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.