PDF herunterladen
Synlett 2008(11): 1627-1630  
DOI: 10.1055/s-2008-1078489
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Novel Route Towards the Synthesis of Spirocyclic Bislactones

Francisco Alonso*, Jaisiel Meléndez, Miguel Yus*
Departamento de Química Orgánica, Facultad de Ciencias and Instituto de Química Orgánica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
Fax: +34(96)5903549; e-Mail: falonso@ua.es; e-Mail: yus@ua.es;
Weitere Informationen

Publikationsverlauf

Received 4 March 2008
Publikationsdatum:
11. Juni 2008 (online)

    Lizenzen und Reprints Alle Artikel dieser Rubrik

Abstract

A novel route towards the synthesis of 1,7-dioxa­spiro[4.4]nonane-2,6-diones, based on the versatile reactivity of an acyclic trimethylenemethane dianion synthon, is presented.

Key words

trimethylenemethane - dianion synthon - lithiation - ­spirocyclization - bislactones

22

General Procedure for the Preparation of Compounds 3
A solution of 2-chloromethyl-3-(2-methoxyethoxy)propene (164 mg, 1 mmol) and the corresponding ketone (0.95 mmol) in THF (2 mL), was added over 1.5 h to a green suspension of lithium powder (50 mg, 7 mmol) and DTBB (27 mg, 0.1 mmol) in THF (3 mL) at -78 °C. The mixture was allowed to reach 0 °C and then neat 2-(2-iodoeth-oxy)tetrahydro-2H-pyran [27] (1.5 mmol) was added over 1.5 h continuing the stirring for 2 h at r.t. The reaction mixture was hydrolyzed with H2O (5 mL), extracted with EtOAc (3 × 10 mL), and the organic phase was dried over anhyd MgSO4. After removal of the solvent under reduced pressure (2·10-2 bar), the resulting residue was purified by column chroma-tography (SiO2, hexane-EtOAc) to yield compounds 3.
1-[2-Methylidene-5-(tetrahydro-2 H -pyran-2-yloxy)pentyl]cyclohexanol (3b) Colorless oil; R f = 0.53 (hexane-EtOAc, 4:1). IR (neat): 3472 (OH), 3071, 1638 (C=CH), 1137, 1076, 1033 cm-1 (CO). 1H NMR (300 MHz, CDCl3): δ = 1.40-1.90 [m, 19 H, OH, (CH2)5, CH 2CH 2CH 2CH, CH 2CH2C=CH2], 2.15-2.25 (m, 4 H, 2 × CH 2C=CH2), 3.35-3.45, 3.45-3.55, 3.71-3.80, 3.83-3.90 (3 m, 4 H, 2 × CH2O), 4.56 (t, J = 4.3 Hz, 1 H, 2 × CHO), 4.82, 4.95 (2 s, 2 H, CH2=C). 13C NMR (75 MHz, CDCl3): δ = 19.6, 22.2, 25.4, 25.7, 28.0, 30.7 (CH2 CH2 CH2CH, CH2CH2C=CH2, CH2 CH2 CH2CH2COH), 34.4 (CH2 CH2C=CH2), 37.8 (2 × CH2COH) 48.1 (CCH2C), 62.3, 67.0 (2 × CH2O), 71.0 (COH), 98.9 (CHO), 113.6 (CH2=C), 146.0 (C=CH2). MS (EI): m/z (%) = 282 (<1) [M+], 99 (31), 85 (100), 81 (23), 67 (18), 55 (15). HRMS (EI): m/z calcd for C17H30O3: 270.2195; found: 270.2201.

23

The stereochemistry in 3c and 4c was established on the basis of the X-ray crystal structure of the methylidene diol resulting from the reaction of the analogue 3-methyl-idenepentane-1,5-dianion synthon with (-)-fenchone. [19g]

24

General Procedure for the Deprotection of Compounds 3
A flake of PTSA was added to a solution of the protected alcohol 3 (1 mmol) in MeOH (5 mL). After stirring for 1 h, the volatiles were removed under vacuum (2·10-2 bar), and H2O (10 mL) was added to the residue followed by extraction with EtOAc (3 × 10 mL). The organic phase was dried over anhyd MgSO4 and the solvent evaporated under reduced pressure to give the pure product 4 which did not require further purification.
1-(5-Hydroxy-2-methylidenepentyl)cyclohexanol (4b) Colorless oil; R f = 0.40 (hexane-EtOAc, 4:1). IR (neat): 3373 (OH), 3072, 1638 (C=CH), 1146, 1059 cm-1 (CO). 1H NMR (300 MHz, CDCl3): δ = 1.40-1.70 [m, 10 H, (CH2)5], 1.72-1.80 (m, 2 H, CH 2CH2OH), 2.10-2.20 (m, 6 H, 2 × OH, 2 × CH 2C=CH2), 3.65 (t, J = 6.2 Hz, 2 H, CH 2OH), 4.82, 4.94 (2 s, 2 H, CH2=C). 13C NMR (75 MHz, CDCl3): δ = 22.2, 25.7, 30.8, 33.8 (2 × CH2CH2CO, CH2CH2CH2CO, CH2CH2O, CH2CH2CH2O), 37.8 (2 × CH2CO), 48.1 (CCH2C), 62.1 (CH2O), 71.3 (CO), 113.6 (CH2=C), 146.0 (C=CH2). MS (EI): m/z (%) = 180 (<1) [M+ - 18], 99 (100), 81 (54), 55 (18). HRMS (EI): m/z calcd for C12H22O2: 198.1620; [M+ - H2O]: 180.1514; found: 180.1515.

