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, PhDPavel.Mykhailiuk@mail.enamine.net 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.