Asymmetric synthesis of phosphonotrifluoroalanine derivatives via proline-catalyzed direct enantioselective CC bond formation reactions of NH trifluoroacetimidoyl phosphonate

Tetrahedron: Asymmetry xxx (2014) xxx–xxx

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Asymmetric synthesis of phosphonotrifluoroalanine derivatives via proline-catalyzed direct enantioselective CAC bond formation reactions of NAH trifluoroacetimidoyl phosphonate Yuliya V. Rassukana a,b, Ivanna P. Yelenich a, Yurii G. Vlasenko a, Petro P. Onys’ko a,⇑ a b

Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmans’ka str., Kyiv 02660, Ukraine Department of Organic Chemistry, National Technical University of Ukraine ‘Kyiv Polytechnic Institute’, 37, Prospect Peremogy, Kyiv 03056, Ukraine

a r t i c l e

i n f o

Article history: Received 24 June 2014 Accepted 22 July 2014 Available online xxxx

a b s t r a c t Based on enantioselective proline-catalyzed reactions between NH-iminotrifluoroethylphosphonate and acetone, an effective synthetic approach to both enantiomers of a-amino-a-trifluoromethyl-coxobutylphosphonate was developed. The synthetic potential of these novel chiral synthons was illustrated by their cyclocondensation reactions with 4-chlorophenylisocyanate or 2,5-dimethoxytetrahydrofuran to afford the first representatives of phosphorylated 3,4-dihydropyrimidin-2-ones or 3H-pyrrolizines, incorporating pharmacophoric optically active fragments of phosphonotrifluoroalanine. Ó 2014 Elsevier Ltd. All rights reserved.

1. Introduction

Most of the reported methods for the asymmetric synthesis of

a-aminophosphonates 1 involve the asymmetric addition of phosThe development of new stereoselective approaches for making optically active compounds remains one of the most important and challenging tasks for chemists. Of particular interest is the synthesis of enantiomerically enriched compounds bearing the a-aminophosphonate functionality. This class of compounds has attracted considerable interest because of their wide range of biological activities.1 Many phosphonic analogues of protein and non-protein amino acids exhibit antibacterial, anticancer, and antiviral properties as well as pesticidal, insecticidal, and herbicidal activity. A few have found commercial applications in agriculture and medicine. Of special interest in modern drug discovery are derivatives of non-racemic fluorine-containing aminophosphonic acids. It is generally accepted that the substitution of a hydrogen by a fluorine, or the introduction of a trifluoromethyl group in place of a methyl, may improve the pharmacodynamic and pharmacokinetic profiles of the compound by concomitant alteration of its electronic, lipophilic, and steric characteristics as well as its metabolic stability.2 However, in contrast to the widely investigated a-aminophosphonic acids, synthetic approaches to enantiomeric fluorine-containing analogues are few in number and of limited applicability.3 For this reason, the development of new synthetic methodologies for preparing enantiomerically enriched compounds of this type is a challenging task.

phites to non-phosphorylated imines 2 as the key step (Scheme 1, path a).1a,4 Recently we have disclosed an alternative and general approach to enantiomerically enriched a-aminophosphonates and their respective aminophosphonic acids based on the use of C-phosphorylated imines 3 (Y = H),5a as starting materials, and catalytic asymmetric reduction as a model reaction.5b Compounds of type 3 with a free NAH group (Y = H) seem especially promising for this purpose since their functionalization leads directly to N-unprotected aminophosphonates; it should be noted that the removal of the protecting groups in highly functionalized aminophosphonates (especially in those bearing electron-withdrawing groups) is not infrequently accompanied by the cleavage of the CAP bond. On the other hand, asymmetric organocatalytic Mannich reactions of imines with carbonyl compounds have become over the last decade a powerful tool for the preparation of synthetically and biologically important fluorinated b-aminocarbonyl compounds with a substituted6a–d or free NH2 group.6e At the same time this reaction has never been used for the synthesis of compounds incorporating an a-aminophosphonate moiety. O X N R

⇑ Corresponding author. Tel./fax: +380 44 573 25 94. E-mail address: [email protected] (P.P. Onys’ko).

