chemistry and biology of 2 imidazoliness/davis flyer.pdf · n n r1 r2 r4 r3 r5 r6 n n o n nh o ipro...

NN

R1

R2

R4R3

R5R6

N

N

NO

NH

O

iPrO

OMe

H

H

Cl

Cl

Chemistry and Biology of 2‐Imidazolines 

Tyler A. DavisJohnston Lab

December 10, 2009

Imidazolines throughout Science Natural Products: 4,5-Dihydro-6’-deoxybromotopsentin

• Isolated off the coast of the Bahamas• From the deep sea Caribbean sponge from the family Halichondriidae• isolated as chiral non-racemic material• many topsentin (imidazole) derivatives found in nature

NH

NH

N

O

NH

Br

4,5-Dihydro-6'-deoxybromotopsentin

Review: 2-ImidazolinesDu, D-M.; Liu, H. Adv. Synth. Catal. 2009, 351, 489.

• IBS = Imidazoline Binding Sites• Imidazolines are good ligands for the IBS• Molecules that bind to the IBS have major physiological action

Pharmacophores: IBS

Imidazolines throughout Science Catalysis

Review: 2-ImidazolinesDu, D-M.; Liu, H. Adv. Synth. Catal. 2009, 351, 489.

N

NAr

Ar

P

Asymmetric Mizoroki-Heck Reaction

ArAr

Ar = 3,5-F2C6H3

Imidazoline Binding SitesDiscovery

• Bousquet et al. -1984• Three known subtypes have been proposed• Little characterization exists

Clonidine:

• currently marketed and historically prescribed as an antihypertensive drug • may also be used as treatment for insomnia, menopausal, and ADHD• Interacts with α-2 adrenoceptors (α2-AR)• also interacts with the IBS type 1 (I1)

Types:

• I1 – found in the brainstem and associated with blood pressure• I2 – found predominantly in the brain and liver, regulate monoamine turnover• I3 – located in pancreatic β-cells and regulate insulin secretion

Du, D-M.; Liu, H. Adv. Synth. Catal. 2009, 351, 489.Hudson et al. Brain Res. 2009, 1279, 21-28.

Synthesis of 2‐Imidazolines

R5

NH2

R3

H2N

R1CHO w/ oxidantor

R1CO2H or equivalent

R5

HN

R1

O

OH

+ R2NH2

NR3

R4

R2

R5CN

R6

+

R5

HN

R1

ONHR2

R3

N

R5

R2

R1CN+

R3

R5

MeCN

TsNCl2

+

+

Review: 2-ImidazolinesDu, D-M.; Liu, H. Adv. Synth. Catal. 2009, 351, 489.

1,2‐Diamines plus Carboxylic Acid Equivalents

R NH2

NH2R

R

R

R

R

N

HN

N

HN

Ar

ArO

NAr

Me

Me

Me

MeCN, rt, 2hthen reflux, 2h

94-97%

EtOH, rt, 1hthen reflux, 4h

83-97%

Ar

NH2

OEt

I

Cl

Ph

Ph N

HN

ArN

HN

Ar

Dauwe, C.; Buddrus, J. Synthesis. 1995, 171.

Synthesis of 2‐imidazolines from β‐hydroxyamides

Casey et al . J. Org. Chem. 2002, 67, 3919

Synthesis of 2‐imidazolines from Isocyanides and Imines

Top: Hayashi et al . Tetrahedron Lett. 1996, 37, 4969.Bottom: Lin et al . J. Org. Chem. 1999, 64, 1331.

CO2Me

NC R1

N

H

R2

R1 = aryl, alkenylR2 = Ts, Bs

N NR2

R1 CO2Me

N NTs

R1 CO2Me

1 mol%AuCl(c-HexNC)

MeCN20-35 °C

1 mol%AuCl(c-HexNC)

MeOH:CH2Cl23:1

25 °C

>95% yield>9:1 dr

up to 95% yield20:1 dr

FePPh2

NMe

Me

N

PPh2

NN

CO2EtAr

Ts

6-24:1 dr46-88% ee

CO2Et

NC Ar

N

H

Ts Me2SAuCl (0.6 mol%)

CH2Cl2, 25 °Ccatalyst (0.5 mol%)

Synthesis of 2‐imidazolines from Dehydrative Cyclization of Amides

Kelly, J; You, S-L . Org Lett. 2004, 6, 1681.Further extension of this workPemberton et al. Tetrahedron. 2008, 64, 9368.

