functionalized dialdehydes: h 2 o c o nh c op h p h e t f ...€¦ · fluorine in medicinal...
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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
Fluorine in medicinal chemistry. Fluorine
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
(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.
7
Fluorine in medicinal chemistry. Fluorine
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 )
(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.
8
Fluorine in medicinal chemistry. Fluorine
containing pharmaceuticals- fluorine containing antitumoral drugs:
Fulvestrant (Faslodex)
HO
H
Me OH
HS
O
CF2CF3
H
(AstraZeneca, 2002)
2011: 546 million USD
Gefitinib (Iressa)
2011: 554 million USD
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)
2011: 1.53 billion USD
OMe
OHHO
N
NO
F
HN
O
Me
Sunitinib (Sutent)(Sugen, Pfizer, 2006)
2011: 1.18 billion USD
NH
O
F NH
Me
Me
NH
O NEt2
Nilotinib (Tasigna)
(Novartis, 2007)
2011: 716 million USD
Me
NH
N
N
N
HN
O
CF3
N
N
Me
(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.
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
Synthesis of fluorinated cyclic β-amino acid scaffolds
- “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
Synthesis of fluorinated cyclic β-amino acid scaffolds
- “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.
- direct fluorination: oxo-difluor exchange
- chemodiscrimination
- substrate directable
fluorinations
- nucleophilicity:
NHCOPh vs fluoride
13
Synthesis of fluorinated cyclic β-amino acid scaffolds
- “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.
- direct fluorination: oxo-difluor exchange
- chemodiscrimination
- substrate directable
fluorinations
- nucleophilicity:
NHCbz vs NHCOPh
14
Synthesis of fluorinated cyclic β-amino acid scaffolds
- 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
- fluorine-containing building blocks: fluorinated amines
- 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
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
( ± ) - 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
Synthesis of fluorinated cyclic β-amino acid scaffolds
- fluorine-containing azepane β-amino esters from cis and trans β-aminocyclohexanecarboxylic acids
Ábrahámi RA, Kiss L, Barrio P, Fülöp F, Tetrahedron 2016, 72, 7526-7535
- fluorine-containing building blocks: fluorinated amines
- 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
N a H C O 3 , N a B H 3 C N
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
N a H C O 3 , N a B H 3 C N
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
Synthesis of fluorinated cyclic β-amino acid scaffolds
- fluorine-containing piperdine β-amino esters from cis and trans β-aminocyclopentanecarboxylic acids
Ábrahámi RA, Kiss L, Barrio P, Fülöp F, Tetrahedron 2016, 72, 7526-7535
- fluorine-containing building blocks: fluorinated amines
- 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
- fluorine-containing building blocks: fluorinated amines
- 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!
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