A Novel Route Towards the Synthesis of Spirocyclic Bislactones

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.

trimethylenemethane - dianion synthon - lithiation - ­spirocyclization - bislactones

References and Notes

<A NAME="RD06808ST-1">1</A> For a microreview, see: Wong HNC. Eur. J. Org. Chem.  1999,  1757 

<A NAME="RD06808ST-2">2</A> Hon PM. Lee CM. Shang HS. Cui YX. Wong HNC. Chang HM. Phytochemistry  1991,  30:  354 

<A NAME="RD06808ST-3">3</A> Tasdemir D. Sitcher O. J. Nat. Prod.  1997,  60:  874 

<A NAME="RD06808ST-4">4</A> Bindseil KU. Henkel T. Zeeck A. Bur D. Niederer D. Séquin U. Helv. Chim. Acta  1991,  74:  1281 

<A NAME="RD06808ST-5A">5a</A> Edwards RL. Maitland DJ. Oliver CL. Pacey MS. Shields L. Whalley AJS. J. Chem. Soc., Perkin Trans. 1  1999,  715 

<A NAME="RD06808ST-5B">5b</A> Goss RJM. Fuchser J. O’Hagan D. Chem. Commun.  1999,  2255 

<A NAME="RD06808ST-6">6</A> Aramaki Y. Chiba K. Tada M. Phytochemistry  1995,  38:  1419 

<A NAME="RD06808ST-7">7</A> Midland SL. Keen NT. Sims JJ. J. Org. Chem.  1995,  60:  1118 

<A NAME="RD06808ST-8">8</A> Randi K. Phytochemistry  1975,  14:  2710 

<A NAME="RD06808ST-9">9</A> Perold GW. Carlton L. Howard AS. Michael JP. J. Chem. Soc., Perkin Trans. 1  1988,  881 

<A NAME="RD06808ST-10">10</A> Li X.-L. Cheng X. Yang L.-M. Wang RR. Zheng Y.-T. Xiao W.-L. Zhao Y. Xu G. Lu Y. Chang Y. Zheng Q.-T. Zhao Q.-S. Sun H.-D. Org. Lett.  2006,  8:  1937 

<A NAME="RD06808ST-11A">11a</A> Itazaki H. Nagashima K. Kawamura Y. Matsumoto K. Nakai H. Terui Y. J. Antibiot.  1992,  45:  38 

<A NAME="RD06808ST-11B">11b</A> Tanaka K. Itazaki H. Yoshida T. J. Antibiot.  1992,  45:  50 

<A NAME="RD06808ST-12">12</A> Naito S. Escobar M. Kym PR. Liras S. Martin SF. J. Org. Chem.  2002,  67:  4200 

For some total syntheses, see:

<A NAME="RD06808ST-13A">13a</A> Poss AJ. Tetrahedron Lett.  1987,  28:  5469 

<A NAME="RD06808ST-13B">13b</A> Cuzzupe AN. Di Florio R. Rizzacasa MA. J. Org. Chem.  2002,  67:  4392 

<A NAME="RD06808ST-13C">13c</A> Cuzzupe AN. Di Florio R. White JM. Rizzacasa MA. Org. Biomol. Chem.  2003,  1:  3572 

<A NAME="RD06808ST-14A">14a</A> Paju A. Kanger T. Pehk T. Lindmaa R. Müürisepp A.-M. Lopp M. Tetrahedron: Asymmetry  2003,  14:  1565 

<A NAME="RD06808ST-14B">14b</A> Paju A. Kanger T. Niitsoo O. Pehk T. Müürisepp A.-M. Lopp M. Tetrahedron: Asymmetry  2003,  14:  2393 

<A NAME="RD06808ST-15">15</A> Singh P. Mittal A. Kaur P. Kumar S. Tetrahedron  2006,  62:  1063 

<A NAME="RD06808ST-16">16</A> Chatani N. Amako K. Tobisu M. Asaumi T. Fukumoto Y. Murai S. J. Org. Chem.  2003,  68:  1591 