2

Y

(R'O)2POH a

R

P(OR')2 N H

X

Y

1

O X-H b

(R'O)2P N R

Y

3

Scheme 1.

http://dx.doi.org/10.1016/j.tetasy.2014.07.007 0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

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Y. V. Rassukana et al. / Tetrahedron: Asymmetry xxx (2014) xxx–xxx

Herein we report on the reaction of NAH trifluoroacetimidoyl phosphonate 4 with acetone producing the first representative of a-amino-c-oxophosphonates with a free NH2 group, and some transformations of this novel chiral synthon. 2. Results and discussion We have found that O,O-diethyl a-iminotrifluoroethylphosphonate 45a reacts with acetone in the presence of L-proline at room temperature in DMSO solution to furnish (R)-diethyl a-aminoa-trifluoromethyl-c-oxobutylphosphonate 5 in 81% isolated yield, ee >90%, [a]25 8.7 (c 1.12, CHCl3). Under the same conditions, D = but using D- or racemic proline as catalyst, we have obtained enantiomerically enriched (S)-5 {yield 80%, ee >90%, [a]25 D = +8.6 (c 1.14, CHCl3)} or racemic (RS)-5, which had no specific rotation (Scheme 2).

O (EtO)2P L-proline

DMSO O (EtO)2P

H N

F3C

O

F3C H2N (R)-5 ~80% ee 90,5%

O

+

O

4 D-proline

DMSO

(EtO)2P

O

H2N F3C (S)-5

Scheme 2.

The presence of amino and keto groups in the enantiomers of 5 makes them promising chiral building blocks for the preparation of various optically active biologically important compounds bearing the trifluoromethyl group and the pharmacophoric aminophosphonate moiety on the same carbon atom. The synthetic potential of compounds 5 as chiral bifunctional synthons is illustrated by their cyclocondensation reactions with 4-chlorophenylisocyanate 6 and 2,5-dimethoxytetrahydrofuran 7 (Scheme 3).

(EtO)2P F3C

O

O

O ArNCO 6 Ar = 4-ClC6H4

NH2

O

(EtO)2P

O

NH

HN

N

NHAr O

O

Ar

(R)-8

A

O

O

OMe 7

AcOH

P(OEt)2

F 3C

(R)-5

OMe

F3C

(EtO)2P F3C

O N

N

(EtO)2P O B

CF3 (R)-9

Scheme 3.

It was found that the reaction of (R)-5 with isocyanate 6 (100 °C, 10 h) leads to (R)-diethyl [1-(4-chlorophenyl)-6-methyl-2-oxo-4(trifluoromethyl)-1,2,3,4-tetrahydropyrimidin-4-yl]phosphonate 8 in 89% yield and with 90.5% ee. Recrystallization from benzene

afforded enantiomerically pure (R)-8, [a]25 D = +58.5 (c 1.37, CHCl3). The formation of 8 most probably involves an initial carbamoylation of the amino group of 5, followed by an intramolecular cyclization of intermediate urea A (Scheme 3) as was recently shown for similar reactions of b-aminoketones with isocyanates.7 Heating a mixture of (R)-5 and 7 in acetic acid solution at reflux for 90 min afforded (R)-diethyl [1-methyl-3-(trifluoromethyl)-3Hpyrrolizin-3-yl]phosphonate 9 in 84% yield and with >90% ee, {[a]25 D = +164.5 (c 1.20, CHCl3)}. The reaction obviously proceeds via intermediate N-substituted pyrrole B undergoing intramolecular cyclization at the C-2 atom of the pyrrole ring;8 the reaction of 2,5-dimethoxytetrahydrofuran 7 with amines is a widely used synthetic approach to make N-substituted pyrroles.9 Compounds 5 and 9 are viscous oily substances, whereas dihydropyrimidinone 8 is a crystalline solid. We managed to grow a single crystal of 8 suitable for the determination of its absolute configuration by XRD analysis. The perspective view of the molecule is given in Figure 1. Two independent molecules 8a and 8b are crystallized in the unit cell. The 6-membered cycle N(6)C(7)C(9)C(10)N(19)C(20) is non planar and has the flattened half-boat 8a and boat 8b conformations. The N(19) atom has a trigonal-planar bond configuration in both 8a and 8b [sum of the bond angles are 359.6(9) and 359.8(9)° respectively]. In the solid state, molecules 8 are organized in dimers by strong intermolecular hydrogen bonds10 N(19)-H


