O NH

O

F3C

Cl

O NH

O

F3C

Cl

N

NN

OH

O

HN

OHPh

O NHtBuF

O

O

OHHOOH

F

Et

O O

O OH

OMeOO

HO N

Fluorine in Medicinal Chemistry

Niyi FadeyiLindsley’s Group

Introduction of fluorine can be highly advantageous in pharmaceutical compounds

Alter chemical properties, disposition and biological activity, including its stability, lipophilicity, and bioavailability

20% of pharmaceuticals on the market are estimated to contain fluorine, including half of the top 10 drugs sold in 2005

Small size with high electronegativity

June 5, 2006 Volume 84, Number 23 pp. 15-24 and pp. 27-32 Chemical & Engineering News

Fabulous Fluorine

The Effect of Fluorine Substitution on pKa

William K. Hagmann, J.Med. Chem., 2008, 51, 4359–4369Ve´ronique Gouverneur, et al, Chem. Soc. Rev., 2008, 37, 320–330

Lange’s Handbook of Chemistry, 15th ed.; Dean, J. A., Ed.; McGraw-Hill Inc.: New York, 1999.Brown, H. C.; . In Determination of Organic Structures by Physical Methods; Braude, E. A.,

Nachod, F. C., Eds.; Academic Press; New York, 1955

Fluorine have strong effects on the acidity (and basicity) of neighboring functional groups.

Effect of Fluorine on physicochemical and Conformational Properties

Perturbation of pKa

Strongly modify pharmacokinetic properties of a pharmaceutical agent.

Modify binding affinity : reinforcement of the binding between drug and biological target.

Modulation of pKa may impact bioavailability by affecting transportation and absorption of the drug.

Ve´ronique Gouverneur, et al, Chem. Soc. Rev., 2008, 37, 320–330D. A. Smith, H. van de Waterbeemd and D. K. Walker, Methods and Principles in Medicinal

Chemistry, vol. 31: Pharmacokinetics and Metabolism in Drug Design, Wiley-VCH, Weinheim, 2006.

Basicity and Bioavailability of 3-piperidiylindole Antipsychotics

Greater affinity for serotonin 5-HT2 receptors than for dopamine D2 receptorsReduce side effects, such as delusions and hallucinations

M. Rowley, et al. J. Med. Chem., 2001, 44, 160. Sophie Purser, et al . Chem. Soc. Rev., 2008, 37, 320–330

Moderate bioavailability in rats Good pharmacokinetics in dogsGood selectivity for 5-HT2 receptors

Basicity and bioavailability in a series of piperidinyl and piperazinyl indoles

Must be selective for 5-HT1D receptors over 5-HT1B receptors, as 5-HT1B receptors are implicated in coronary vasoconstriction

M. B. Van Niel., et. al . J. Med. Chem.,1999, 42, 2087.

Improved oral bioavailability

The hERG (human ether a-go-go–related gene) is best known for its contribution to the electrical activity of the heart that coordinates the heart's beating

hERG K+ channel is a major component of the toxicity observed with many pharmaceuticals and it is estimated that 25-40% of all lead compounds show some activity towards the hERGion channel.

Introduction of fluorine strongly reduces amine basicity, impacting membrane permeability and interference with the hERG K+ channel associated with cardiovascular toxicity.

hERG K+ Channel

β and γ fluorine to attenuate amine basicity: J. Med. Chem. 1999, 42, 2087.

hERG Toxicity

Conformational Changes

Substitution of a hydrogen or hydroxyl group for a fluorine in biologically active molecules is commonly tolerated

Fluorine substitution therefore exerts only a minor steric demand at receptor sites.

William K. Hagmann, J.Med. Chem., 2008, 51, 4359–4369

Effect on Conformational Changes

Sophie Purser, et al . Chem. Soc. Rev., 2008, 37, 320–330A. G. Myers, J. K. Barbay and B. Zhong, J. Am. Chem. Soc., 2001, 123, 7207.

Conformational study on fluorinated analogues of HIV-1 protease inhibitor “Indinavir”

Efavirenz is a non-nucleoside reverse transcriptase inhibitor used in the treatment of patients with HIV

SAR studies showed that the presence of the trifluoromethyl group improved drug potency by lowering the pKa of the cyclic carbamate

Makes a key hydrogen bonding interaction with the protein.