<A NAME="RD06808ST-17">17</A> Paju A. Kanger T. Phek T. Eek M. Lopp M. Tetrahedron  2004,  60:  9081 

<A NAME="RD06808ST-18A">18a</A> Alonso F. Lorenzo E. Yus M. Tetrahedron Lett.  1997,  38:  2187 

<A NAME="RD06808ST-18B">18b</A> Alonso F. Lorenzo E. Yus M. Tetrahedron Lett.  1998,  39:  3303 

<A NAME="RD06808ST-18C">18c</A> Lorenzo E. Alonso F. Yus M. Tetrahedron Lett.  2000,  41:  1661 

<A NAME="RD06808ST-18D">18d</A> Lorenzo E. Alonso F. Yus M. Tetrahedron  2000,  56:  1745 

<A NAME="RD06808ST-18E">18e</A> Alonso F. Lorenzo E. Meléndez J. Yus M. Tetrahedron  2003,  59:  5199 

<A NAME="RD06808ST-18F">18f</A> Alonso F. Meléndez J. Yus M. Russ. Chem. Bull.  2003,  52:  2628 

<A NAME="RD06808ST-18G">18g</A> Alonso F. Meléndez J. Yus M. Tetrahedron Lett.  2005,  46:  6519 

<A NAME="RD06808ST-19A">19a</A> Alonso F. Falvello LR. Fanwick PE. Lorenzo E. Yus M. Synthesis  2000,  949 

<A NAME="RD06808ST-19B">19b</A> Alonso F. Meléndez J. Yus M. Helv. Chim. Acta  2002,  85:  3262 

<A NAME="RD06808ST-19C">19c</A> Alonso F. Meléndez J. Yus M. Tetrahedron Lett.  2004,  45:  1717 

<A NAME="RD06808ST-19D">19d</A> Alonso F. Dacunha B. Meléndez J. Yus M. Tetrahedron  2005,  61:  3437 

<A NAME="RD06808ST-19E">19e</A> Dacunha B. Alonso F. Meléndez J. Yus M. Acta Crystallogr., Sect. A: Found. Crystallogr.  2005,  61:  C157 

<A NAME="RD06808ST-19F">19f</A> Meléndez J. Alonso F. Yus M. Tetrahedron Lett.  2006,  47:  1187 

<A NAME="RD06808ST-19G">19g</A> Alonso F. Meléndez J. Soler T. Yus M. Tetrahedron  2006,  62:  2264 

<A NAME="RD06808ST-19H">19h</A> Alonso F. Meléndez J. Yus M. Tetrahedron  2006,  62:  4814 

For reviews, see:

<A NAME="RD06808ST-20A">20a</A> Yus M. Synlett  2001,  1197 

<A NAME="RD06808ST-20B">20b</A> Yus M. In The Chemistry of Organolithium Compounds   Rappoport Z. Marek I. Wiley; Chichester: 2004.  Chap. 11.

<A NAME="RD06808ST-21">21</A> For a review, see: Alonso F. Yus M. Recent Res. Dev. Org. Chem.  1997,  1:  397 

<A NAME="RD06808ST-22">22</A>

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.

<A NAME="RD06808ST-23">23</A>

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]

<A NAME="RD06808ST-24">24</A>

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.

<A NAME="RD06808ST-25">25</A>

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.

<A NAME="RD06808ST-26">26</A>

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) ų; 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.

<A NAME="RD06808ST-27">27</A> 2-Iodoethanol was protected as the tetrahydro-2H-pyranyl derivative with catalytic PTSA in CH₂Cl₂ at 0-25 °C for 1.25 h, following a standard literature procedure: Bernady KF. Floyd MB. Poletto JF. Weiss MJ. J. Org. Chem.  1979,  44:  1438 

<A NAME="RD06808ST-28">28</A> For some applications of this oxidation system, see for instance: Berkowitz WF. Perumattam J. Amarasekara A. J. Org. Chem.  1987,  52:  1119