O(21) (N(19)


O(21) 2.884(9) Å, N(19)-H 0.88(2) Å, O(21)


H 2.01(1) Å, N(19)HO(21) 172.0(2)° for 8a, N(19)


O(21) 2.854(9) Å, N(19)-H 0.87(2) Å, O(21)


H 1.99(1) Å, N(19)HO(21) 170.2(2)° for 8b) (Fig. 2). Since the stereogenic center of aminoketone 5 is not involved in the reactions in Scheme 3, it can be concluded that the original configuration of this center is retained in compounds 8 and 9. The simple preparative access to optically active derivatives of type 8 is of special importance when the wide range of biological activities exhibited by compounds containing a 3,4-dihydropyrimidin2-one structural scaffold is taken into consideration. Drugs based on these compounds include a number of compounds with antibacterial, antiviral, anticancer, and antihypertensive activity, enzyme inhibitors, etc.11 Great pharmacological potential is also shown by 3H-pyrrolizine derivatives.7,12 Compounds 8 and 9 also incorporate a pharmacophoric aminophosphonate moiety and trifluoromethyl groups, the introduction of which in an organic molecule is widely used for pharmacological improvements.2 One of the most important requirements in modern drug design is the synthesis of both enantiomers of optically active compounds, since bioactive derivatives in different enantiomeric forms and racemic mixtures often show different and sometime opposite effects on a biological target.11a,13 Having in hand (R)-, (S)-, and racemic (RS)-forms of aminoketone 5, we prepared (R)-, (S)-, and racemic (RS)-forms of compounds 8 and 9 (see Section 4). The enantiomeric excess of phosphonate 8 (Scheme 3) was determined by using a enantiomerically pure (+)-(RP)-tert-butylphenylphosphinothioic acid [(+)-(RP)-tert-Bu(Ph)P(S)OH], as the chiral solvating agent (CSA). This CSA has turned out to be very useful for the enantiomeric discrimination of chiral heteroatom containing compounds by 1H or 31P NMR spectroscopy.14 It was found that at a 1:1 ratio of CSA and 8, the resonance signals of the diastereomeric complexes formed were nicely separated in the 19F NMR spectra (Dd 0.12–0.15 ppm) (Fig. 3) thus allowing the precise determination of the enantiomeric excesses. The determination of ee for a racemic sample of 8 revealed a 1:1 enantiomeric ratio (Fig. 3), thus substantiating the correctness of the method. At the same time, the CSA proved to be ineffective for the discrimination of enantiomers of 5 and 9. Since the stereogenic center of 5 is not affected during the transformations 5?8 and 5?9, we believe that the ee determined experimentally for phosphonate 8 is approximately the same as for aminoketone 5 and

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Y. V. Rassukana et al. / Tetrahedron: Asymmetry xxx (2014) xxx–xxx

Figure 1. Molecular structure of compound (R)-8.

in the 19F spectra (Dd 0.155 ppm) thus allowing only an approximate estimation of the ee values. For enantiomerically enriched (R)-5 and (S)-5 (Scheme 2), the enantiomeric excess was estimated to be >90%, that was in accordance with the ee value for 8 determined by the CSA. Taking into account the results from the proline-catalyzed Mannich reaction6,15 and the fact that the starting imine 4 exists predominantly in the Z-configuration (Z/E 10:1),5 the stereochemical outcome of the reaction in Scheme 2 can be explained by the transition state C (Fig. 4), which originates from the energetically more favorable anti-configuration of an assumed acetone derived enamine intermediate6c,15 and the Z-configuration of imine 4.

