Functionalized dialdehydes: H 2 O C O NH C OP h P h E t F ...€¦ · Fluorine in medicinal...

Functionalized dialdehydes:promising scaffolds for access to

fluorinated heterocycles and highly functionalized β-amino acids

Loránd Kiss, Renáta Anita Ábrahámi, Ferenc Fülöp

Institute of Pharmaceutical Chemistry, University of Szeged, Hungary

XVII International Conference on Heterocycles in Bioorganic Chemistry, May 28-31, 2017, Galway

CO2Et

NHCOPh

CHO

CHO

O

O

NHCbz

CO2Et

H

H

N

EtO2CNHCOPh

CF3

N

CO2Et

NHCbzF2HC

F

F

NHCbz

CO2Et

HF

HF

CO2Et

HF

F

O

N

Ph

HH

FH

Kiss L, Fülöp F, Chem. Rev. 2014, 114, 1116-1169.

2

Cyclic β-amino acidsBioactive compounds. Small molecular entities

N

CO2HH2N

O Ot-Bu

A-87380 (8)

N

CO2HH2N

NO

HN

O

F3C

A-192558(10)

CO2EtPh

NMe2

tilidin (7)

CO2H

NH2

BAY Y9379 (5)

OH

NH2

O

O

CO2H

Me

H2N CO2H

HO2C

NH2

HO2C NH2

cyclic-amino acids

peptides

antibiotics

chiralbuilding blocks

-lactams

bioactive derivatives

natural compounds

NH

H2N CO2H

O

CO2HH2N oryzoxymicin (3)oxetin (2)

cispentacin (1)

icofungipen (4)

transpentacin (6)

APC (9)

Kiss L, Fülöp F, Chem. Rev. 2014, 114, 1116-1169.

3

Cyclic β-amino acidsBioactive compounds with cyclic β-amino acid moieties

- antibiotics

- antitumoral agents

- cardioprotective products

- antiviral agents

4

Fluorine in medicinal chemistry

- F atom: high electronegativity, small steric size

- C-F bond (485 kJ/mol, 116 kcal/mol):

- oxidative, thermal and metabolic stability

- polar character

- H-F exchange: remarkable changes in physical-chemical and

biological properties

- changes in acidic-basic character

- high dipole moment, hydrogen-bonding interactions

- polar hydrophobicity

- effect on reactivity and stability

- profound changes in biological properties

- fluorinated organic molecules: virtually absent in the nature

25% of the drugs introduced to the market contain at least one

fluorine atom

(a) Wang J, Sánchez-Roselló M, Aceña JL, del Pozo C, Sorochinsky AE, Fustero S, Soloshonok VA, Liu H, Chem. Rev. 2014, 114, 2432. (b) Fluorine in Pharmaceutical

and Medicinal Chemistry: From Biophysical Aspects to Clinical Applications, Imperial College Press, London 2012. Edited by Gouverneur, V. and Müller, K.

5

Fluorine in medicinal chemistry. Fluorine

containing pharmaceuticals- fluorine containing cardioprotective drugs:

N

F

OH

H

HO

CO2H

Pitavastatin

NO

OH

F

OH

F

Ezetimibe

(Zetia, Schering-Plough, 2002)

2011: 2.4 billion USD(Kowa, Sankio, 2003)

Lipitor (Atorvastatin) (Pfizer)

N Me

Me

F

ONH

CO2H

HO

HO

2008 best-selling (5.9 billion USD)

N

NNMe

S

i-Pr OH OH

CO2H

FOO

Me

Rosuvastatin (Crestor)

(Astra-Zenekc, 2003)Lansoprazol (Prevacid)

N

HN

S

O

N

Me

O

CF3

Prasugrel (Effient)

(Effient, Eli-Lilly, 2009)

2011: 302.5 million USD

N

FO

S

OAc

2008: 1.7 billion USD2008: 3.3 billlion USD

(a) Wang J, Sánchez-Roselló M, Aceña JL, del Pozo C, Sorochinsky AE, Fustero S, Soloshonok VA, Liu H, Chem. Rev. 2014, 114, 2432. (b) Zhou Y, Wang Y, Gu Z, Wang S, Zhu W, Acena

JL, Soloshonok VA, Izawa K, Liu H, Chem. Rev. 2016, 116, 442.

