Synthesis and Conformational Analysis of Fluorinated Pipecolic Acids

Sukhdev Singh; Claire-Marie Martinez; Sandrine Calvet-Vitale; Ashok K. Prasad; Thierry Prangé; Peter I. Dalko; Hamid Dhimane

doi:10.1055/s-0032-1316770

Synlett, Inhaltsverzeichnis

Synlett 2012; 23(16): 2421-2425
DOI: 10.1055/s-0032-1316770

letter

Synthesis and Conformational Analysis of Fluorinated Pipecolic Acids

Sukhdev Singh

^aLaboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques – UMR 8601 CNRS/Université Paris Descartes, UFR Biomédicale, 45, Rue des Saints-Pères, 75270 Paris Cedex 06, France Fax: +33(1)42868387 eMail: hamid.dhimane@parisdescartes.fr

^bBioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi 110 007, India

,

Claire-Marie Martinez

^aLaboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques – UMR 8601 CNRS/Université Paris Descartes, UFR Biomédicale, 45, Rue des Saints-Pères, 75270 Paris Cedex 06, France Fax: +33(1)42868387 eMail: hamid.dhimane@parisdescartes.fr

,

Sandrine Calvet-Vitale

^aLaboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques – UMR 8601 CNRS/Université Paris Descartes, UFR Biomédicale, 45, Rue des Saints-Pères, 75270 Paris Cedex 06, France Fax: +33(1)42868387 eMail: hamid.dhimane@parisdescartes.fr

,

Ashok K. Prasad

^bBioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi 110 007, India

,

Thierry Prangé

^cLaboratoire de Cristallographie et RMN Biologiques – UMR 8015 CNRS/Université Paris Descartes, Faculté de Pharmacie 4, Avenue de l’Observatoire, 75270 Paris Cedex 06, France

,

Peter I. Dalko

^aLaboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques – UMR 8601 CNRS/Université Paris Descartes, UFR Biomédicale, 45, Rue des Saints-Pères, 75270 Paris Cedex 06, France Fax: +33(1)42868387 eMail: hamid.dhimane@parisdescartes.fr

,

Hamid Dhimane*

^aLaboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques – UMR 8601 CNRS/Université Paris Descartes, UFR Biomédicale, 45, Rue des Saints-Pères, 75270 Paris Cedex 06, France Fax: +33(1)42868387 eMail: hamid.dhimane@parisdescartes.fr

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Abstract

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Abstract

A short sequence to methyl cis- and trans-5-fluoro pipecolate is described via electrophilic fluorination of a pipecolate-based endocyclic enecarbamate by using Selectfluor^® as a fluorinating agent. Methyl 5,5-difluoro pipecolate was also obtained by difluorodeoxygenation of the corresponding ketone, which was obtained in two steps from the same enecarbamate. The conformational profile of both methyl 5-fluoropipecolate isomers was investigated by NMR spectroscopy in solution and X-ray crystallography of the corresponding piperidinium picrates.

Key words

pipecolic acid - enecarbamate - electrophilic addition - fluorine - stereoselectivity - fluoropipecolate - conformational analysis

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Referenzen

References

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First we optimized the sequences with racemic 1,⁷ then we used enantiopure (S)-1, which was prepared, in four steps, from l-lysine according to:

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9 Use of (PhSO₂)₂NF as electrophilic fluorinating source in MeOH resulted in production of an inseparable mixture of 6a and methyl 1-methoxycarbonyl-5-fluoro-6-[N-(phenyl-sulfonyl)pheylsulfonamido]pipecolate