O EtO

Figure 3.

N

H

EtO

Figure 2. Fragment of the crystal packing of compound (R)-8. Trifluoromethyl and ethoxy groups are omitted for clarity.

pyrrolizine 9. The enantiomeric excess of a-amino-3-ketophosphonate 5 (Scheme 2) was also estimated directly by NMR techniques using the commercially available chiral shift reagent (ESR), europium tris[3-(trifluoromethylhydroxymethylene)]-(+)-camphorate. It was found that the diastereomeric complex, formed at a 1:1 ratio of ESR and 5, gives distinct, although broadened, resonance signals

P

H

O

N O CH3

CF3 C

Fig. 4. Possible transition state for the reaction of L-proline-enamine of acetone with iminophosphonate 4.

3. Conclusion Based on the enantioselective proline-catalyzed reaction between NH-iminotrifluoroethylphosphonate and acetone, we

19

F NMR spectra for enantiomerically enriched (S)-8 (left) and racemic compound 8 (right) in the presence of 100 mol % of (+)-(RP)-tert-Bu(Ph)P(S)OH.

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have developed an efficient synthetic approach to previously unknown chiral a-amino-c-ketophosphonates with a free NH2 group obtained with >90% enantiomeric excess. The synthetic potential of these novel chiral synthons is demonstrated by their reactions with 4-chlorophenylisocyanate and 2,5-dimethoxytetrahydrofuran to produce biorelevant phosphonotrifluoroalanine derivatives: (R)-, (S)-, and (RS)-[1-(4-chlorophenyl)-6-methyl2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidin-4-yl]phosphonates and (R)-, (S)-, and (RS)-[1-methyl-3-(trifluoromethyl)3H-pyrrolizin-3-yl]phosphonates, respectively. Compounds 8 and 9 are the first representatives of phosphorylated 3,4-dihydropyrimidin-2-ones and 3H-pyrrolizines, respectively. 4. Experimental 4.1. General IR spectra were obtained on an UR-20 instrument. 1H NMR spectra were recorded on a Varian VXR-300 spectrometer (operating frequency 299.95 MHz), 19F NMR and 31P NMR spectra—on a Gemini 200 Varian (188.14 and 80.95 MHz respectively) and Varian VXR-300 instrument (282.2 and 121.42 MHz respectively). 13 C NMR spectra were obtained on a Bruker Avance DRX 500 spectrometer operating at 125.76 MHz. Chemical shifts are reported relative to internal TMS (1H) or CFCl3 (19F) and external 85%H3PO4 (31P) standards. Mass spectra were recorded on an Agilent 1100/DAD/HSD/VLG119562 spectrometer. Melting points are uncorrected. Solvents were dried before use according to standard methods. Elemental analysis was carried out in the analytical laboratory of Institute of Organic Chemistry, NAS of Ukraine. 4.2. (R)-Diethyl [1-amino-3-oxo-1-(trifluoromethyl)butyl]phosphonate 5 L-Proline (0.429 mmol, 0.049 g) was added to a solution of iminophosphonate 4 (4.29 mmol, 1 g) and acetone (21.4 mmol, 1.24 g, 1.57 mL) in dry DMSO (6 mL) and left at room temperature for 7 days. The mixture was diluted with water (10 mL) and extracted with DCM (3  10 mL). To the organic phase was added 15% HCl (15 mL) with intensive stirring, after which the aqueous layer was separated and neutralized with NaHCO3. The product was extracted with DCM (3  10 mL) and dried over MgSO4. The solvent was evaporated under reduced pressure. Yellow oil, yield 1.01 g (81%, ee >90%). [a]D25 = 8.7 (c 1.12, CHCl3). IR (neat) mmax: 1050 (POC), 1250 (P@O), 1720 (C@O), 3410 (NH2) cm 1. 1H NMR (300 MHz, CDCl3) d: 1.30 (t, 3JHH = 7 Hz, 3H, CH3CH2), 1.31 (t, 3JHH = 7 Hz, 3H, CH3CH2), 2.20 (s, 3H, C(O)CH3), 2.45 (br s, 2H, NH2), 2.86–3.00 (m, 2H, CH2CO), 4.09–4.26 (m, 4H, CH2O) ppm. 13C NMR (125.8 MHz, CDCl3) d: 16.26 (d, 3JCP = 5.4 Hz, CH3CH2), 16.29 (d, 3JCP = 5.4 Hz, CH3CH2), 32.3 (s, C(O)CH3), 40.9 (s, CH2C(O)), 60.1 (dq, 1JCP = 156.1, 2 JCF = 27.9 Hz, CP), 63.8 (d, 2JCP = 7.5 Hz, CH2O), 64.3 (d, 2JCP = 7.5 Hz, CH2O), 125.2 (qd, 1JCF = 285.2, 2JCP = 8.8 Hz, CF3), 205.6 (d, 3JCP = 9.4 Hz, C@O) ppm. 19F NMR (188 MHz, CDCl3) d: 73.9 ppm. 31P NMR (81 MHz, CDCl3) d: 18.3 ppm. m/z 292.2 (M+1). Anal. Calcd for C9H17F3NO4P (291.2): C 37.12; H 5.88; N 4.81; P 10.64. Found: C 36.98; H 5.86; N 4.83; P 10.61. The reaction with D- or racemic proline as the catalyst gave aminophosphonate (S)-5, ee >90%, [a]25 D = +8.6 (c 1.14, CHCl3) or (RS)-5, respectively.

