enamine proline analogues 2015

28
Proline analogues: advanced building blocks for drug discovery (Enamine Ltd, Kyiv, Ukraine) Dr. Pavel Mykhailiuk

Upload: enamine-ltd

Post on 16-Apr-2017

161 views

Category:

Health & Medicine


1 download

TRANSCRIPT

Page 1: Enamine proline analogues 2015

Proline analogues: advanced building blocks

for drug discovery

(Enamine Ltd, Kyiv, Ukraine)Dr. Pavel Mykhailiuk

Page 2: Enamine proline analogues 2015

www.enamine.net 2

Tel-Aviv

Kyiv

Page 3: Enamine proline analogues 2015

www.enamine.net

World's largestproducer of building blocks

Founded in 1991

Page 4: Enamine proline analogues 2015

www.enamine.net

~120.000 building blocksin stock

~120.000: population of Rehovot

Founded in 1991

1 building block / citizen

Page 5: Enamine proline analogues 2015

www.enamine.net

50 papers

Page 6: Enamine proline analogues 2015

www.enamine.net

Analogues of Proline

Page 7: Enamine proline analogues 2015

www.enamine.net 7

Drugs with substituted Prolines

N

HN

O

O

Cl

HO

HOOH

SMe

Clindamycin

abtibacterial drug

N

CO2H

O

NH

CO2Et

Ph

Spirapril

antihypertensive drug

S

S

N

CO2H

O

P

O OH

Ph

Fosinopril

antihypertensive drug

Melogliptin

abtibacterial agent

N CN

F

O

HN

N

N

N

phase III

Glenmark Prarm.

Page 8: Enamine proline analogues 2015

www.enamine.net 8

Why Proline?

- bifunctional scaffold

- cyclic (conformationally restricted)

- saturated (high Fsp3 -“Escape the Flatland”)

- cheap (natural amino acid)

Page 9: Enamine proline analogues 2015

www.enamine.net

Many simple analogues of Prolinesare still unknown!!!

Why?

Page 10: Enamine proline analogues 2015

www.enamine.net

Some representative syntheses

Page 11: Enamine proline analogues 2015

www.enamine.net 11

NH

CO2H

CF3

Fluorinated 4,5-methano-Prolines

Page 12: Enamine proline analogues 2015

www.enamine.net 12P. Mykhailiuk et al. Angew. Chem. Int. Ed. 2008, 5765.

Synthesis of CF3-4,5-methano-Proline

5 g

CF3

N2

Page 13: Enamine proline analogues 2015

www.enamine.net 13

Ar

P. Mykhailiuk et al. Angew. Chem. Int. Ed. 2008, 5765.

Page 14: Enamine proline analogues 2015

www.enamine.net 14

Vova Kubyshkin

Synthesis of F2-4,5-methano-Proline

14

V. Kubyshkin et al. Org.Lett. 2012, 5765.

V. Kubyshkin et al. J. Fluorine Chem. 2013, 136.

V. Kubyshkin et al. J. Fluorine Chem. 2015, 73.

5 g

Page 15: Enamine proline analogues 2015

www.enamine.net

In 2012 Ledipasvir was in clinical trials.

Page 16: Enamine proline analogues 2015

www.enamine.net

Synthesis of 3,3’-cyclopropyl-Proline

A. Tymtsunik et al. Tetrahedron Lett. 2012, 3847

Andrei Tymtsunik

5 g

Page 17: Enamine proline analogues 2015

www.enamine.net

2014

FDA approved Ledipasvir (Gilead Sciences)

M. Baenzinger, C. Bucher Chemistry Today 2015, 33, 50.

C. Gütz et al. Org. Proc.ess Res. Dev. 2015, 19, 1428.

2015

Large-scale synthesis of the amino acidby Novartis:

A. Tymtsunik et al. Tetrahedron Lett. 2012, 3847

2012

Page 18: Enamine proline analogues 2015

www.enamine.net 18

Melogliptin

abtibacterial agent

N CN

F

O

HN

N

N

N

phase III

Glenmark Prarm.

Page 19: Enamine proline analogues 2015

www.enamine.net

NH

CO2H

F

N CO2Me

F

Bz

N CO2Me

F

Bz

H2N CO2H

OHF

OMs

73%

366 nm

[2+2]

HCl

99%

77%

POCl3MeOH

71% H2N CO2Me

Cl BzCl

HN CO2Me

Cl

82%

Bz

KOtBu

Ph2CO

CH3CN

Synthesis of F-2,4-methano-Proline

Manuscript under preparation

5 g

A. Tkachenko et al. Org. Lett. 2009, 5674.

Anton Tkachenko

Page 20: Enamine proline analogues 2015

www.enamine.net 20

In collaboration with Prof. T. Bach

(TU Muenchen)

20 mg scale 5 g scale

Photochemistry

Page 21: Enamine proline analogues 2015

www.enamine.net 21

Melogliptinantibacterial agent

N CN

F

O

HN

N

N

N

phase III

Glenmark Prarm.

