RSS-Feed abonnieren
DOI: 10.1055/s-2006-951541
New Cyclic Aspartic Acid and N-Glucosyl Asparagine Mimetics
Publikationsverlauf
Publikationsdatum:
23. November 2006 (online)
![](https://www.thieme-connect.de/media/synlett/200619/lookinside/thumbnails/10.1055-s-2006-951541-1.jpg)
Abstract
Enantiopure tert-butyl 4-oxopipecolic esters were converted into cyclic analogues of bishomoaspartic acid and homoglutamic acid by Horner-Wadsworth-Emmons olefination and hydrogenation. Condensation of the side chain carboxylic group with anomeric glucosylamine and suitable protection of the α-amino acid moiety afforded the corresponding N-glucosyl asparagine or glutamine mimetics as useful building blocks in glycopeptidomimetic synthesis.
Key words
glycoamino acids - piperidines - stereoselectivity
-
1a
Mukhtar TA.Wright GD. Chem. Rev. 2005, 105: 529 -
1b
Di Giambattista M.Nyssen E.Percher A.Cocito C. Biochemistry 1990, 29: 9203 -
1c
Reed JW.Purvis MB.Kingston DGI.Blot A.Gossele F. J. Org. Chem. 1989, 54: 1161 -
1d
Kessler H.Kühn M.Löschner T. Liebigs Ann. Chem. 1986, 1 -
1e
Hollstein U. Chem. Rev. 1974, 74: 625 -
1f
Vanderhaeghe H.Parmentier G. J. Am. Chem. Soc. 1960, 82: 4414 -
2a
Machetti F.Cordero FM.De Sarlo F.Papini AM.Alcaro MC.Brandi A. Eur. J. Org. Chem. 2004, 2928 -
2b
Sata NU.Kuwahara R.Murata Y. Tetrahedron Lett. 2002, 43: 115 -
2c
Golubev AS.Schedel H.Radics G.Sieler J.Burger K. Tetrahedron Lett. 2001, 42: 7941 -
2d
Beaulieu PL.Anderson PC.Cameron DR.Croteau G.Gorys V.Grand-Maître C.Lamarre D.Liard F.Paris W.Plamondon L.Soucy F.Thibeault D.Wernic D.Yoakim C. J. Med. Chem. 2000, 43: 1094 -
2e
Ornstein PL.Arnold MB.Lunn WHW.Heinz LJ.Leander JD.Lodge D.Schoepp DD. Bioorg. Med. Chem. Lett. 1998, 8: 389 -
2f
Bellier B.Da Nascimento SH.Gincel E.Roques BP.Garbay C. Bioorg. Med. Chem. Lett. 1998, 8: 1419 -
2g
Skiles JW.Giannousis PP.Fales KR. Bioorg. Med. Chem. Lett. 1996, 6: 963 -
2h
Pellicciari R.Natalini B.Luneia R.Marinozzi M.Marinella R.Rosato GC.Sadeghpour BM.Snyder JP.Monahan JB.Moroni F. Med. Chem. Res. 1992, 2: 491 -
2i
Hays SJ.Malone TC.Johnson G. J. Org. Chem. 1991, 56: 4084 -
2j
Ornstein PL.Schoepp DD.Arnold MB.Leander JD.Lodge D.Paschal JW.Elzey T. J. Med. Chem. 1991, 34: 90 - 3
Toniolo C. Int. J. Peptide Protein Res. 1990, 35: 287 -
4a
Varki A. Glycobiology 1993, 3: 97 -
4b
Dwek RA. Chem. Rev. 1996, 96: 683 -
4c
Rudd PM.Elliott T.Cresswell P.Wilson IA.Dwek RA. Science 2001, 291: 2370 -
4d
Pratt MR.Bertozzi CR. Chem. Soc. Rev. 2005, 34: 58 - 5
Gillard J.Abraham A.Anderson PC.Beaulieu PL.Bogri T.Bousquet Y.Grenier L.Guse I.Lavallée P. J. Org. Chem. 1996, 61: 2226 - 6
Ley SV.Norman J.Griffith WP.Marsden SP. Synthesis 1994, 639 ; and references cited therein - 9
Sugg EE.Griffin JF.Portoghese PS. J. Org. Chem. 1985, 50: 5032 - 11
Esteves AP.Rodrigues LM.Silva ME.Gupta S.Oliveira-Campos AMF.Machalicky O.Mendonça AJ. Tetrahedron 2005, 61: 8625
References and Notes
For examples of oxidation of 4-hydroxypipecolic acid derivatives with other oxidants, see refs. 2c, 2g and 2j.