4.3. (R)-Diethyl [1-(4-chlorophenyl)-6-methyl-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidin-4-yl]phosphonate 8 A mixture of aminophosphonate (R)-5 (0.84 mmol, 0.24 g) and 4-chlorophenylisocyanate (0.84 mmol, 0.13 g) was heated at 100 °C for 10 h. The volatile products were evaporated off to give phosphonate (R)-8, which was purified by preparative TLC (silica

gel 60 F254, EtOAc–hexane, 10:1, Rf = 0.73). White crystals, yield 0.32 g (89%, 90.5% ee), after crystallization from benzene ee >99%, [a]D25 = +58.5 (c 1.37, CHCl3), mp: 150–152 °C. IR (KBr) mmax: 1035 (POC), 1270 (P@O), 1710 (C@O), 3125, 3260 (NH) cm 1. 1H NMR (300 MHz, CDCl3) d: 1.38 (t, 3JHH = 6.9 Hz, 3H, CH3CH2), 1.39 (t, 3JHH = 6.9 Hz, 3H, CH3CH2), 1.64 (dd, 5JHP = 3.3 Hz, 4JHH = 1.2 Hz, 3H, 6-Me), 4.17–4.34 (m, 4H, CH2O), 4.84 (br q, 4JHH = 3.6 Hz, 1H, CH), 5.65 (br s, 1H, NH), 7.13 (d, 3JHH = 8.2 Hz, 2H, Ar), 7.40 (d, 3 JHH = 8.2 Hz, 2H, Ar) ppm. 13C NMR (125.8 MHz, CDCl3) d: 16.4 (d, 3JCP = 6.2 Hz, CH3CH2), 16.5 (d, 3JCP = 6.2 Hz, CH3CH2), 20.6 (s, CH3), 61.3 (dq, 1JCP = 161.2, 2JCF = 31.0 Hz, CP), 64.5 (d, 2JCP = 7.7 Hz, CH2O), 64.6 (d, 2JCP = 7.7 Hz, CH2O), 89.4 (d, 2JCP = 7.9, CH@), 123.3 (qd, 1JCF = 286.6, 2JCP = 15.8 Hz, CF3), 129.4, 130.8, 134.5, 135.5 (s, Ar), 140.6 (d, 3JCP = 9.4 Hz, CH3C@), 151.8 (d, 3JCP = 4.3 Hz, C@O) ppm. 19F NMR (188 MHz, CDCl3) d: 76.6 (d, 3JFP = 2.2 Hz) ppm. 31 P NMR (81 MHz, CDCl3) d: 12.6 ppm. m/z 427.1 (M)+. Anal. Calcd for C16H19ClF3NO4P (426.8): C 45.03; H 4.49; Cl 8.31; N 6.56; P 7.26. Found: C 4.85; H 4.49; Cl 8.28; N 6.57; P 7.28. The same reaction of isocyanate 6 with (S)-5 or (R,S)-5 gave compound (S)-8, ee 90.5%, [a]25 56.3 (c 1.34, CHCl3) or (RS)-8, respectively. D = 4.3.1. X-ray structure determination of (R)-8 Crystal data: C16H18Cl1F3N2O5P, M = 426.76, monoclinic, space group P21, a = 8.3925(2), b = 19.4974(5), c = 12.2293(3) Å, b = 99.262(2)°, V = 1975.01(9) Å3, Z = 4, dc = 1.435 g cm 3, l = 0.326 mm 1, F(0 0 0) = 880, crystal size ca. 0.17  0.48  0.59 mm. All crystallographic measurements were performed at 173 K on a Bruker Smart Apex II diffractometer operating in the x and u