Proline analogues: advanced building blocks
for drug discovery
(Enamine Ltd, Kyiv, Ukraine)Dr. Pavel Mykhailiuk
www.enamine.net 2
Tel-Aviv
Kyiv
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Founded in 1991
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Founded in 1991
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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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