Efficient Enantioselective Formal Synthesis of Ro 67-8867, a NMDA 2B Receptor Antagonist

Ingrid Déchamps; Domingo Gomez Pardo; Phillipe Karoyan; Janine Cossy

doi:10.1055/s-2005-865225

LETTER

Efficient Enantioselective Formal Synthesis of Ro 67-8867, a NMDA 2B Receptor Antagonist

Ingrid Déchamps^a, Domingo Gomez Pardo^a, Phillipe Karoyan^b, Janine Cossy*^a
^a Laboratoire de Chimie Organique associé au CNRS, Ecole Supérieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI), 10 rue Vauquelin, 75231 Paris Cedex 05, France
^b UMR, CNRS 7613, Structure et Fonction de Molécules Bioactives, Université Paris VI, case 45, 4 place Jussieu, 75252 Paris Cedex 05, France
Fax: +33(1)40794660; e-Mail: janine.cossy@espci.fr;

Abstract

All articles of this category

Abstract

An efficient enantioselective formal synthesis of Ro 67-8867 has been achieved in 7 steps using an amino-zinc-ene-enolate cyclization and an enantioselective ring enlargement of a substituted prolinol as the key steps.

Key words

amino-zinc-ene-enolate cyclization - asymmetric synthesis - ring expansion - piperidines - prolinol

Full Text

References

1a Grauert M. Bechtel WD. Ensinger HA. Merz H. Carter AJ. J. Med. Chem. 1997, 40: 2922

1b Guzikowski AP. Whittemore ER. Woodward RM. Weber E. Keana JFW. J. Med. Chem. 1997, 40: 2424

1c Gee KR. Niu L. Schaper K. Jayaraman V. Hess G. Biochemistry 1999, 38: 3140

2a Alanine A, Burner S, Buettelmann B, Heitz Neidhart M.-P, Jaeschke G, Pinard E, and Wyler R. inventors; WO 0075109. ; Chem. Abstr. 2000, 134, 42064

2b Crameri Y, Scalone M, Waldmeier P, and Widmer U. inventors; EP 1136475. ; Chem. Abstr. 2001, 135, 272882

2c Alanine A, Buettelmann B, Fisher H, Huwyler J, Heitz Neidhart M.-P, Jaeschke G, Pinard E, and Wyler R. inventors; WO 0216321. ; Chem. Abstr. 2002, 136, 216649

2d Scalone M. Waldmeier P. Org. Process Res. Dev. 2003, 7: 418

3a Karoyan P. Chassaing G. Tetrahedron Lett. 1997, 38: 85

3b Lorthiois E. Marek I. Normant J. Tetrahedron Lett. 1997, 38: 89

3c Karoyan P. Chassaing G. Tetrahedron: Asymmetry 1997, 8: 2025

3d Lorthiois E. Marek I. Normant J. J. Org. Chem. 1998, 63: 2442

3e Karoyan P. Chassaing G. Tetrahedron Lett. 2002, 43: 253

3f Karoyan P. Chassaing G. Tetrahedron Lett. 2002, 43: 1221

3g Karoyan P. Quancard J. Vaissermann J. Chassaing G. J. Org. Chem. 2003, 68: 2256

3h Quancard J. Magellan H. Lavielle S. Chassaing G. Karoyan P. Tetrahedron Lett. 2004, 45: 2185

3i Quancard J. Labonne A. Jacquot Y. Chassaing G. Lavielle S. Karoyan P. J. Org. Chem. 2004, 69: 7940

For comprehensive reviews, see:

4a Cossy J. Gomez Pardo D. Chemtracts 2002, 15: 579

4b Cossy J. Gomez Pardo D. Targets in Heterocyclic Systems 2002, 6: 1

5

Analytical Data.
Compound 5: [α]_D ²⁰ +39.2 (c 1.4, CHCl₃). IR (neat): 2962, 1724, 1491, 1450, 1371, 1160, 1089, 1026, 769, 740, 706 cm^-1. ¹H NMR: δ = 7.23-7.02 (m, 10 H), 4.06 (m, 2 H), 3.64 (q, J = 6.8 Hz, 1 H), 3.36 (d, J = 7.9 Hz, 1 H), 2.97 (dt, J = 8.3, 3.4 Hz, 1 H), 2.80-2.69 (m, 2 H), 2.54 (m, 1 H), 2.23 (dd, J = 13.2, 10.6 Hz, 1 H), 1.75-1.61 (m, 2 H), 1.29 (d, J = 6.8 Hz, 3 H), 1.15 (t, J = 7.2 Hz, 3 H). ¹³C NMR: δ = 173.4 (s), 144.5 (s), 140.5 (s), 128.6 (d), 128.3 (d), 128.2 (d), 127.5 (d), 127.1 (d), 126.0 (d), 66.7 (d), 61.8 (d), 59.9 (t), 50.2 (t), 43.7 (d), 37.1 (t), 29.7 (t), 22.7 (q), 14.3 (q). MS (EI): m/z (relative intensity) = 337 (1) [M⁺], 265 (23), 264 (100), 143 (4), 106 (5), 105 (56), 104 (3), 103 (6), 91 (19), 79 (7), 77 (6), 68 (5).

