stereo --- and and and regioselective ... filestereo-stereo --- and and and regioselective...
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StereoStereoStereoStereo---- and and and and regioselectiveregioselectiveregioselectiveregioselective synthesissynthesissynthesissynthesis of of of of fluorinatedfluorinatedfluorinatedfluorinated cispentacinscispentacinscispentacinscispentacinsMelinda Nonn1,2, Loránd Kiss1, Ferenc Fülöp1,2
1I n s t i t u t e o f P h a r m a c e u t i c a l C h e m i s t r y, University of Szeged, H-6720, Eötvös 6, Hungary, 2Stereochemistry Research Group of the Hungarian Academy of Sciences, University of Szeged, H-6720 Szeged, Eötvös
6, Hungary
CO2Et
NHBoc12
NaOEt, EtOHr.t., 20 h
CO2Et
NHBoc
15
CO2Et
NHBoc
ON
CO2Et
NHBocN
O
13 45% 14 6%
N OH
Et3N, NCSTHF, ∆∆∆∆, 15h
N OH
Et3N, NCSTHF, ∆∆∆∆, 15h
CO2Et
NHBocN
O
16 50%
100% regio- and stereoselectivity
Scheme 4.
CO2Et
NHBoc
ON
13
CO2Et
NHBocN
O16
NiCl2, Boc2O
NaBH4, EtOH/THFr.t., 6 h
NiCl2, Boc2O
NaBH4, EtOH/THFr.t., 6 h
CO2Et
NHBoc
HO
H
BocHN
CO2Et
NHBoc
HO
H
BocHN
CO2Et
NHBoc22, 58%
HO
BocHN
HCO2Et
NHBocHO
BocHN
H
20, 53% 21, 27%
23, 20%
diastereomeric ratio3:1
diastereomeric ratio4:1
Scheme 6.
Recently, our group reported the formation of a highlyfunctionali-zed cispentacinstereoisomers4 and5 from the bicyclic�-lactam1 by the 1,3-dipolar cyclo-addition of nitrileoxide to the ethyl cis- and trans-2-aminocyclopentenecarboxylates [3] (Scheme 2).Our aim was to synthetize fluorine containing�− and γ−aminocyclopentanecarboxylate regio- and stereoisomers, which may be regarded as fluorinated precursors for the synthesis of Peramivir analogues. The hydroxyl containing, multifunctionalized amino carboxylates were prepared, by reductive ring opening of the isoxazoline skeleton of6 and 7 and furnished two diastereomers8, 9 and 10, 11respectively, in a ratio of 4:1 (Scheme 3).
CO2EtBocHN
HOBocHN
HR
24a: R= Me24b: R= Et
Deoxo-Fluordry toluene
0°C, 2 h
CO2EtBocHN
FBocHN
HR
CO2EtBocHN
BocHN
HR
30a: R= Me30b: R= Et, 20%
31a: R= Me31b: R= Et, 42%
mixture of two products
Scheme 9 .
The fluorinations wereperformed with Deoxo-Fluor reagent in drytoluene at 0°C for 2 h, affording thefluorinated compounds26a-c and 28a,b and elimination materials27a-c and 29a-crespectively. (Scheme8), which could be separated by columnchromatography.When compound24aunderwent fluorination, an unseparable mixture of two products30aand 31awas produced(Scheme 9). Fluorination of 24b resulted in fluorinated product30b in 20% yield and the elimination product31b in 42% yield (Scheme 9), which could be separated.
Fluorinated aminocyclopentancarboxylate regio- and stereoisomers have been synthetizedfrom �- or �-aminocyclopentencarboxylates across the 1,3-dipolar cycloaddition of nitrile-oxides and the reductive ring opening of the isoxazolineskeleton, followed by hydroxyl-fluorine exchange. The synthetized fluornated derivative smay be regarded as precursors forthe preparation of Peramivir analogues.
IntroductionIntroductionIntroductionIntroduction
ResultsResultsResultsResults
ConclusionConclusionConclusionConclusion ReferencesReferencesReferencesReferences
The reductive ring opening reactions were accomplished with NaBH4 in the presence of NiCl2 resulting infrom 13 two diastereomers20 and 21 as well as from16 compounds22 and 23 (Scheme 6), which wereseparated.
In order to prepare several hydroxyl group containing cispentacin analogues, the cycloaddition withnitrile oxide derived from 2-ethyl-butyraldehyde oxime was exectued to12 and15 and (Scheme 4). The cycloaddition to12 gave two regioisomers13 and 14 in a ratio of 8:1 (Scheme 4), which wereseparated by chromatography. The trans representative15, gave only one cycloadduct16 (Scheme4).
1. a) Kiss, L. et al Synthesis of carbocyclic�-amino acids. Amino Acids, Peptides and Proteins in Organic Chemistry. Vol. 1, Ed. A. B. Hughes, Wiley, Weinheim, 2009, 367. b) Nonn, M. et alTetrahedron, 2011, 67, 4079. c) Ji, H. et alJ. Med. Chem. 2006, 49, 6254. d) Wang, G. T. et alJ. Med. Chem. 2001, 44, 1192. e) Yi, X. et alBioorg. Med. Chem. 2003, 11, 1465. f) Ishikawa, H. et al Chem. Eur. J. 2010, 16, 12616. g) Ko, J. S. et alJ. Org. Chem. 2010, 75, 7006. h) Zhu, S. et alAngew. Chem. Int. Ed. 2010, 49, 4656. i) Oakley, A. J. et alJ. Med. Chem. 2010, 53, 6421. j) Lu, W. J. et alEur. J. Med. Chem. 2008, 43, 569.
