A Stereoselective Synthesis of (±)-3-Aryl-6-phenyl-1-oxa-7-azaspiro[4.5]-decanes

Abstract

A novel stereoselective synthesis of the 3-aryl-6-phenyl-1-oxa-7-azaspiro[4.5]decane ring is reported. Palladium(0)-mediated cyclocarbonylation of γ-iodoallylic alcohol is a key step in the formation of the spirocyclic ring.

spirocyclic compounds - lactones - stereoselective synthesis - regioselective lithiation - substance P (NK₁ receptor) antagonist

References

<A NAME="RD18803ST-1">1</A> Kramer MS. Cutler N. Feighner J. Shrivastava R. Carman J. Sramek JJ. Reines SA. Liu G. Snavely D. Wyatt-Knowles E. Hale JJ. Mills SG. MacCoss M. Swain CJ. Harrison T. Hill RG. Hefti F. Scolnick EM. Cascieri MA. Chicchi GG. Sadowski S. Williams AR. Hewson L. Smith D. Carlson EJ. Hargreaves RJ. Rupniak NMJ. Science  1998,  281:  1640 

<A NAME="RD18803ST-2">2</A> Snider RM. Constantine JW. Lowe JA. Longo KP. Lebel WS. Woody HA. Drozda SE. Desai MC. Vinick FJ. Spencer RW. Hess H.-J. Science  1991,  251:  435 

<A NAME="RD18803ST-3">3</A> Seward EM. Swain CJ. Expert Opin. Ther. Pat.  1999,  9:  571 

For recent advances, see:

<A NAME="RD18803ST-4A">4a</A> Shaw D. Chicchi GG. Elliott JM. Kurtz M. Morrison D. Ridgill MP. Szeto N. Watt AP. Williams AR. Swain CJ. Bioorg. Med. Chem. Lett.  2001,  11:  3031 

<A NAME="RD18803ST-4B">4b</A> Elliott JM. Castro JL. Chicchi GG. Cooper LC. Dinnell K. Hollingworth GJ. Ridgill MP. Rycroft W. Kurtz MM. Shaw DE. Swain CJ. Tsao K.-L. Yang L. Bioorg. Med. Chem. Lett.  2002,  12:  1755 

<A NAME="RD18803ST-4C">4c</A> Cooper LC. Carlson EJ. Castro JL. Chicchi GG. Dinnell K. Di Salvo J. Elliott JM. Hollingworth GJ. Kurtz MM. Ridgill MP. Rycroft W. Tsao K.-L. Swain CJ. Bioorg. Med. Chem. Lett.  2002,  12:  1759 

<A NAME="RD18803ST-4D">4d</A> Seward EM. Carlson E. Harrison T. Haworth KE. Herbert R. Kelleher FJ. Kurtz MM. Moseley J. Owen SN. Owens AP. Sadowski SJ. Swain CJ. Williams BJ. Bioorg. Med. Chem. Lett.  2002,  12:  2515 

<A NAME="RD18803ST-4E">4e</A> Williams BJ. Cascieri MA. Chicchi GG. Harrison T. Owens AP. Owen SN. Rupniak NMJ. Tattersall DF. Williams A. Swain CJ. Bioorg. Med. Chem. Lett.  2002,  12:  2719 

<A NAME="RD18803ST-4F">4f</A> Gale JD. O’Neill BT. Humphrey JM. Expert Opin. Ther. Pat.  2001,  11:  1837 

<A NAME="RD18803ST-5">5</A> Maligres PE. Waters MM. Lee J. Reamer RA. Askin D. Ashwood MS. Cameron M. J. Org. Chem.  2002,  67:  1093 

<A NAME="RD18803ST-6A">6a</A> Kulagowski JJ. Curtis NR. Swain CJ. Williams BJ. Org. Lett.  2001,  3:  667 

<A NAME="RD18803ST-6B">6b</A> Wallace DJ. Bulger PG. Kennedy DJ. Ashwood MS. Cottrell IF. Dolling U.-H. Synlett  2001,  3:  357 

<A NAME="RD18803ST-7">7</A> Kersey ID. Fishwick CWG. Findlay JBC. Ward P. Bioorg. Med. Chem. Lett.  1995,  5:  1271 

<A NAME="RD18803ST-8">8</A> Hollingworth GJ. Dinnell K. Dickinson LC. Elliott JM. Kulagowski JJ. Swain CJ. Thomson CG. Tetrahedron Lett.  1999,  40:  2633 

