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