scans mode. Intensity data were collected within the range of 1.69 6 h 6 26.29° using Mo-Ka radiation (k = 0.71078 Å). Intensities of 19385 reflections were collected (7560 unique reflections, Rint = 0.039). Data were corrected for Lorentz and polarization effects. The structure was solved by direct methods and refined by the full-matrix least-squares technique in the anisotropic approximation for non-hydrogen atoms using the SHELXS97 and SHELXL97 programs16,17 and CRYSTALS program package.18 Hydrogen atoms participating in the hydrogen bonds were located in difference Fourier maps and refined isotropically. SADABS absorption correction was applied.19 In the refinement 5487 reflections with I P 3r(I) were used. Convergence was obtained at R1(F2) = 0.044 and wR2(F2) = 0.092, GOF = 0.935 (506 parameters; observed/variable ratio 10.8; the largest and minimal peaks in the final difference map 0.30 and 0.34 e/Å3, In the refinement the Chebyshev weighting scheme 20 was used (weighting coefficients are 37.8, 48.3, 30.1, 10.5). Full crystallographic details have been deposited at the Cambridge Crystallographic Data Centre (CCDC). Any request to the CCDC for these materials should quote the full literature citation and reference number CCDC 1006908. 4.4. (R)-Diethyl [1-methyl-3-(trifluoromethyl)-3H-pyrrolizin-3yl]phosphonate 9 2,5-Dimethoxytetrahydrofuran (2.18 mmol, 0.29 g, 0.28 mL) was added to a solution of aminophosphonate (R)-5 (2.18 mmol, 0.63 g) in 15 mL of acetic acid, the mixture was heated for 90 min at reflux. The solvent was evaporated under reduced pressure after which diethyl ether (50 mL) was added to the residue. The resulting mixture was washed with saturated aq. NaHCO3 (30 mL) and water (15 mL). The organic phase was dried (MgSO4) and evaporated under reduced pressure to leave a dark oil, which was purified by preparative TLC (silica gel 60 F254, EtOAc–hexane, 1:2, Rf = 0.56). Brown oil, yield 0.59 g (84%, ee >90%), [a]D25 = +164.5 (c 1.2, CHCl3). IR (neat) mmax: 1060 (POC), 1255 (P@O) cm 1. 1H NMR (300 MHz, CDCl3) d: 1.15 (t, 3JHH = 7.1 Hz, 3H, CH3CH2), 1.26 (t, 3JHH = 7.1 Hz, 3H, CH3CH2), 2.12

