a stereocontrolled novel synthesis of ......a stereocontrolled novel synthesis of fluorinated...
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A STEREOCONTROLLED NOVEL SYNTHESISOF FLUORINATED CISPENTACINS
Loránd Kiss 1, Melinda Nonn 2, Reijo Sillanpää 3, Santos Fustero 4, Ferenc Fülöp 1,21Institute of Pharmaceutical Chemistry, 2Stereochemistry Research Group of the Hungarian Aca demy of Sciences, University of Szeged,
H-6720 Szeged, Eötvös u. 6, Hungary3Department of Chemistry, University of Jyväskylä, F IN-40014, Jyväskylä, Finland
4Universidad de Valencia, Facultad de Farmàcia, Depar tamento de QuímicaOrgánica, Valencia, Spain
E-mail: [email protected]
�-Amino acids have received increasing relevance in biological and medicinal chemistry last twenty years . These compounds are components of bioactive product s and are of high importance in peptide based drug research. The cyclopentane �-amino acids cispentacin and icofungipen are represen tatives of this class of products with strong antifungal properties [1-2]. F luorinated amino acids and peptides as a result of a series of biological activities are valuable deriva tives in pharmaceutical chemistry. These derivative s are known as enzyme inhibitors, antitoumoral agents or a ntibiotics. However, in the area of cyclic �-amino acids only few fluorinated cyclic analogues have be en synthetized [3-6].
Scheme 2. Fluorination of dihydroxylated ethyl �-aminocyclopentanecarboxylate 5.
Scheme 4. Fluorination of amino lactone 11..
Scheme 5. Fluorination of dihydroxylated ethyl �-aminocyclopentanecarboxylate 13.
[1] L. Kiss, E. Forró, F. Fülöp, Synthesis of carboc yclic �-amino acids. Amino Acids, Peptides and Proteins in O rganic Chemistry. Vol. 1, Ed. A. B. Hughes, Wiley, Weinheim, 367 (2009). [2] L. Kiss, F. Fülöp, Synlett 1302 (2010).[3] K. Mikami, S. Fustero, M. Sanchez-Rosello, J. L. Acena, V. Soloshonok, A. Sorochinsky, Synthesis 304 (2011).[4] L. Kiss, E. Forró, S. Fustero, F. Fülöp, Eur J Or g Chem 4993 (2011). [5] L. Kiss, E. Forró, E.; S. Fustero, F. Fülöp, Org Biomol Chem 9, 6528 (2011).[6] M. Nonn, L. Kiss, M. M. Hänninen, R. Sillanpää, F. Fülöp, Chem. Biodiv. 9, 2571 (2012).
Summary: Starting from bicyclic �-amino acids 1, 7 or 15 novel fluorinated �-amino ester derivatives have been prepared. The sy ntheses were based on selective ring C-C double bond functionalization by dihydroxylation, oxidative C-C bond cleavage followed by a hydroxyl or oxo-fluorine interconversion.
Scheme 3. Fluorination of diformyl ethyl �-aminocyclopentanecarboxylate 9.
Next, diformyl amino ester 3 was reduced with NaBH 4 affording the corresponding dihydroxylated amino ester 5, which in reaction with Deoxofluor furnished fluorinated cispenatcin derivative 6, with two fluo rine atoms in its structure (Scheme 2).
Dialdehyde 9 when was reduced at 0 °C for 30 min yie lded dihydroxylated amino ester 13, which in reactio nwith Deoxofluor afforded difluorinated cispentacin der ivative 14 (Scheme 5). Fluorinated O-heterocyclic �-amino acid derivative 18 was prepared starting fro m oxabicyclic amino acid 15 following similar protoc ol, Involving C-C cleavage and fluorination (Scheme 6).
Scheme 1. Fluorination of diformyl ethyl �-aminocyclopentanecarboxylate 3.
The syntheses started from unsaturated bicyclic �-amino acids 1, 7 or 15, and were based on dihydroxylation of the ring C-C double bond followed by oxidative ring cleavage and fluorinations. Dihydroxylated amino ester 2 derived from diexo -�-amino acid 1 when subjected to oxidative ring cleav age gave diformyl �-amino ester 3. Amino ester 3 in reaction with Deox ofluor underwent fluorination with simultaneous intramolecular ring-closure via amide O -atom to yield fluorinated product 4 with three fluorine atom in its structure (Scheme 1).
Scheme 6. Fluorination of dihydroxylated tetrahydrofu rane amino ester 17
4
12
11
13
CO2EtNHCOPh
HOHO
O
ONHCOPh
CO2Et
20 °C, 10 min 75%
NaIO4
H
H
CO2Et
HF
F
DeoxofluorCH2Cl2, 20 °C, 2 h, 87%
CO2HNH2
1
2
3
4
THF, H2O
O
N
PhF
O
ONHCOPh
CO2Et
H
H
NaBH4
THF, H2O, 53% NHCOPh
CO2EtHO
HO
NHCOPh
CO2EtF
F
Deoxofluor
CH2Cl2, 20 °C 2 h, 74%
35
6
Diendo -�-amino acid 7, isomer to 1 was transformed by olefin bond dihydroxylation into dihydroxylatedderivative 8, which on treatment with NaIO 4 resulted in all-cis diformyl �-amino ester 9. Compound 9 when reacted with Deoxofluor gave fluorinated cispenatcin derivative 10, with four fluorine atoms in its structure (Scheme 3). Next dialdehyde 9 was reacted w ith NaBH 4 at 20 °C providing via intramolecularcyclization amino lactone 11. Lactone 11 in reaction w ith Deoxofluor yielded through intramolecularamide O-atom attack the tricyclic compound 12 (Scheme 4).
O
ONHCOPh
CO2Et
20 °C, 10 min 75%
CO2EtNHCOPh
HOHO
NaIO4, THF, H2O
H
H
FNHCOPh
CO2Et
H
H
F
FF
CO2HNH2
DeoxofluorCH2Cl2, 20 °C, 2 h
7
8
9
10
O
ONHCOPh
CO2Et
H
H
NHBzHO
O
ONaBH4, THF/H2O
20 °C, 1 h, 51%
911
DeoxofluorCH2Cl2, 20 °C 2 h, 87%
12
O
O
ON
Ph
O
ONHCOPh
CO2Et
H
H
NaBH4, THF/H2O
0 °C, 30 min, 42%
HO
HONHCOPh
CO2Et
913
DeoxofluorCH2Cl2, 20 °C, 4 h
F
FNHCOPh
CO2Et
14
OCO2Et
NHCOPh
HOHO
20 °C, 10 min
1. NaIO4, THF, H2O
2. NaBH4
O
NHCOPh
CO2EtHO
HO
O
NHCOPh
CO2EtF
F
OCO2H
NH2
Deoxofluor, CH 2Cl2,
20 °C, 2 h, 74%
15
1617
18