2. a) Acena, J. L. et alCurr. Med. Chem. 2010, 14, 928. b) Mikami, K. et alSynthesis 2011, 304. c) Kiss, L. et alEur J Org Chem 2011, 4993. d) Kiss, L. et alOrg Biomol Chem 2011, 9, 6528.
3. Nonn, M. et alBeilstein J. Org. Chem. 2012, 8, 100.
Alicyclic �-amino acids have attracted considerable interest in recent yearsbecause of their pharmacological potential, e.g. the naturally occurringCispentacin or Icofungipen are antifungal agents, while Oryzoxymycin an antibiotic [1a-b]. A number of multifunctionalized cyclic amino acids such asPeramivir, Tamiflu or Zanamivir are known as neuraminidase inhibitors [1c-j](Scheme 1). Fluorinated amino acids and peptides areconsidered of valuable derivatives in medicinal chemistry as enzyme inhibitors, antitumoural agents or antibiotics [2].
The opening of thecycloadduct 18a,bresulted in twohydroxyl groupcontainingdiastereomers24a, 24band 25a, 25b on a ratio of 3:1 and 4:1 respectively (Scheme7).
TÁMOP-4.2.2/B-10/1-2010-0012
CO2Et
NHBoc
HO
HR
BocHN
CO2Et
NHBocHO
RH
BocHN
4: R= Me8: R= Et20: R= -CH-(CH2-CH3)2
5: R= Me10: R= Et22: R= -CH-(CH2-CH3)2
Deoxo-Fluor
dry toluene0°C, 2 h
CO2Et
NHBoc
F
HR
BocHN
26a: R= Me, 24%26b: R= Et, 19%26c: R= -CH-(CH2-CH3)2, 28%
CO2Et
NHBocHR
BocHN
27a: R= Me, 45%27b: R= Et, 43%27c: R= -CH-(CH2-CH3)2, 27%
CO2Et
NHBocF
RH
BocHN
28a: R= Me, 19%28b: R= Et, 15%28c: R= -CH-(CH2-CH3)2, 0%
CO2Et
NHBoc
RH
BocHN
29a: R= Me, 48%29b: R= Et, 39%29c: R= -CH-(CH2-CH3)2, 58%
Deoxo-Fluor
dry toluene0°C, 2 h
Scheme 8.
CO2H
NH2 H2N CO2H
Cispentacin IcofungipenOH
NH2
O
O
CO2H
Oryzoxymycin
CO2Et
AcHNNH2*H3PO4
O
Tamiflu(Oseltamivir)
O CO2HOH
OHAcHN
HN
NH
NH2
HOH
Zanamivir
CO2H
HN
H2N NH
OHNHAc
Peramivir
Scheme 1.
CO2Et
NHBoc
ON
NO
CO2Et
NHBoc
NH
O
1
2
3
Scheme 2.
CO2Et
NHBoc
HO
H
BocHN
CO2Et
NHBocHO
H
BocHN
4, 80%
5, 82%
NiCl2, Boc 2O
NaBH4, EtOH/THFr.t, 6 h
NiCl2, Boc 2O
NaBH4, EtOH/THFr.t, 6 h
CO2Et
NHBoc
ON
6
NO NHBoc
CO2Et
7
NiCl2, Boc 2O
NaBH4, EtOH/THFr.t, 6 h
NaBH4, EtOH/THFr.t, 6 h
NiCl2, Boc 2O
CO2Et
NHBoc
HO
H
BocHN
CO2Et
NHBoc
HO
H
BocHN
diastereomeric ratio 4:1
CO2Et
NHBocHO
H
BocHNCO2Et
NHBocHO
H
BocHN
diastereomeric ratio 4:1
8, 57% 9, 18%
10, 64% 11, 21%
Scheme 3.
Next, the cycloadditionreaction to 17 wasperformed (Scheme 5) and affordedregioisomers 18a,b and 19a,b, which wereseparated.
CO2EtBocHN
ON R
18a: R= Me18b: R= Et
NiCl2, Boc 2O
NaBH4, EtOH/THFr.t., 6 h
CO2EtBocHN
HOBocHN
HR
CO2EtBocHN
HOBocHN
HR
25a: R= Me60%
25b: R= Et22%
diastereomeric ratio 3:1
diastereomeric ratio 4:1
Scheme 7.
24a: R=Me55%
24b: R= Et29%
CO2EtBocHN EtNO2/ PrNO2
Boc 2O, DMAPTHF, r.t., 18 h
CO2EtBocHN CO2EtBocHN
ON N
OR R17
18a: R= Me, 41%18b: R= Et, 39%
19a: R=Me, 5%19b: R= Et, 7%
Scheme 5.