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(dd, 5JHP = 3.7 Hz, 4JHH = 1.6 Hz, 3H, 1-Me), 3.69–3.82 (m, 1H, OCH2), 3.97–4.15 (m, 3H, OCH2), 5.86 (dqq, 3JHP = 2.7 Hz, 4JHH = 1.6 Hz, 4JHF = 1.1 Hz, 1H, 2-HHet), 6.04 (ddd, 3JHH = 3.5 Hz, 5 JHP = 2.2 Hz, 4JHH = 1.1 Hz, 1H, 7-HHet), 6.30 (ddd, 3J6–7 = 3.5 Hz, 3 J6–5 = 2.9 Hz, 5JHP = 1 Hz, 1H, 6-HHet), 7.13 (dddq, 3J5–6 = 2.9 Hz, 4JHP = 2 Hz, 4J5–7 = 1.1 Hz, 5JHF = 1 Hz, 1H, 5-HHet) ppm. 13C NMR (125.7 MHz, CDCl3) d: 12.2 (d, 4JCP = 2.4 Hz, CH3), 15.7 (d, 3JCP = 5.9 Hz, CH3CH2), 15.8 (d, 3JCP = 5.9 Hz, CH3CH2), 63.8 (d, 2JCP = 7.2 Hz, CH2O), 64.0 (d, 2JCP = 7.2 Hz, CH2O), 69.9 (dq, 1JCP = 155.3, 2 JCF = 32.0 Hz, CP), 98.9 (d, J = 4.5 Hz, CH@), 113.0 (d, J = 2.0 Hz, Het), 117.5 (d, J = 8.0 Hz, Het), 118.1 (d, J = 2.3 Hz, Het), 122.6 (qd, 1JCF = 282.5, 2JCP = 6.4 Hz, CF3), 138.6 (d, J = 9.1 Hz, Het), 142.2 (s, Het) ppm. 19F NMR (188 MHz, CDCl3) d: 71.7 (m, 3JFP = 2.6 Hz) ppm. 31P NMR (81 MHz, CDCl3) d: 10.3 ppm. m/z 292.2 (M+1). Anal. Calcd for C13H17F3NO3P (323.3): C 48.30; H 5.30; N 4.33; P 9.58. Found: C 48.22; H 5.28; N 4.31; P 9.61. The reaction of aminophosphonate (S)-5 with 2,5-dimethoxytetrahydrofuran gave compound (S)-9 in 86% yield, ee >90%, [a]25 163.3 (c 1.46, CHCl3). D = Acknowledgements Authors are grateful to Prof. Jozef Drabowicz and Dr. Piotr Lyzwa (CBMM, Lodz, Poland) who provided the sample of (+)-(RP)-tertbutylphenylphosphinothioic acid. References 1. (a)Aminophosphonic and Aminophosphinic Acids. Chemistry and Biological Activity; Kukhar, V. P., Hudson, H. R., Eds.; John Wiley & Sons: New York, 2000; (b) Kafarski, P.; Lejczak, B. Phosphorus, Sulfur, Silicon Relat. Elem. 1991, 63, 193–215; (c) Mucha, A.; Kafarski, P.; Berlicki, L. J. Med. Chem. 2011, 54, 5955– 5980. 2. Organic Compounds in Medicinal Chemistry and Biomedicinal Applications; Filler, R., Kobayshi, Y., Yagupolskii, L. M., Eds.; Elsevier: Amsterdam, 1993. 3. Romanenko, V. D.; Kukhar, V. P. Chem. Rev. 2006, 106, 3868–3935. 4. Cherkasov, R. A.; Galkin, V. I. Russ. Chem. Rev. 1998, 67, 857–882. 5. (a) Rassukana, Yu. V.; Kolotylo, M. V.; Sinitsa, O. A.; Pirozhenko, V. V.; Onys’ko, P. P. Synthesis 2007, 2627–2630; (b) Rassukana, Yu. V.; Onys’ko, P. P.; Kolotylo, M. V.; Sinitsa, A. D.; Lyzwa, P.; Mikolajczyk, M. Tetrahedron Lett. 2009, 50, 288– 290.

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Please cite this article in press as: Rassukana, Y. V.; et al. Tetrahedron: Asymmetry (2014), http://dx.doi.org/10.1016/j.tetasy.2014.07.007