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11 Following a referee’s remark regarding the effect of the nucleophile/co-solvent on the diastereoselectivity, additional experiments were carried out by using AcOH or EtOH instead of H₂O or MeOH in the first step of the sequence 1 → 6 → 5. Similar diastereoselectivities to those observed with MeOH and H₂O were obtained when 1 was reacted with Selectfluor^® in the presence of AcOH–MeCN prior to reductive deacetoxylation with Et₃SiH–MeSO₃H (trans-5/cis-5 = 63:37); while fluoroethoxylation in EtOH–MeCN and subsequent deoxygenation with Et₃SiH–BF₃·OEt₂ resulted in a great amount of defluorinated compound 7 (5/7 = ca. 1:1) with trans-5/cis-5 = 55:45. Actually we found that the latter is an apparent diastereoselctivity; indeed, treatment of trans-5/cis-5 = 40:60 mixture with Et₃SiH–BF₃·OEt₂ in CDCl₃ (for NMR monitoring) revealed that under these conditions, trans-5 is reduced much faster than cis-5. Probably, for stereoelectronic reasons, the fluorine atom in trans-5 is likely more prone to BF₃-assisted nucleophilic displacement with triethylsilane; indeed, according to NMR analysis, F–C5 is axially oriented in trans-5 while it is equatorially oriented in cis-5 (Scheme 4)

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16 The solution population of the form with an axial fluorine atom (n_ax) was determined according to the ³ J value method (ref. 14): n_ax = (³ J _obs – ³ J _ee)/(³ J _aa – ³ J _ee), where ³ J _obs is the observed coupling constant between F-5 and the H-6 which is trans to F-5, ³ J _ee = 12.4 and ³ J _aa = 39.3 Hz are the extreme values for H6ax,F5ax and H6eq,F5eq coupling constants, respectively, according to ref. 15