Hydrogen Bonding

Sophie Purser, et al . Chem. Soc. Rev., 2008, 37, 320–330G. L. Plosker, C. M. Perry and K. L. Goa, PharmacoEconomics, 2001, 19, 421.

J. C. Adkins and S. Noble, Drugs, 1998, 56, 1055.S. R. Rabel, S. Sun and M. B. Maurin, AAPS PharmSci, 2001, 3, 1.

Rapid oxidative metabolism by liver enzymes (P450 cytochrome enzymes) and/or stomach acidic medium may decompose the drug.

Introducing fluorine atoms has been shown to be a powerful strategy.

P.N. Edwards in Organofluorine Chemistry: Principles and Commercial Applications R.E. Banks, B.E. Smart, J.C. Tatlow Eds, Plenum Press, N-Y 1994, pp. 502-509.

P.N. Edwards in Organofluorine Chem: Principles and Commercial Applications Plenum Press, N-Y 1994, pp. 502-509 F. Chorki, et al. J. Med. Chem. 2004, 47, 1423-1433.

Ki (nM) Plasmatic concentration(M receptor) ng/Kg

(after 1h, 30mg/Kg p.o)

0.45 21

0.40 805

Metabolic stability

O

O

OHHOOH

Et

O O

O OH

OMeOO

HO N

Erythromycin

Macrolide antibiotic against pathogenic bacteriaUnsuitable for the treatment of the Helicobacter pyloriinfection, which causes gastritis

The drug decomposes under the acidic conditions of the stomach.

Better bioavailabilityLonger biological half lifeReaches tissue concentrations than Erythromycin

Effect of Fluorine on Metabolic Stability

S. Mabe, J. Eller and W. S. Champney, Curr. Microbiol., 2004, 49, 248.M. T. Fera, M. Giannone, S. Pallio, A. Tortora, G. Blandino and

M. Carbone, Int. J. Antimicrob. Agents, 2001, 17, 151.Sophie Purser, et al . Chem. Soc. Rev., 2008, 37, 320–330

Examples of Fluorinating Reagents

N+N+

F2BF4

-

Cl

Selectfluor(1-chloromethyl-4-fluorodiazoniabicyclo [2.2.2]octane

bis(tetrafluoroborate))

SO

ONS

O

O

F

NFSI(N-fluorobenzene-

sulfonimide)

SO2

N F

N-fluorocamphor sultam

NF

R1

R2 R3+

N-fluoropyridinium salt

R1 = H, MeR2 = H, Me, ClR3 = H, Me, ClX = BF4

-, OTf-

X-

ElectrophilicReagents

Unstable to heatExplosive

Stable to heat

3

R

O

HTf2O

R CH

OTfOTf

nBu4N+ Ph SnF

F

PhPh

-

RFF

O

R1 R2

DASTR1 R2

F F

ketones Gem-difluorides

OHR1 DFI

FR1

Alcohol

Aldehyde

Examples of Nucleophilc Fluorination

Angew. Chem., Int. Ed. 2005, 44, 214–231.

Tetrahedron Lett. 1992, 33, 7787.Synlett. 1993, 587

J. Org. Chem. 1999, 64, 5264.J. Org. Chem. 1999, 64, 7048.J. Org. Chem. 2000, 65, 4830.J. Am. Chem. Soc. 1997, 119,

11743.

NSF3

DAST

J. Am. Chem. Soc. 1997, 119, 11743.

Synthesis of Glycosyl Fluoride

Examples of Nucleophilc Fluorination

Tetrahedron Lett. 1979, 20, 2023.CsF, HF.Pyr, TBAF can be used

Examples of Electrophilc Fluorination

Acc. Chem. Res. 2005, 38, 803–812.

J. Org. Chem. 1992, 57, 1597.

J. Org. Chem. 1999, 64, 5264.

J. Org. Chem. 1993, 58, 2791.

J. Org. Chem. 1997, 62, 3340.

NH

Me

NH

Selectfluor

CH3CN/H2O (1:1)RT, 71%

Me F

O

NH

NH

HNO

O

HN

HH Selectfluor

CH3CNTHF44% N

H

NN

HNH

H

H

F

F

H

O

O

Org. Lett. 2000, 2, 639.

