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DOI: 10.1055/s-2005-865225
Efficient Enantioselective Formal Synthesis of Ro 67-8867, a NMDA 2B Receptor Antagonist
Publication History
Publication Date:
14 April 2005 (online)
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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
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.
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).
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).