6


containing pharmaceuticals- fluorine containing antiviral drugs:

F F

NHO

NN

N

N

Me

i-Pr

Maraviroc (Selzentry, Celsentri)

(Pfizer, 2007)

2011: 176.4 million USD

Tripanavir (Aptivus)

(Pfizer, 2005)

HN

SO

O

N

CF3

O

OHMe

O

Me

Me

Raltegravir (Isentress)

(Merck, 2007)

2011: 1.3 billion USD

N

N

O

OHMe

HN

O

HN

F

MeMeO

NN

OMe

- fluorine containing antidepressants:

Paliperidone (Invega) Iloperidone (Fanapt, Zomaril)(Janssen, 2006) (Vanda Pharmaceuticals, 2009)

N

N

O

Me

N

ON

F

OH

N

ON

FO

OMeMe

O

Ioflupane

(2011)

N

CO2Me

I

F

- antidiabetic drug:

N

ON H 2

NN

N

F

F

F

C F 3S i t a g l i p t i n ( J a n u v i a )

( M e r c k , 2 0 0 6 )

2 0 1 1 : 3 . 3 b i l l i o n U S D



7


containing pharmaceuticals- fluorine containing antifungal agents, antibiotics:

N

O

C O 2 HF

OM e

N

NM e

O f lo x a c in

N

O

C O 2 HF

N

H N

C ip r o f lo x a c in

N

O

C O 2 HF

M e

N

H N

N o r f lo x a c in

O

H O

F

n -C 5 H 1 1

H O

C O 2 H

P r o s ta c y c l in

- fluorine containing analgetics, antiinflamatory drugs:

O

F

F

H O

H

H

M e

O

OS

F

F lu tic a s o n e (A d v a ir , S e re tid e )

(G la x o S m ith K lin e )

C O 2 H

M e

N

OF

P r ia x im

O

M e

O

HN

N

C l

C l

O

F 2H C

R o flu m ila s t (D a x a s , D a lis re p )

(N y c o m e d , 2 0 1 0 )



8


containing pharmaceuticals- fluorine containing antitumoral drugs:

Fulvestrant (Faslodex)

HO

H

Me OH

HS

O

CF2CF3

H

(AstraZeneca, 2002)

2011: 546 million USD

Gefitinib (Iressa)


N

NO

MeO

HN

N

O

F

Cl

Sorafenib (Nexavar)(Bayer, 2005)

(AstraZeneca, 2002)

HN

O

N

MeHNOC

HN

OCl

CF3

2011: 1 billion USD

Capecitabine (Xeloda)

(Roche)


OMe

OHHO

N

NO

F

HN

O

Me

Sunitinib (Sutent)(Sugen, Pfizer, 2006)


NH

O

F NH

Me

Me

NH

O NEt2

Nilotinib (Tasigna)

(Novartis, 2007)


Me

NH

N

N

N

HN

O

CF3

N

N

Me



9

Synthesis of highly functionalized fluorinated

cyclic β-amino acid scaffolds

- direct fluorination:

- hydroxy-fluorine exchange

- oxo-difluor exchange

(late-stage fluorination)

- selective iodolactonization

- selective iodooxazine or iodooxazoline formation

- selective epoxidation and oxirane opening

- selective aziridination and aziridine opening

- highly functionalized fluorine containing three dimensional scaffolds

- regio- and stereoselectivity

- stereo- and substrate control

- polysubstituted, fluorinated cyclic building blocks with multiple chiral centers

