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

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

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 
• 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 

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).

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).