Demystifying the Magic Methyl Effect
■ Methylation of C(sp3)-H Bonds
■ C-H activation examples - emerging interest
O
O
OMe
trimethylboroxine
10 mol% Pd(OAc) 2
OMe
N
Cu(OAc)2, BQ, O2
AcOH, 100 °C
N
Me
Me
70%
favored alkylation of primary position
Me
Me
Me
Me
Me
Me
10 mol% Pd(OAc) 2
1.6 equiv MeB(OH) 2, K 2CO3
Me
O
BQ, air, 80 °C, 48 h
Me
O
HN
HN
OMe
dehydroabietic acid
OMe
40%
other alkyl groups compatible with transformation
for late-stage funcationalization
Chen, X.; Goodhue, C. E., Yu, J.-Q. J. Am. Chem. Soc. 2006, 128 , 12634-12635.
Wang, D.; Wasa, M.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130 , 7190-7191.
Demystifying the Magic Methyl Effect
■ Methylation of C(sp3)-H Bonds
■ C-H activation examples - emerging interest
2-3 equiv MeI, 10 mol% Pd(OAc) 2
20 mol% (BnO) 2PO 2H
N
O
Me
NH
Me
Ag2CO3, NaI, Tol/tAmOH
110 °C, 2-20 hr
N
O
NH
Me
Me
86%
γ-Methylation
Zhang, S. Y.; He, G.; Nack, W. A.; Zhao, Y.; Li, Q.; Li, Chen, G. J. Am. Chem. Soc. 2013, 135 , 2124-2127.
Demystifying the Magic Methyl Effect
■ Methylation of C(sp3)-H Bonds
■ C-H activation examples - emerging interest
2-3 equiv MeI, 10 mol% Pd(OAc) 2
20 mol% (BnO) 2PO 2H
N
O
Me
N
O
Ag2CO3, NaI, Tol/tAmOH
110 °C, 2-20 hr
NH
Me
NH
Me
Me
86%
γ-Methylation
excess of MeI leads to multiple C-H activations:
Me
Me
N
H
N
O
5 equiv MeI
Me
Me
N
H
N
N
H
N
O
O
N
H
N
O
77%
Zhang, S. Y.; He, G.; Nack, W. A.; Zhao, Y.; Li, Q.; Li, Chen, G. J. Am. Chem. Soc. 2013, 135 , 2124-2127.
Demystifying the Magic Methyl Effect
■ Methylation of C(sp3)-H Bonds
■ no silver salt oxidant
5 mol% Pd(OAc) 2
3-4 equiv MeI, K 2CO3
N
HN
O
Me
Me
Me
20 mol% PivOH, tAmOH
110 °C
N
HN
O
Me
Me
Me
68%
isolated palladacycle:
O
N
Pd
N
O
Me
Me
CNR
Br 2, CH2Cl2
-78 °C
N Br
Pd
N
Br
Me
Me
CNR
85%
Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010, 132 , 3965-3972.
"You sort of start thinking anything's possible if you've got enough nerve."
Me