Angew. Chem. Int. Ed. 2001, 40, 4461.

Examples of Trifluoromethylation

J. Med. Chem. 1992, 35, 641.J. Org. Chem. 2002, 67, 7162.

Trifluoromethylated amino alcohol

Trifluoromethyl-L-proline

Trifluoromethylation

Tetrahedron Lett. 1991, 32, 91.Chem. Rev. 1997, 97, 757-786

Aromatic Fluorination

Science. 325, 1661. (2009)

Enantioselective Electrophilic Fluorination

Substrate-controlled fluorination: diastereoselective electrophilic fluorination of chiralenolates or enol ethers

Reagent-controlled fluorination: asymmetric fluorination of enolates using chiralelectrophilic fluorinating agents

Catalytic asymmetric fluorination

Substrate-controlled Fluorination

NFSI

SO

ONS

O

O

F

Tetrahedron. Lett. 1992, 33, 1153.Tetrahedron. Lett. 1998, 39, 6135J. Org. Chem. 62, 7546

Angew. Chem., Int. Ed. Engl. 1997, 36, 2362.Synthesis. 2001, 2307.

Reagent-controlled Fluorination

Moderate yields and low to moderate enantioselectivities (<90% ee)

Wong, C.-H., Angew. Chem. Int. Ed., 2005, 44, 192Taylor, S. D.; Kotoris, C. C. and Hum, G. Tetrahedron, 1999, 55,12431-12477

Reagent-controlled Fluorination

Org. Lett. 2000, 2, 3699. PCT Int. Appl. WO2001090107. 2001J. Am. Chem. Soc. 2000, 122, 10728

N

NOR2

F+ X-

R1

O

BnF

O

CO2EtF O

O

CO2EtF N

H

FPh

O

86% yield, 91% ee 89% yield, 78% ee 92% yield, 80% ee 100% yield, 78% ee

Cinchona Alkaloids Fluorinating Reagents

Fluorobenzofurancarboxylate

Fluoro-indolinoneFluoro-indenecarboxylate

Fluoro-indenone

Catalytic Asymmetric Fluorination

O

R2

O

R1 OR3

5 mol%catalyst

SelectfluorCH3CN, rt

O

R2

O

R1 OR3F

OO

OTi

OCl

ClMeCN NCMe

1-napt

1-napt1-napt

1-naptO

Me

O

OPhF

O

Me

O

SPhF

O

Me

O

OF

i-Pr

i-Pr i-Pr

O

Cl

O

Ph OEtF

O

O

F

O

Bn

50% yield, 88% ee 76% yield, 91% ee

53% yield, 33% ee89% yield, 90% ee

63% yield, 51% ee

TADDOL-Titanium complexes

TADDOL-Titanium catalyzed asymmetric fluorination

Hintermann, L. ; Togni, A. Angew. Chem. Int. Ed. 2000, 39, 4359 – 4362Ibrahim, H.; Togni, A. Chem. Commun. 2004, 1147 – 1155

Asymmetric Fluorination Catalyzed by Other Lewis Acids

NFSI

SO

ONS

O

O

F

Tetrahedron: Asymmetry, 2004, 15, 1007Synlett 2004, 1703 –1706

J. Am. Chem. Soc., 2002, 124, 14530–14531.

BINAP-Palladium Complexes

NO

Boc

MeO

Cl

F3C

PAr2PAr2

Pd

2.5 mol%

NFSI, acetone, 0oCii. deboc N

H

OF3C

F

i.

MeO Cl

BMS-204352MaxiPost

Phase III clinical trials for treatment of acute ischemic stroke

Organo-Catalytic Enantioselective Fluorination

Excellent yields and high enantioselectivity

Beeson, T. D. and MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127Marigo, M. ; Jørgensen, K. A. et al Angew. Chem. Int. Ed. 2005, 44, 2 – 5

Organo-Catalytic Enantioselective Trifluoromethylation

J. Am. Chem. Soc. 2009, 131, 10875–10877