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18 Picrate of cis-10: monoclinic C₁₃H₁₃FN₄O₉, P2₁/c, a = 14.784(1), b = 6.666(1), c = 17.308(1) Å, β = 111.97(5)°; R = 0.057 for 1484 Fo. Picrate of trans-10: triclinic C₁₃H₁₃FN₄O₉, P-1, a = 8.819(1), b = 9.966(1), c = 11.449(1) Å, α = 91.58(4), β = 111.48(5), γ = 116.08(4). R = 0.079 for 3501 Fo. Coordinates deposited with the Cambridge Crystallographic Data Centre, CCDC 811750 (cis-10) and CCDC 811751 (trans-10). Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:+44 (1223)336033 or email: deposit@ccdc.cam.ac.uk]
19 Procedure and Data for the Synthesis of Picrates 10 To the mixture of diastereomers of compound 5 (3.1 mmol) in MeCN (15 mL) were added TMSCl (9.3 mmol) and NaI (9.3 mmol) at r.t., and the reaction mixture was stirred for 2 h. After completion of the reaction (monitored by TLC), the solvent was removed under vacuum, then H₂O (30 mL) was added to the residue and stirred for 5 min more. The reaction mixture was extracted with CH₂Cl₂ (3 × 30 mL), then the combined organic layers were washed with sat. aq solution of Na₂S₂O₃ (30 mL). The organic layer was dried over MgSO₄ and concentrated in vacuo to obtain the crude mixture of diastereomers 9 which were purified and easily separated by column chromatography using 1% MeOH in CH₂Cl₂ as eluent. The first fraction was obtained as a pure trans-9 isomer and the second one as pure cis- 9 isomer, in 92% overall yield. Methyl trans-(±)-5-Fluoropipecolate (trans-9) Obtained as colorless liquid. IR (neat): ν_max = 1039, 1205, 1438, 1738, 2957, 3347 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.63–1.77 (2 H, m), 2.04–2.23 (2 H, m), 2.51 (1 H, br s), 2.80 (1 H, ddd, J = 12.2, 8.0, 6.6 Hz), 3.34 (1 H, dddd, J = 13.3, 12.3, 4.1, 1.6 Hz), 3.46 (1 H, dd, J = 7.4, 3.8 Hz), 3.75 (3 H, s), 4.56 (1 H, dtt, J = 48.6, 8.3, 4.2 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 26.15 (d, ³ J _CF = 7.7 Hz), 29.56 (d, ² J _CF = 20.0 Hz), 48.88 (d, ² J _CF = 24.5 Hz), 52.25, 56.94, 87.42 (d, ¹ J _CF = 173.9 Hz), 173.08. MS: m/z calcd [M + H]⁺ for C₇H₁₂FNO₂: 162; found: 162. For trans-(2S,5R)-9: [α]_D ²⁸ –3.6 (c 0.9, CH₂Cl₂). Methyl cis-(±)-5-Fluoropipecolate (cis-9) Obtained as colorless liquid. IR (neat): ν_max = 1047, 1218, 1443, 1742, 2957, 3373 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.79–2.17 (4 H, m), 2.87 (1 H, ddd, J = 35.3, 14.2, 2.0 Hz), 3.26 (1 H, dddd, J = 14.2, 10.9, 3.6, 2.3 Hz), 3.44 (1 H, ddd, J = 7.4, 6.4, 1.7 Hz), 3.75 (3 H, s), 4.60 (1 H, dddt, J = 47.3, 4.4, 3.5, 2.2 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 24.4, 28.81 (d, ² J _CF = 21.3 Hz), 48.83 (d, ² J _CF = 24.5 Hz), 52.06, 57.56, 85.71 (d, ¹ J _CF = 170.3 Hz), 173.34. MS: m/z calcd [M + H]⁺ for C₇H₁₂FNO₂: 162; found: 162. For cis-(2S,5S)-9: [α]_D ²⁸ –16.3 (c 0.625, CH₂Cl₂). In a 50 mL conical flask, compound trans-9 (or cis-9; 0.277 mmol) was mixed with picric acid (0.277 mmol) in EtOH (2 mL). The resulting mixture was heated for 5 min and cooled to r.t. EtOH was removed under vacuum, and the residue was recrystallized with Et₂O, CH₂Cl₂–MeOH to grow crystals of compound trans- 10 (or cis- 10). trans-(±)-5-Fluoro-2-(carbomethoxy)piperidin-1-ium-2′,4′,6′-trinitrophenolate (trans-10) Obtained as yellow crystals. ¹H NMR (500 MHz, MeOD): δ = 1.88–2.44 (4 H, m), 3.39 (1 H, ddd, J = 13.7, 9.3, 5.6 Hz), 3.65 (1 H, ddd, J = 26.5, 13.6, 2.8 Hz), 3.86 (3 H, s), 4.34 (1 H, dd, J = 6.0, 4.9 Hz), 4.95 (1 H, dtt, J = 46.0, 5.8, 3.1 Hz), 8.77 (2 H, s). ¹³C NMR (125 MHz, MeOD): δ = 22.39 (d, ³ J _CF = 6.4 Hz), 27.3 (d, ² J _CF = 20.9 Hz), 46.70 (d, ² J _CF = 25.4 Hz), 54.83, 56.58, 86.16 (d, ¹ J _CF = 173.0 Hz), 127.51, 129.46, 144.33, 164.18, 170.34. ESI-HRMS: m/z calcd for C₇H₁₃FNO₂ ⁺: 162.0930; found: 162.0924 (for piperidinium cation). cis-(±)-5-Fluoro-2-(carbomethoxy)piperidin-1-ium-2′,4′,6′-trinitrophenolate (cis-10) Obtained as yellow crystals. ¹H NMR (500 MHz, MeOD): δ = 1.87–2.31 (4 H, m), 3.39 (1 H, ddd, J = 38.5, 13.8, 4.6 Hz), 3.68 (1 H, ddd, J = 13.8, 10.6, 3.4 Hz), 3.83 (3 H, s), 4.15 (1 H, dt, J = 11.6, 2.9 Hz), 5.04 (1 H, dd, J = 45.4, 4.4 Hz), 8.76 (2 H, s). ¹³C NMR (125 MHz, MeOD): δ = 22.39, 28.53 (d, ² J _CF = 21.3 Hz), 48.82 (d, ² J _CF = 21.3 Hz), 54.65, 58.18, 85.81 (d, ¹ J _CF = 172.1 Hz), 127.49, 130.12, 144.03, 163.47, 170.48. ESI-HRMS: m/z calcd for C₇H₁₃FNO₂ ⁺: 162.0930; found: 162.0925 (for piperidinium cation)
20 See Supporting Information for experimental procedures and analytical data of other compounds (4–10)

Zusatzmaterial

Supporting Information