8(2R,4S)-6: [α]D
24 6.45 (c = 0.93, CHCl3). 1H NMR (400 MHz): δ = 7.49-7.52 (m, 2 H, Ph), 7.28-7.34 (m, 2 H, Ph), 7.19-7.24 (m, 1 H, Ph), 4.01 (q, J = 6.9 Hz, 1 H, CHMe), 3.65 (s, 3 H, OCH3), 3.27 (dd, J = 2.8, 10.9 Hz, 1 H, 2-H), 2.44 (dt, J = 3.5, 11.4 Hz, 1 H, 6-H), 2.22 (d, J = 7.0 Hz, 2 H, CH
2CO2Me), 2.15 (dt, J = 2.5, 11.6 Hz, 1 H, 6-H), 1.92 (dm, J = 12.3 Hz, 1 H, 3-H), 1.76-1.88 (m, 1 H, 4-H), 1.43-1.57 (m, 2 H, 3-H, 5-H), 1.48 (s, 9 H, t-Bu), 1.32 (d, J = 6.9 Hz, 3 H, CHCH
3), 1.12 (dq, J = 3.8, 12.0 Hz, 1 H, 5-H). 13C NMR (100 MHz): δ = 173.1 (s, CO), 172.9 (s, CO), 143.4 (s, Ph), 127.9 (d, 2 × C, Ph), 127.8 (d, 2 × C, Ph), 126.6 (d, Ph), 80.9 (s, t-Bu), 64.3 (d, C-2), 57.3 (d, CHMe), 51.5 (q, OCH3), 43.2 (t, C-6), 40.7 (t, CH2CO2Me), 36.2 (t, C-3), 32.6 (d, C-4), 31.6 (t, C-5), 28.0 (q, 3 × C, t-Bu), 9.0 (q, CHCH3).
(2R,4R)-6: [α]D
22 -0.55 (c = 1.02, CHCl3). 1H NMR (400 MHz): δ = 7.25-7.38 (m, 4 H, Ph), 7.17-7.23 (m, 1 H, Ph), 4.00 (q, J = 6.7 Hz, 1 H, CHMe), 3.86-3.91 (m, 1 H, 2-H), 3.65 (s, 3 H, OCH3), 2.86 (dt, J = 2.3, 12.1 Hz, 1 H, 6-H), 2.45 (dm, J = 11.7 Hz, 1 H, 6-H), 2.11-2.27 (m, 3 H, CH
2CO2Me, 3-H), 1.86-1.98 (m, 1 H, 4-H), 1.46-1.56 (m, 2 H, 3-H, 5-H), 1.51 (s, 9 H, t-Bu), 1.25 (d, J = 6.7 Hz, 3 H, CHCH
3), 1.11 (dq, J = 4.5, 12.4 Hz, 1 H, 5-H). 13C NMR (100 MHz): δ = 173.0 (s, CO), 172.9 (s, CO), 147.2 (s, Ph), 128.2 (d, 2 × C, Ph), 127.0 (d, 2 × C, Ph), 126.6 (d, Ph), 80.6 (s, t-Bu), 61.7 (d, CHMe), 57.1 (d, C-2), 51.4 (q, OCH3), 45.5 (t, C-6), 41.2 (t, CH2CO2Me), 34.9 (t, C-3), 32.1 (t, C-5), 29.6 (d, C-4), 28.3 (q, 3 × C, t-Bu), 22.0 (q, CHCH3).
The X-ray CIF file for this structure has been deposited at the Cambridge Crystallographic Data Centre and allocated with the deposition number CCDC 607916. Copies of the data can be obtained free of charge from CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK (e-mail: deposit@ccdc.cam.ac.uk; internet://www.ccdc.cam.ac.uk).
12A slurry of diester (2S,4R)-6 (358 mg, 0.99 mmol) in THF (0.5 mL) was treated dropwise with an aq 1 M NaOH solution (1.6 mL, 1.6 mmol). The mixture was stirred at r.t. for 3 h and concentrated. The residue was dissolved in THF (1.0 mL) and NMM (0.109 mL, 0.99 mmol) and CDMT (174 mg, 0.99 mmol) were added. The reaction mixture was stirred at r.t. for 30 min and then a solution of 2,3,4,6-tetra-O-acetyl-β-d-glucopyranosylamine (321 mg, 0.99 mmol) in THF (1.3 mL) was added. The resulting mixture was stirred at r.t. overnight, diluted with EtOAc, and washed sequentially with H2O and brine. The separated organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (eluent: PE-EtOAc = 2:3) to afford (2S,4R)-7 (423 mg, 63%) as a white solid.