6

Compound 5 was the only product detected by ¹H NMR and GC-MS.

7

Analytical Data.
Compound 6: [α]_D ²⁰ +8.6 (c 4.3, CHCl₃). IR (neat): 3420, 3015, 2920, 1600, 1485, 1445, 1370, 1310, 1155, 1080, 1025, 765, 745, 705, 700 cm^-1. ¹H NMR: δ = 7.28-7.14 (m, 7 H), 7.13-7.05 (m, 3 H), 3.72 (q, J = 6.8 Hz, 1 H), 3.54 (dd, J = 10.9, 3.02 Hz, 1 H), 3.46 (dd, J = 11.1, 4.1 Hz, 1 H), 3.04 (m, 1 H), 2.86-2.73 (m, 2 H), 2.60 (m, 1 H), 2.32-2.15 (m, 2 H), 1.54-1.40 (m, 2 H), 1.36 (d, J = 6.8 Hz, 3 H).
¹³C NMR: δ = 143.5 (s), 141.2 (s), 128.6 (d), 128.4 (d), 128.4 (d), 127.7 (d), 127.2 (d), 125.9 (d), 62.6 (d), 62.2 (d), 60.4 (t), 50.8 (t), 43.1 (d), 36.2 (t), 31.3 (t), 22.3 (q). MS (EI): m/z (relative intensity): 295 (1) [M⁺], 280 (5), 265 (22), 264 (100), 161 (8), 160 (66), 143 (6), 106 (8), 105 (79), 103(8), 91 (27), 79 (10), 77 (9), 68 (7).

8a Cossy J. Dumas C. Michel P. Gomez Pardo D. Tetrahedron Lett. 1995, 36: 549

8b Cossy J. Dumas C. Gomez Pardo D. Synlett 1997, 905

8c Cossy J. Dumas C. Gomez Pardo D. Bioorg. Med. Chem. Lett. 1997, 7: 1343

8d Wilken J. Kossenjans M. Saak W. Haase D. Pohl S. Martens J. Liebigs Ann. 1997, 573

8e Langlois N. Calvez O. Synth. Commun. 1998, 28: 4471

8f Davis PW. Osgood SA. Hébert N. Sprankle KG. Swayze EE. Biotechnol. Bioeng. 1999, 61: 143

8g Cossy J. Dumas C. Gomez Pardo D. Eur. J. Org. Chem. 1999, 1693

8h Michel P. Rassat A. J. Org. Chem. 2000, 65: 2572

8i Cossy J. Mirguet O. Gomez Pardo D. Synlett 2001, 1575

8j Brandi A. Cicchi S. Paschetta V. Gomez Pardo D. Cossy J. Tetrahedron Lett. 2002, 43: 9357

8k Deyine A. Delcroix J.-M. Langlois N. Heterocycles 2004, 64: 207

9

Analytical Data.
Compound 7: [α]_D ²⁰ -24.6 (c 1.1, CHCl₃). IR (neat): 3492, 3009, 2910, 2798, 1600, 1491, 1451, 1395, 1210, 1095, 1060, 762, 709 cm^-1. ¹H NMR: δ = 7.27-7.13 (m, 7 H), 7.12-7.05 (m, 3 H), 3.55-3.40 (m, 2 H), 2.99 (m, 1 H), 2.90-2.80 (m, 1 H), 2.76-2.64 (m, 2 H), 2.45 (dd, J = 13.2, 6.4 Hz, 1 H), 1.98 (m, 1 H), 1.80 (m, 1 H), 1.54-1.31 (m, 3 H), 1.28 (d, J = 6.8 Hz, 3 H). ¹³C NMR: δ = 143.0 (s), 140.8 (s), 129.2 (d), 128.3 (d), 128.2 (d), 127.6 (d), 127.1 (d), 125.7 (d), 66.7 (d), 63.6 (d), 56.5 (t), 50.6 (t), 42.6 (d), 38.8 (t), 26.9 (t), 18.4 (q). MS (EI): m/z (relative intensity) = 295 (11) [M⁺], 281 (23), 280 (100), 218 (14), 190 (6), 105 (32), 103 (4), 91 (18), 79 (5), 77 (5).

10

Analytical Data.
Compound 8: [α]_D ²⁰ -36.6 (c 1, CHCl₃). IR (neat): 3290, 2915, 1604, 1532, 1452, 1282, 1263, 1110, 1001, 848, 753, 706 cm^-1. ¹H NMR: δ = 7.24-7.07 (m, 5 H), 3.52-3.46 (m, 1 H), 2.99-2.86 (m, 2 H), 2.68 (d, J = 13.6, 7.5 Hz, 1 H), 2.58-2.47 (m, 5 H), 1.65-1.27 (m, 3 H). ¹³C NMR: δ = 140.6 (s), 129.2 (d), 128.2 (d), 125.8 (d), 66.3 (d), 53.1 (t), 46.5 (t), 42.6 (d), 39.3 (t), 27.2 (t). MS (EI): m/z (relative intensity) = 191 (100) [M⁺], 162 (9), 147 (8), 131 (7), 118 (32), 115 (13), 100 (20), 92 (11), 91 (67), 82 (22), 77 (11), 72 (11), 71 (42), 65 (22), 57 (30), 56 (30), 55 (26).