Bicyclic amines for drug discoveryby [2+2]-photocyclization T. Druzhenko, E. Skalenko, O. Denisenko, V. Levterov, O. Datsenko, A. Tkachenko, D. Radchenko, A. Tolmachev, A. Gomon, O. Michurin, V. Kubyshkin, I. Komarov, Y. Moroz, P. Mykhailiuk
Results
EN300-300093 EN300-252488EN300-300536 EN300-252734 EN300-301433EN300-28750 EN300-307460 EN300-53468
NH
CO2HNH
CO2H
F
NH
NH
FNH
F
FNH
CF3
NH
CO2H
NH
CO2HNH
CO2H
NNH2
Boc
NH S
NH N
CO2H
H H
NH
H H
NH
H H
OH OH
NH
H
H
O
H
H
NH
H
H
S
H
HO
ONH
H
HO
H
H
NBoc
H
H
HN
H
H
EN300-299747
NH
CO2H
CF3
N
NH2
NH
OHNH
CO2H
EN300-268516 EN300-82932
EN300-310213 EN300-312268
EN300-82933
EN300-305373 EN300-307461EN300-307418
EN300-82931
EN300-128723 EN300-298031
EN300-309175
EN300-204155
EN300-312488 EN300-307561 EN300-179023
NH
NH2
O
NH
EN300-312267
Boc
BocNBoc
O
N
O
EN300-300210Boc
Synthesis
O N NH76%
2) aq. HCl
CH2Cl2, 64%
O
N
N
N
NH83%
2) aq. HCl
CH2Cl2, 47%
(CF3CO)2O
1) NH2
N
O N NH91%
2) aq. HCl
CH2Cl2, 78%(CF3CO)2O
1)
2)
NH2
N N N N
OCF3
OCF3
OCF3N N
2)
(CF3CO)2O
1) NH2
2)
1) hv
1) hv
1) hv
N CO2Me
Bz[2+2]77%
CH3CN
Scale:
20 mg 5 g
1 kg
1 kg (in �ow)
N CO2Me
Bz
hv
1) LiAlH4Et2O
76%N
O
O
Ph
N
O
O
PhH
H
MeO2CNH
H
H
HO
N
O
O
PhH
H
MeO2CNH
H
H
HO
N
O
O
Ph
NH
H
H
NH
H
H
O
H
H
SO
O
H
H
N
H
H
N
H
H
O
H
H
SO
O
H
H
Ph
PhO
O
O
O
O
SO
O
53%
49%
MeO2C
65%
2) Pd/H2MeOH
1) LiAlH4Et2O
85%
2) Pd/H2MeOH
1) LiAlH4Et2O
61%
2) Pd/H2MeOH
1) LiAlH4Et2O
59%
2) Pd/H2MeOH
hv
hv
hv
NH
CO2HN CO2Me
BzN CO2Me
Bz
H2N CO2H
OHBr
aq. HCl
99%77%
POCl3MeOH
71% H2N CO2Me
Cl BzCl
BzHN CO2Me
Cl
82% KOtBu
CH3CN
THF, 73%
Serine
re�ux
O NBz
NH77%
2) aq. HCl
NH2
CH2Cl2, 73%BzCl
1)
2)
CO2EtO N CO2Et
BzNH
CO2H65%
2) aq. HClCH2Cl2, 53%
NH2
BzCl
1)
2)
hv
1) hv
1) hv
“Conformational restriction” concept has already gained a considerable attention in medicinal chemistry.1 Scientists are looking more and more now on 3D-shaped saturated building blocks.2-5 In this context, intrinsically conformationally rigid bicyclic amines seem to be promising for drug discovery. In continuation of our ongoing program towards novel building blocks for drug discovery,6,7 herein we synthesized libraries of diverse bicyclic amines by photochemical [2+2]-cyclization as a key step.8-10
Introduction and Aim
N
O
CO2H
Ph
H
H
NH
H
F
N
HN
OON
O
NH2 OH
CN
H
H
Mitiglinideantidiabetic drug
Belaperidoneantischizophrenia drug
Saxagliptinantidiabetic drug
NH
NH
Cyclic amines
NH
NH
NH
Bicyclic amines
Conformationalrestriction
H H
H
H
Pavel Mykhailiuk, [email protected] Enamine Ltd, www.enamine.net78 Chervonotkatska St, 02094 Kyiv, Ukraine
Contact References1. F. Lovering et al. J. Med. Chem. 2009, 6752. 2. F. Lovering et al. J. Med. Chem. 2009, 6752. 3. O. Wlochal et al. Org. Lett. 2014, 4094.4. M. Westphal et al. ChemMedChem. 2015, 461.5. Y. Ling Goh et al. Org. Lett. 2014, 1884.
6. O. Denisenko et al. Org. Lett. 2010, 4372. 7. T. Druzhenko et al. Org. Lett. 2015, 1922. 8. A. Tkachenko et al. Org. Lett. 2009, 5674. 9. T. Druzhenko et al. manuscript under preparation.10. V. Levterov et al. manuscript under preparation.
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