(2S,4R)-7: [α]D
27 -32.65 (c = 0.525, CHCl3). 1H NMR (400 MHz): δ = 7.23-7.34 (m, 3 H, Ph), 7.14-7.19 (m, 2 H, Ph), 6.18 (d, J = 9.3 Hz, 1 H, NH), 5.28 (t, J = 9.5 Hz, 1 H, 3′-H), 5.19 (t, J = 9.4 Hz, 1 H, 1′-H), 5.04 (t, J = 9.7 Hz, 1 H, 4′-H), 4.87 (t, J = 9.6 Hz, 1 H, 2′-H), 4.29 (dd, J = 4.2, 12.5 Hz, 1 H, 6′-H), 4.04 (dd, J = 2.0, 12.5 Hz, 1 H, 6′-H), 3.97 (q, J = 7.0 Hz, 1 H, CHMe), 3.78 (ddd, J = 2.0, 4.2, 10.1 Hz, 1 H, 5′-H), 3.00 (dm, J = 11.4 Hz, 1 H, 6-H), 2.77 (dd, J = 2.9, 11.2 Hz, 1 H, 2-H), 2.07 (A part of an ABX system, J = 6.7, 14.6 Hz, 1 H, CHHCON), 2.06 (s, 3 H, CH3CO), 2.02 (s, 3 H, CH3CO), 2.00 (s, 3 H, CH3CO), 1.99 (s, 3 H, CH3CO), 1.96 (B part of an ABX system, J = 7.0, 14.6 Hz, 1 H, CHHCON), 1.79 (dm, J = 12.4 Hz, 1 H, 3-H), 1.71 (tm, J = 11.5 Hz, 1 H, 6-H), 1.50-1.60 (m, 2 H, 4-H, 5-H), 1.53 (s, 9 H, t-Bu), 1.48 (d, J = 7.0 Hz, 3 H, CHCH
3), 1.36 (q, J = 11.8 Hz, 1 H, 3-H), 1.19-1.30 (m, 1 H, 5-H). 13C NMR (100 MHz): δ = 173.1 (s, CO), 171.6 (s, CO), 171.0 (s, CO), 170.6 (s, CO), 169.8 (s, CO), 169.5 (s, CO), 137.7 (s, Ph), 128.9 (d, 2 × C, Ph), 127.7 (d, 2 × C, Ph), 127.2 (d, Ph), 80.9 (s, t-Bu), 78.0 (d, C-1′), 73.5 (d, C-5′), 72.6 (d, C-3′), 70.5 (d, C-2′), 68.1 (d, C-4′), 64.5 (d, C-2), 61.6 (t, C-6′), 59.4 (d, CHMe), 43.8 (t, C-6), 43.2 (t, CH2CON), 36.3 (t, C-3), 32.6 (d, C-4), 31.3 (t, C-5), 28.1 (q, 3 × C, t-Bu), 20.7 (q, CH3CO), 20.6 (q, CH3CO), 20.5 (q, 2 × C, CH3CO), 18.5 (q, CH3CH).
A solution of (2S,4R)-7 (105 mg, 0.155 mmol) in MeOH (1.6 mL) and AcOH (18 µL, 0.310 mmol) was hydrogenated in the presence of 10% Pd/C (9 mg) at r.t. and atmospheric pressure overnight. The reaction mixture was filtered through cotton wool and concentrated. The residue was dissolved in the minimum amount of TFA at 0 °C and the mixture was stirred at r.t. for 2.5 h and then concentrated. The residue was dissolved in anhyd MeOH (217 µL) and treated sequentially with DIPEA (67 µL, 0.386 mmol) and Boc2O (28.1 mg, 0.129 mmol) at 0 °C. The reaction mixture was stirred at r.t. overnight, and then concentrated. The residue was dissolved in a mixture of EtOAc and CH2Cl2 (1:1, 2.8 mL), treated with 5% aq KHSO4 solution (1 mL) and stirred at r.t. for 1 h. After the organic layer was separated, the aqueous layer was extracted with EtOAc (3 × 1.4 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (eluent: CH2Cl2-MeOH, 10:1) to afford (2S,4R)-8 (32.4 mg, 34%) as a white solid. Molecular mass determinations by electrospray ionization mass spectrometry (ESI-MS) was used to identify the N-protected amino acid (2S,4R)-8. MS (ESI): m/z = 639.3 [M + Na+].