proline analogues: advanced building blocks for ... - enamine€¦ · analogues of proline. 7 drugs...

Proline analogues: advanced building blocks

for drug discovery

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

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Tel-Aviv

Kyiv

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50 papers

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Analogues of Proline

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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.

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Why Proline?

- bifunctional scaffold

- cyclic (conformationally restricted)

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

- cheap (natural amino acid)

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Many simple analogues of Prolinesare still unknown!!!

Why?

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Some representative syntheses

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NH

CO2H

CF3

Fluorinated 4,5-methano-Prolines

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

Synthesis of CF3-4,5-methano-Proline

5 g

CF3

N2

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Ar

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

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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

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In 2012 Ledipasvir was in clinical trials.

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Synthesis of 3,3’-cyclopropyl-Proline

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

Andrei Tymtsunik

5 g

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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

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Melogliptin

abtibacterial agent

N CN

F

O

HN

N

N

N

phase III

Glenmark Prarm.

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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

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In collaboration with Prof. T. Bach

(TU Muenchen)

20 mg scale 5 g scale

Photochemistry

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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.

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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

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also 19F-NMR label for peptides

In collaboration with Prof. A. Ulrich

(KIT Karlsruhe)

with Prof. N. Budissa(TU Berlin)

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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

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Poster (synthesis)

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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

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