New Cyclic Aspartic Acid and N-Glucosyl Asparagine Mimetics

Franca M. Cordero; Paolo Fantini; Alberto Brandi

doi:10.1055/s-2006-951541

LETTER

New Cyclic Aspartic Acid and N-Glucosyl Asparagine Mimetics

Franca M. Cordero*, Paolo Fantini, Alberto Brandi*
Department of Organic Chemistry ‘Ugo Schiff’, Laboratory of Design, Synthesis and Study of Biologically Active Heterocycles, University of Firenze, via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy
Fax: +39(055)4573531; e-Mail: franca.cordero@unifi.it; e-Mail: alberto.brandi@unifi.it;

Abstract

All articles of this category

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

Full Text

References

References and Notes

<A NAME="RG25106ST-1A">1a</A> Mukhtar TA. Wright GD. Chem. Rev. 2005, 105: 529

<A NAME="RG25106ST-1B">1b</A> Di Giambattista M. Nyssen E. Percher A. Cocito C. Biochemistry 1990, 29: 9203

<A NAME="RG25106ST-1C">1c</A> Reed JW. Purvis MB. Kingston DGI. Blot A. Gossele F. J. Org. Chem. 1989, 54: 1161

<A NAME="RG25106ST-1D">1d</A> Kessler H. Kühn M. Löschner T. Liebigs Ann. Chem. 1986, 1

<A NAME="RG25106ST-1E">1e</A> Hollstein U. Chem. Rev. 1974, 74: 625

<A NAME="RG25106ST-1F">1f</A> Vanderhaeghe H. Parmentier G. J. Am. Chem. Soc. 1960, 82: 4414

<A NAME="RG25106ST-2A">2a</A> Machetti F. Cordero FM. De Sarlo F. Papini AM. Alcaro MC. Brandi A. Eur. J. Org. Chem. 2004, 2928

<A NAME="RG25106ST-2B">2b</A> Sata NU. Kuwahara R. Murata Y. Tetrahedron Lett. 2002, 43: 115

<A NAME="RG25106ST-2C">2c</A> Golubev AS. Schedel H. Radics G. Sieler J. Burger K. Tetrahedron Lett. 2001, 42: 7941

<A NAME="RG25106ST-2D">2d</A> 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

<A NAME="RG25106ST-2E">2e</A> Ornstein PL. Arnold MB. Lunn WHW. Heinz LJ. Leander JD. Lodge D. Schoepp DD. Bioorg. Med. Chem. Lett. 1998, 8: 389

<A NAME="RG25106ST-2F">2f</A> Bellier B. Da Nascimento SH. Gincel E. Roques BP. Garbay C. Bioorg. Med. Chem. Lett. 1998, 8: 1419

<A NAME="RG25106ST-2G">2g</A> Skiles JW. Giannousis PP. Fales KR. Bioorg. Med. Chem. Lett. 1996, 6: 963

<A NAME="RG25106ST-2H">2h</A> 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

<A NAME="RG25106ST-2I">2i</A> Hays SJ. Malone TC. Johnson G. J. Org. Chem. 1991, 56: 4084

<A NAME="RG25106ST-2J">2j</A> Ornstein PL. Schoepp DD. Arnold MB. Leander JD. Lodge D. Paschal JW. Elzey T. J. Med. Chem. 1991, 34: 90

<A NAME="RG25106ST-3">3</A> Toniolo C. Int. J. Peptide Protein Res. 1990, 35: 287

<A NAME="RG25106ST-4A">4a</A> Varki A. Glycobiology 1993, 3: 97

<A NAME="RG25106ST-4B">4b</A> Dwek RA. Chem. Rev. 1996, 96: 683

<A NAME="RG25106ST-4C">4c</A> Rudd PM. Elliott T. Cresswell P. Wilson IA. Dwek RA. Science 2001, 291: 2370

<A NAME="RG25106ST-4D">4d</A> Pratt MR. Bertozzi CR. Chem. Soc. Rev. 2005, 34: 58

<A NAME="RG25106ST-5">5</A> Gillard J. Abraham A. Anderson PC. Beaulieu PL. Bogri T. Bousquet Y. Grenier L. Guse I. Lavallée P. J. Org. Chem. 1996, 61: 2226

<A NAME="RG25106ST-6">6</A> Ley SV. Norman J. Griffith WP. Marsden SP. Synthesis 1994, 639 ; and references cited therein

For examples of oxidation of 4-hydroxypipecolic acid derivatives with other oxidants, see refs. 2c, 2g and 2j.

(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).

<A NAME="RG25106ST-9">9</A> Sugg EE. Griffin JF. Portoghese PS. J. Org. Chem. 1985, 50: 5032

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).

<A NAME="RG25106ST-11">11</A> Esteves AP. Rodrigues LM. Silva ME. Gupta S. Oliveira-Campos AMF. Machalicky O. Mendonça AJ. Tetrahedron 2005, 61: 8625

A 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⁺].