<A NAME="RD18803ST-9">9</A> Ohira S. Synth. Commun.  1989,  19:  561 

<A NAME="RD18803ST-10">10</A>

Experimental Procedure for the Preparation of 3: A solution of EtMgBr in THF (1 M, 4.1 mL, 4.1 mmol) was added dropwise to a stirred solution of 5 (1.0 g, 4.1 mmol) in THF (10 mL) at r.t. After 30 min, the mixture was cooled to 0 °C and a solution of 4 (1.07 g, 3.9 mmol) in THF (10 ml) was added dropwise over 5 min. The mixture was stirred at 0 °C for 2 h and at r.t. overnight. After quenching with sat. aq NH₄Cl, the mixture was extracted into 2-methylpentane. The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified on silica gel (2-methylpentane-Et₂O) to give the alcohol 3 (1.17 g, 62%). ¹H NMR (360 MHz, CDCl₃): δ = 0.78-0.90 (m, 4 H), 1.32 (s, 9 H), 1.80 (m, 1 H), 2.00-2.15 (m, 2 H), 2.14 (s, 1 H), 2.22 (m, 1 H), 3.11 (m, 1 H), 3.78 (m, 1 H), 4.15 (dd, J = 5.6, 13.4 Hz, 1 H), 5.48 (s, 1 H), 7.15 (dd, J = 2.0, 9.2 Hz, 1 H), 7.17-7.40 (m, 6 H), 7.55 (d, J = 7.2 Hz, 2 H). Relative stereochemistry was assigned by ¹H NMR experiments. [6a]

<A NAME="RD18803ST-11">11</A>

Experimental Procedure for the Preparation of 8: A solution of Red-Al^® in toluene (0.9 mL, 3.1 mmol) was added dropwise to a stirred solution of 3 (1.17 g, 2.25 mmol) in anhyd Et₂O (15 mL) at 0 °C. The ice bath was removed and the reaction mixture was stirred at r.t. for 2.5 h. The mixture was cooled to -78 °C and a solution of I₂ (1 g, 4 mmol) in anhyd Et₂O (10 mL) was added over 5 min. The reaction mixture was allowed to warm to r.t. over 2 h and quenched with sat. aq Na₂SO₃. The mixture was extracted into Et₂O. The combined organic extracts were dried (Na₂SO₄) and concentrated. The residue was purified on silica gel (2-methylpentane-Et₂O) to give the iodide 8 (1.14 g, 78%). ¹H NMR (360 MHz, CDCl₃): δ = 0.80-0.90 (m, 4 H), 1.34 (s, 9 H), 1.74-1.90 (m, 2 H), 2.05 (m, 1 H), 2.31 (dt, J = 5.2, 13.2 Hz, 1 H), 2.63 (s, 1 H), 3.18 (ddd, J = 5.8, 11.3, 13.6 Hz, 1 H), 3.78 (m, 1 H), 4.10 (m, 1 H), 5.39 (s, 1 H), 6.35 (s, 1 H), 7.06 (d, J = 2.8 Hz, 1 H), 7.20 (dd, J = 2.3, 8.5 Hz, 1 H), 7.22 (d, J = 8.9 Hz, 1 H), 7.25-7.40 (m, 4 H), 7.52 (d, J = 7.2 Hz, 2 H).

<A NAME="RD18803ST-12">12</A> El AB. Alper H. J. Org. Chem.  1991,  56:  5357 

<A NAME="RD18803ST-13">13</A> Cowell A. Stille JK. J. Am. Chem. Soc.  1980,  102:  4193 

<A NAME="RD18803ST-14">14</A>

Experimental Procedure for the Preparation of 2: A solution of hydrazine in THF (0.07 mL, 0.07 mmol) was added, under an atmosphere of CO, to a stirred mixture of 8 (320 mg, 0.5 mmol), (Ph₃P)₂PdCl₂ (50 mg, 0.07 mmol), K₂CO₃ (138 mg, 1 mmol) and THF (5 mL). The mixture was stirred at 50 °C for 5 d. After cooling to r.t., the mixture was diluted with Et₂O and filtered through a pad of Celite. The filtrate was concentrated and the residue purified on silica gel (2-methylpentane-EtOAc) to give the lactone 2 (184 mg, 68%). ¹H NMR (360 MHz, CDCl₃): δ = 0.76-0.94 (m, 4 H), 1.39 (s, 9 H), 1.82-2.04 (m, 3 H), 2.30 (m, 1 H), 3.20 (dt, J = 4.8, 13.7 Hz, 1 H), 3.82 (m, 1 H), 4.22 (dd, J = 5.6, 13.4 Hz, 1 H), 5.25 (s, 1 H), 7.19 (dd, J = 1.4, 9.2 Hz, 1 H), 7.22-7.33 (m, 4 H), 7.39 (d, J = 7.3 Hz, 1 H), 7.98 (d, J = 2.9 Hz, 1 H), 8.08 (s, 1 H).

<A NAME="RD18803ST-15">15</A> Baker R, Curtis NR, Elliott JM, Harrison T, Hollingworth GJ, Jackson PS, Kulagowski JJ, Seward EM, Swain CJ, and Williams BJ. inventors; WO Patent  97/49710.  ; Chem. Abstr. 1998, 128, 88921

<A NAME="RD18803ST-16">16</A>

The spectral data exhibited by 1 was identical to reported. [15]