J. R. Del Valle et al. Angew. Chem. Int. Ed. 2002, 1600.

X.-l. Qiu et al. JOC 2002, 7162.

Page 22: Enamine proline analogues 2015

www.enamine.net 22

Vova Kubyshkin

Synthesis of CF3-Proline

NH

CO2H

HO

N CO2Me

HO

Boc

1. SOCl2/MeOH

2. Boc2O, NEt3, CH2Cl2 N CO2Me

O

Boc

N CO2Me

Boc

N CO2Me

CF3

Boc

N CO2Me

CF3

Boc

N CO2H

CF3

Boc

90 %

77 %

96%

SO3*Py

DMSO, NEt3

1. CF3TMS,

NBu4F (cat.)

2. aq. NH4Cl

3. aq. NBu4F

HO

CF3 1. SOCl2/Py

2. water

72%

Pd-C/H2

94%

MeOH

1. NaOH

2. HCl

97%

TFA

97%

CH2Cl2 NH

CO2H

CF3

V. Kubyshkin et al. Org.Biomol.Chem. 2015, 3171.

20 g

Page 23: Enamine proline analogues 2015

www.enamine.net 23

also 19F-NMR label for peptides

In collaboration with Prof. A. Ulrich

(KIT Karlsruhe)

with Prof. N. Budissa(TU Berlin)

Page 24: Enamine proline analogues 2015

www.enamine.net

NH

CO2H

NH

CO2HN CO2H

Boc

F

F

NH

CF3

CO2H NH

CO2HCF3

NH

CO2H

H H

NH

CO2H

NH

CO2H

F

NH

CO2H

NH

CO2H

MeONH

CO2HNH

O

CO2H

NH

CO2H

H

H

NH

CO2H

NH

CO2H

FF

NH

CO2H

S

NH

CO2HCF3

S

NH

CO2H

S

NH

CO2H

S

NH

CO2H

S

NH

CO2HPh

NH

CO2H

H

H

NH

CO2H

NH

CO2H NH

CO2H

NH

CO2H NH

CO2H

Ph

NH

CO2HPh

NH

CF3

CO2H N CO2H

Boc

F

F

NH

CO2H

NH

CO2H

F

NH

CO2H

NH

CO2H

NH

CO2H NH

CO2H

NH

O

CO2H

F

F

NH

O

CO2H

F

F

NH

O

CO2H NH

CO2HNH

CO2H

MeO2C

NH

CO2H

H2N

NH

CO2H

F

NH

CO2H

Proline

> 100 analogues of Proline

V. Kubyshkin et al. Org. Biomol. Chem. 2015, 3171.

A. Tymtsunik et al. Tetrahedron Lett. 2014, 3847.

V. Kubyshkin et al. J. Fluorine Chem. 2013, 136.

V. Kubyshkin et al. Org. Lett. 2012, 5254.

I. Kondratov et al. Org. Biomol. Chem. 2012, 8778.

P. Mykhailiuk et al. Tetrahedron 2011, 3091.

N. Kopylova et al. Tetrahedron: Assym. 2010, 2868.

V. Kubyshkin et al. Synthesis 2009, 3329.

P. Mykhailiuk et al. Angew.Chem.Int.Ed. 2008, 5765.

V. Kubyshkin et al. Tetrahedron Lett. 2007, 4061.

O. Grygorenko et al. Tetrahedron: Assym. 2006, 252.the LARGEST collection of Prolines in the world

Page 25: Enamine proline analogues 2015

www.enamine.net

Poster (synthesis)

Page 26: Enamine proline analogues 2015

www.enamine.net

500 chemists

Alekseenko A.

Artamonov O.

Artemenko A.

Andrushko O.

Arkhipov V.

Bezdudny A.

Bilenko V.

Chalyk B.

Datcenko O.

Denisenko O.

Dolovaniuk V.

Druzhenko T.

Granat D.

Garbuz P.

Gavrilenko K.

Grygorenko O.

Martirosov R.

Mituk A.

Mikhalchuk V.

Michurin O.

Gryshuk S.

Iminov R.

Ivon Y.

Komarov I.

Kondratov V.

Kubyshkin V.

Levchenko K.

Leychenko E.

Logvinenko V.

Ostapchuk E.

Pasternak A.

Parhomenko L.

Pervak I.

Pustovit U.

Radchenko D.

Savich V.

Savchuk T.

Scherbatiuk A.

Shyshlik O.

Slobodianuk E.

Tereshenko O.

Tkachenko A.

Tkachuk G.

Tolmacheva N.

Tolmachev A.

Trofimchuk S.

Tymtsunik A.

Vilchinsky V.

Yarmolchuk V.

Yarmoluk D.

and many others

Page 27: Enamine proline analogues 2015

www.enamine.net

Visit our booth forspecific structures

Page 28: Enamine proline analogues 2015

World's largestproducer of building blocks