25

General Procedure for the Cyclization of Compounds 4
Iodine (0.382 g, 1.5 mmol) was added to a solution of the corresponding diol 4 (1 mmol) in THF (5 mL). The mixture was stirred for 5 min at r.t. and then Ag2O (0.346 g, 1.5 mmol) was added with additional stirring for 24 h. The resulting suspension was filtered and H2O (10 mL) was added to the filtrate, followed by extraction with EtOAc (3 × 10 mL). The organic phase was successively washed with a sat. solution of Na2SO3 (2 × 10 mL) and H2O (2 × 10 mL), and dried over anhyd MgSO4. The solvent was removed under reduced pressure to furnish pure compounds 5.
1,13-Dioxaspiro[4.1.5.2]tetradecane (5b)
Colorless oil; R f = 0.69 (hexane-EtOAc, 4:1). IR (neat): 1058 cm-1 (CO). 1H NMR (300 MHz, CDCl3): δ = 1.30-1.95 [m, 14 H, (CH2)5, CH 2CH 2CH2O], 1.73, 2.02 (AB system, J = 13.1 Hz, 2 H, CCH2C), 3.35-3.50, 3.75-3.85 (2 m, 2 H, CH2CH 2O), 3.63, 3.82 (AB system, J = 9.3 Hz, 2 H, CCH2O). 13C NMR (75 MHz, CDCl3): δ = 23.6, 25.7, 29.4, 34.5, 37.7 (7 × CH2), 49.0 (CCH2C), 67.3 (CH2 CH2O), 75.1 (CO), 82.9 (CCH2O), 89.2 (OCH2 CO). MS (EI): m/z (%) = 196 (32) [M+], 167 (13), 166 (17), 155 (100), 154 (18), 140 (21), 135 (10), 123 (36), 113 (10), 107 (11), 97 (15), 84 (19), 81 (14), 67 (13), 55 (29). HRMS (EI): m/z calcd for C12H20O2: 196.1463; found: 196.1467.

26

1,13-Dioxaspiro[4.1.5.2]tetradecane-2,14-dione (6b)
A suspension of RuO2 (21 mg, 0.16 mmol) and NaIO4 (1.04 g, 4.88 mmol) in H2O (5 mL) was added to a solution of the 1,7-dioxaspiro[4.4]nonane 5b (1.0 mmol) in CCl4 (5 mL) at r.t. [28] After stirring the reaction for 24 h, i-PrOH (3 mL) was added, and the resulting mixture was extracted with CCl4 (2 × 5 mL). The organic layer was dried over anhyd MgSO4, filtered, and evaporated under reduced pressure. The resulting residue was passed through a pad containing Celite in order to eliminate the remaining ruthenium compounds, yielding the corresponding pure spirocyclic bislactone 6b, which did not require any further purification.
Colorless solid; mp 138-140 °C; R f = 0.50 (hexane-EtOAc, 4:1). IR (KBr): 1768 (C=O), 1139 cm-1 (CO). 1H NMR (300 MHz, CDCl3): δ = 1.30-2.65 (m, 16 H, 8 × CH2). 13C NMR (75 MHz, CDCl3): δ = 22.3, 22.5, 24.6, 28.1, 31.3, 37.1, 38.0 (7 × CH2), 45.4 (CCH2C), 83.9, 85.0 (2 × CO), 173.7, 175.1 (2 × C=O). MS (EI): m/z (%) = 180 (29) [M+ - CO2], 139 (23), 138 (26), 137 (100), 124 (29), 120 (24), 111 (21), 109 (30), 99 (93), 98 (63), 96 (22), 95 (51), 82 (53), 81 (65), 80 (57), 79 (27), 70 (22), 69 (23), 67 (50), 56 (55), 55 (79), 54 (25), 53 (21). Anal. Calcd for C12H16O4: C, 64.27; H, 7.19; O, 28.54. Found: C, 64.20; H, 7.23. Selected X-ray Data: C12H16O4, M = 224.25; monoclinic, a = 8.510(2) Å, b = 6.8849(16) Å, c = 9.445(2) Å, β = 95.993(4)°; V = 550.3(2) Å3; space group P21; Z = 2; D c = 1.353 Mg m-3; λ = 0.71073 Å; µ = 0.101 mm-1; F(000) = 240; T = 24 ± 1 °C; CCDC number 679641 contains the supplementary crystallographic data for compound 6b. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.ac.uk/data_request/cif.