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

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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

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References

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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).

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

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).

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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).

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).