R1HN

R2

O

HN

O

OR3

NHTs

R1HN

R2

N

N

Ts

O

OR3

R1 = Fmoc, CbzR2 = iPr, BnR3 = Me, Bn

Ph3PO/Tf2OCH2Cl2

* *

71-88% yieldsingle diastereomer

Synthesis of 2‐imidazolines by Double SN2 Reaction

Oi, R; Sharpless, K. B. Tetrahedron Lett. 1991, 32, 999.

Synthesis of 2‐imidazolines from Aziridines

N

R2

R1

CO2Et

R2

R1

N

NR4

R4CNBF3

45-82% yield

CO2Et

cis trans

Top: Nozaki et al. Tetrahedron. 1973, 29, 3137.Bottom: Concellon et al. Recl. Trav. Chim. Pays-Bas. 1992, 111, 59.

Nutlins: Small Molecule MDM2 Antagonists 

• Class of compounds patented by Hoffman-LaRoche• Activity first reported in Science in 2004• Found to activate p53 pathway as an MDM2 antagonist• Potential to treat cancer

N

N

NO

NH

O

iPrO

OMe

H

H

Cl

Cl

Nutlin-3

First Report:Vassilev et al. Science 2004, 303, 844

Glossary Terms 

Cancer- 6 mechanisms

• Self-sufficiency in growth signals• sustained angiogenesis• limitless replicative potential• tissue invasion and metastasis• evasion of apoptosis• insensitivity to anti-growth signals

The pathways of cancerHanahan, Weinberg . Cell 2000, 100, 57-7.p53 figureCho et al. Science. 1994, 265, 346-355.

The Cell Cycle- Role of p53

• Three major checkpoints (G1, G2, metaphase)• p53 is involved with two (G1, G2)• ~50% of human cancers have mutated p53• p53 is the most frequently inactivated protein in human cancers

p53

• 43.7 kDa• “the guardian of the genome”• “the guardian angel gene”• “the master watchman”• The 1993 “molecule of the year” by Science• tumor suppressor protein

The Tokyo Subway System 

p53 and the Signaling Pathways of the Cell 

Nutlins: Chiral Nonracemic cis‐Imidazolines

first literature report of Nutlins, and inhibition of p53/MDM2Vassilev et al. Science 2004, 303, 844imidazoline binding sites (IBS)Dardonville, C.; Rozas, I. Med. Res. Rev. 2004, 24, 639

Discovery: Hoffmann LaRoche 2006

• potent and selective antagonists of MDM2• replicates p53 binding at native site (characterized by X-ray)• hypothesis: ‘the cis-imidazoline may represent a useful small-molecule scaffold to project functional groups similar to a helical peptide.’• ‘enantiomer-a’ binds 151 times more active than ‘enantiomer-b’

but…• absolute stereochemistry not assigned• Nutlins are prepared as the racemate, then separated using chiral stationary phase chromatography• synthesis reported only in series of patents

Nutlins: Chiral Nonracemic cis-Imidazolines

first patent report of NutlinsKong, Binh Vu (Hoffmann-La Roche) 2003, 2002-EP139052003051360

Synthesis

• absolute stereochemistry not assigned• prepared as the racemate, then separated using chiral stationary phase chromatography• synthesis reported only in series of patents (as many as 15, 2003-2009)• longest linear sequence: 5 steps• total steps: 7 steps

most recent synthesis detailsBartkovitz,Cai, Chu, Li, Lovey, Binh Vu, Zhao (Hoffmann-La Roche) 2009, 2008-EP63053/2009047161

OEtN

EtOH

Cl

Cl

N

N

iPrO

OMephosgene

NEt3, 0 °C

N

N

O

NH2

NH2

Cl

Cl

NH2

NH2

OH

OH

H

O

Cl

MeCN, reflux

mesoaq. H2SO4, MeCN

(85%)

(65%)

HCl (g)

EtOH, -10 °COiPr

OMe

OH

OMe

O H NaOAc, EtNO2AcOH, reflux CN

OiPr

OMe

Cs2CO3

acetone, reflux

(65%)

(87%)reflux

(73%)

(99%)

(87%)

(CH3)2CHI

1.

2.meso

H

1.

2.

H

H

H

meso

rac-Nutlin-3

Resolution of Enantiomers

• preparatory supercritical fluid chromatography• 5 g Nutlin-3 purified in 75 min, 92% recovery: 48 g/day productivity• difficult to determine whether absolute configuration has been publicly correlated with ‘enantiomer-a’