This document summarizes Enamine Ltd, a producer of building blocks for drug discovery based in Kyiv, Ukraine. Some key points: - Enamine has the world's largest collection of small molecule building blocks, with over 120,000 compounds in stock. - They have extensive experience synthesizing analogues of proline, an important building block, with over 100 proline analogues synthesized. - Enamine has 500 chemists who have published over 50 papers on novel syntheses, including syntheses of fluorinated, cyclopropyl, and other substituted proline analogues.

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

2. www.enamine.net 2
Tel-Aviv
Kyiv

3. www.enamine.net
World's largest
producer of building blocks
Founded in 1991

4. www.enamine.net
~120.000 building blocks
in stock
~120.000: population of Rehovot
Founded in 1991
1 building block / citizen

5. www.enamine.net
50 papers

6. www.enamine.net
Analogues of Proline

7. www.enamine.net 7
Drugs with substituted Prolines
N
H
N
O
O
Cl
HO
HO
OH
SMe
Clindamycin
abtibacterial drug
N
CO2H
O
N
H
CO2Et
Ph
Spirapril
antihypertensive drug
S
S
N
CO2H
O
P
O OH
Ph
Fosinopril
antihypertensive drug
Melogliptin
abtibacterial agent
N CN
F
O
H
N
N
N
N
phase III
Glenmark Prarm.

8. www.enamine.net 8
Why Proline?
- bifunctional scaffold
- cyclic (conformationally restricted)
- saturated (high Fsp3 -“Escape the Flatland”)
- cheap (natural amino acid)

9. www.enamine.net
Many simple analogues of Prolines
are still unknown!!!
Why?

10. www.enamine.net
Some representative syntheses

11. www.enamine.net 11
N
H
CO2H
CF3
Fluorinated 4,5-methano-Prolines

12. www.enamine.net 12P. Mykhailiuk et al. Angew. Chem. Int. Ed. 2008, 5765.
Synthesis of CF3-4,5-methano-Proline
5 g
CF3
N2

13. www.enamine.net 13
Ar
P. Mykhailiuk et al. Angew. Chem. Int. Ed. 2008, 5765.

14. 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

15. www.enamine.net
In 2012 Ledipasvir was in clinical trials.

16. www.enamine.net
Synthesis of 3,3’-cyclopropyl-Proline
A. Tymtsunik et al. Tetrahedron Lett. 2012, 3847
Andrei Tymtsunik
5 g

17. 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 acid
by Novartis:
A. Tymtsunik et al. Tetrahedron Lett. 2012, 3847
2012

18. www.enamine.net 18
Melogliptin
abtibacterial agent
N CN
F
O
H
N
N
N
N
phase III
Glenmark Prarm.

19. www.enamine.net
N
H
CO2H
F
N CO2Me
F
Bz
N CO2Me
F
Bz
H2N CO2H
OH
F
OMs
73%
366 nm
[2+2]
HCl
99%
77%
POCl3
MeOH
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

20. www.enamine.net 20
In collaboration
with Prof. T. Bach
(TU Muenchen)
20 mg scale 5 g scale
Photochemistry

21. www.enamine.net 21
Melogliptin
antibacterial agent
N CN
F
O
H
N
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.

22. www.enamine.net 22
Vova Kubyshkin
Synthesis of CF3-Proline
N
H
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 N
H
CO2H
CF3
V. Kubyshkin et al. Org.Biomol.Chem. 2015, 3171.
20 g

23. www.enamine.net 23
also
19F-NMR label for peptides
In collaboration
with Prof. A. Ulrich
(KIT Karlsruhe)
with Prof. N. Budissa
(TU Berlin)

24. www.enamine.net
N
H
CO2H
N
H
CO2H
N CO2H
Boc
F
F
N
H
CF3
CO2H N
H
CO2HCF3
N
H
CO2H
H H
N
H
CO2H
N
H
CO2H
F
N
H
CO2H
N
H
CO2H
MeO
N
H
CO2H
N
H
O
CO2H
N
H
CO2H
H
H
N
H
CO2H
N
H
CO2H
F
F
N
H
CO2H
S
N
H
CO2HCF3
S
N
H
CO2H
S
N
H
CO2H
S
N
H
CO2H
S
N
H
CO2HPh
N
H
CO2H
H
H
N
H
CO2H
N
H
CO2H N
H
CO2H
N
H
CO2H N
H
CO2H
Ph
N
H
CO2HPh
N
H
CF3
CO2H N CO2H
Boc
F
F
N
H
CO2H
N
H
CO2H
F
N
H
CO2H
N
H
CO2H
N
H
CO2H N
H
CO2H
N
H
O
CO2H
F
F
N
H
O
CO2H
F
F
N
H
O
CO2H N
H
CO2H
N
H
CO2H
MeO2C
N
H
CO2H
H2N
N
H
CO2H
F
N
H
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

25. www.enamine.net
Poster (synthesis)

26. 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

27. www.enamine.net
Visit our booth for
specific structures

28. World's largest
producer of building blocks