- high chemical diversity

- generally applicable synthetic methods

C O 2 R

N H P

F

C O 2 R

N H P

FF

*

*

*

*

C O 2 R

N H P

F*

*

C O 2 R

T s N N H

F

O

*

*

C O 2 H

N H 2

C O 2 H

N H 2

*

*

*

*

C O 2 H

N H 2

*

*

C O 2 R

N H PFF

C O 2 R

N H PF

*

*

*

**

C O 2 R

N H PF

N 3

C O 2 R

N H P

*

*

F

*

*

*

*

C O 2 R

N H PF

N 3 *

*

*

*

C O 2 R

H N N H

F

O

C O 2 R

T s N

N HF

O

*

*

***

*

* *

*

*

*

*

*

(a) Kiss L, Forró E, Fustero S, Fülöp F, Org. Biomol. Chem. 2011, 9, 6528. (b) Kiss L, Forró E, Fustero S, Fülöp F, Eur. J. Org. Chem. 2011, 4993. (c) Kiss L, Nonn M, Forró E, Sillanpää

R, Fustero S, Fülöp F, Eur. J. Org. Chem. 2014, 4070. (d) Kiss L, Nonn M, Sillanpää R, Fustero S, Fülöp F, Beilstein J. Org. Chem. 2013, 9, 1164. (e) Kiss L, Remete AM, Nonn M,

Fustero S, Sillanpää R, Fülöp F, Tetrahedron, 2016, 72, 781. (f) Nonn M, Kiss L, Haukka M, Fustero S, Fülöp F, Org. Lett. 2015, 17, 1074.

- fluorine-containing amino acid derivatives

10

Synthesis of fluorinated cyclic β-amino acid scaffolds

- polyfunctionalized building blocks with multiple chiral centers

- selective fluorinations: - selectivity

- stereocontrol

- substrate control

- substrate dependence

- chemoselectivity

- new stereogenic centers

- direct fluorination: oxo-difluorine exchange (late-stage)

- fluorine-containing building blocks: fluorinated amines

(complicated late-stage fluorination)

- a combination of β-amino acid chemistry and fluorine chemistry

readily available starting materials valuable functionalized dialdehydes

- functionalized dialdehydes: useful scaffolds for fluorinated building blocks

11


- “trans” 3,5-diformyl-substituted ethyl β-aminocyclopentanecarboxylate (NHCOPh)

N

SF3

bis(2-methoxyethyl)aminosulfurtrifluoride

(Deoxofluor)

O O

(±)-23

a) Kiss L, Nonn M, Sillanpaa R, Haukka M, Fustero S, Fülöp F, Chem. Asian J. 2016, 11, 3376-3381. b) Kiss L, Cherepanova M, Forró E, Fülöp F, Chem. Eur. J. 2013, 19, 2102–2107.

- direct fluorination: oxo-difluor exchange

- chemodiscrimination

- substrate directable

fluorinations

- nucleophilicity:

NHCOPh vs fluoride

12


- “all-cis” 3,5-diformyl-substituted ethyl β-aminocyclopentanecarboxylate (NHCOPh)

a) Kiss L, Nonn M, Sillanpaa R, Haukka M, Fustero S, Fülöp F, Chem. Asian J. 2016, 11, 3376-3381. b) Cherepanova M, Kiss L, Sillanpaa R, Fülöp F, RSC Advances 2013, 3, 9757-9763.




fluorinations

- nucleophilicity:

NHCOPh vs fluoride

13


- “trans” 3,5-diformyl-substituted ethyl β-aminocyclopentanecarboxylate (NHCbz)

(±)-31

Kiss L, Nonn M, Sillanpaa R, Haukka M, Fustero S, Fülöp F, Chem. Asian J. 2016, 11, 3376-3381.




fluorinations

- nucleophilicity:

NHCbz vs NHCOPh

14


- fluorine-containing azepane β-amino esters from “trans” and „all-cis” 3,5-diformyl-substituted

ethyl β-aminocyclopentanecarboxylates

Ábrahámi RA, Kiss L, Barrio P, Fülöp F, Tetrahedron 2016, 72, 7526-7535


- stereocontrol

( ± ) - 3 3( 4 2 % , t w o s t e p s , f r o m d i o l )

C F 3 C H 2 N H 2 H C l , E t O H

N a H C O 3 , N a B H 3 C N

A c O H , 2 0 ° C , 3 h

O

O

N H C b z

C O 2 E t

H

H

C O 2 HN H 2

( ± ) - 2 1

( ± ) - 2 9

1

23

4

51 . d i h y d r o x y l a t i o n

2 . N a I O 4 m e d i a t e do x i d a t i v e r i n g - o p e n i n g

d i e x o

" t r a n s - d i a l d e h y d e "

N

N H C b z

C O 2 E t

F 3 C

C O 2 H

N H 2

( ± ) - 2 5

d i e n d o

1 . d i h y d r o x y l a t i o n

2 . N a I O 4 m e d i a t e do x i d a t i v e r i n g - o p e n i n g

( ± ) - 3 4 ( 7 8 % , t w o s t e p s , f r o m d i o l )

C F 3 C H 2 N H 2 H C l , E t O H


A c O H , 2 0 ° C , 3 h

O

O

N H C b z

C O 2 E t

H

H

( ± ) - 3 2

1

23

4

5

" a l l - c i s - d i a l d e h y d e "

N

N H C b z

C O 2 E t

F 3 C

15


- fluorine-containing azepane β-amino esters from cis and trans β-aminocyclohexanecarboxylic acids



- stereocontrol

N H 2

C O 2 H

N H C b z

C O 2 E t

H O

( ± ) - 3 5 ( ± ) - 3 6

( ± ) - 3 7 ( 2 1 % , t w o s t e p s , f r o m d i o l )

N a I O 4

T H F / H 2 O C F 3 C H 2 N H 2 H C l , E t O H


A c O H , 2 0 ° C , 3 h

H O

N

N H C b zE t O 2 C

C F 3

d i h y d r o x y l a t i o n

N H C b z

C O 2 E t

I - 2

2 0 ° C , 1 h

O H

O H

N H 2

C O 2 H

N H C b z

C O 2 E t

H O

( ± ) - 3 8

( ± ) - 3 9( ± ) - 4 0

( 2 6 % , t w o s t e p s , f r o m d i o l )

N a I O 4

T H F / H 2 O C F 3 C H 2 N H 2 H C l , E t O H


A c O H , 2 0 ° C , 3 h

N

C F 3

d i h y d r o x y l a t i o n

N H C b z

C O 2 E t

I - 3

2 0 ° C , 1 h

OO H

H

O

HC O 2 E t

N H C b z

16


- fluorine-containing piperdine β-amino esters from cis and trans β-aminocyclopentanecarboxylic acids



- stereocontrol

17

Synthesis of fluorinated N-heterocyclic scaffolds

- synthesis of fluorine-containing functionalized N-heterocycles

Ábrahámi RA, Kiss L, Fustero S, Fülöp F, Synthesis 2017, 49, 1206–1213.

N

CF3

NHCbz

N

CF3

NHCbz

N

F3C

CO2MeMeO2C

CO2H

CO2H

CO2Me

CO2Me

CO2Me

CO2Me

N

CHF2

CO2R

N

CH2F

CO2R

OHC

CO2Me

CO2Me

CO2Me

CO2MeOHC

OHC

NHCbzNHCbz

CHO

OHC

OHC CHO

CHO

NHCbz

NHCbz

oxidativering-opening

CO2RCO2R

OHC

OHC CHO

CHO

reductivering-closure

N

CF3

CO2R

N

CF3

CO2R

N

F3C

CO2MeMeO2C


- general applicability

18

Synthesis of fluorinated cyclic β-amino acid scaffoldsSummary and outlook:- a combination of β-amino acid chemistry and fluorine chemistry

- highly functionalized fluorine containing scaffolds

- stereocontrol

- substrate control

- polysubstituted cyclic building blocks with multiple chiral centers

- high chemical diversity

- biological (antifungal or antiviral) evaluations

- synthesis of novel peptides

- three dimensional building blocks for

pharmaceutical research

- readily accessible funcionalized olefins

- valuable substituted dialdehydes

Thank you for your attention!

Functionalized dialdehydes: H 2 O C O NH C OP h P h E t F ...€¦ · Fluorine in medicinal...

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