Stepwise Cross-Couplings of a Dibromo-γ-methylenebutenolide as an Access to Z-Configured α-Alkenyl-γ-alkylidenebutenolides. Straightforward ­Synthesis of the Antibiotic Lissoclinolide

Abstract

The Z-isomer of α-bromo-γ-(bromomethylene)butenol­ide was prepared from α-angelica lactone or levulinic acid in three and four steps, respectively. Successive Stille-couplings with an ­unsaturated stannane, with the potential to use a different second unsaturated stannane, involved the γ-substituent first and the α-substituent thereafter. Thereby, α-alkenyl-γ-alkylidenebutenolides and their arene analogs were obtained Z-selectively.

enol lactone - natural product synthesis - palladium - ­regioselectivity - stereoselectivity - Stille-coupling

References

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6 See also: Schmidt-Leithoff J. Brückner R. Helv. Chim. Acta  2005,  88:  in press ; and the literature cited therein

7 Sorg A. Siegel K. Brückner R. Synlett  2004,  321 

Reviews:

8a Stille JK. Angew. Chem., Int. Ed. Engl.  1986,  25:  508 ; Angew. Chem. 1986, 98, 504

8b Farina V. Roth GP. In Advances in Metal-Organic Chemistry   Vol. 5:  Liebeskind LS. JAI Press; Greenwich, Connecticut: 1996.  p.1 

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12 Synthetic sequence 22® 23® 25: Ochoa de Echagüen C. Ortuño RM. Tetrahedron  1994,  50:  12457 

13

Compound 24 resulted from an initial 1:1-addition, rather than 2:1-addition of bromine to protoanemonin (2).

14 Still WC. Kahn M. Mitra A. J. Org. Chem.  1978,  43:  2923 

15

All new compounds except 23 gave satisfactory ¹H and ¹³C NMR spectra and provided either correct combustion analyses or HRMS.

16

( Z )-3-Bromo-5-(bromomethylene)-2(5 H )-furanone (Z-8): Et₃N (0.46 mL, 0.34 g, 3.3 mmol, 1.1 equiv) was added dropwise at -78 °C to a solution of 3,5-dibromo-5-(bromomethyl)-2(5H)-furanone (25) (1.002 g, 2.993 mmol) and hydroquinone (a few crystals) in CH₂Cl₂ (5 mL). The mixture was allowed to warm to 0 °C where it darkened gradually. After 1 h and without aqueous work-up, purification by flash chromatography on silica gel (cyclohexane-EtOAc, 10:1→5:1) furnished the title compound (0.5826 g, 78%) as a colorless solid (mp 72-73 °C). ¹H NMR (300.1 MHz, CDCl₃/TMS): δ = 6.19 (s, 1′-H), 7.49 (s, 4-H). ¹³C NMR (125.7 MHz, CDCl₃/CHCl₃): δ = 93.17 (C-1′), 114.53 (C-3), 139.36 (C-4), 150.85 (C-5), 163.97 (C-2). Anal. calcd for C₅H₂Br₂O₂ (251.8): C 23.65; H 0.79. Found: C 23.67; H 0.51.

17 Guntrum E. Kuhn W. Spönlein W. Jäger V. Synthesis  1986,  921 

18

The difficulty of this step also devaluated an improved preparation of bromobutenolide 23 from trans-2-pentenoic acid: 1) NBS (1.04 equiv), AIBN (7.6 mol%), CCl₄, reflux, 3 h; Et₃N (1.5 equiv); filtration; Br₂ (1.20 equiv), reflux, 1.5 h; 91%; 2) H₂O, reflux, 5 h; 74%.

19 Prepared by a procedure analogous to: Gilman H. Rosenberg SD. J. Am. Chem. Soc.  1953,  75:  2507 

20 Preparation: Labadie JW. Tueting D. Stille JK. J. Org. Chem.  1983,  48:  4634 

Conditions:

21a Liebeskind LS. Fengl RW. J. Org. Chem.  1990,  55:  5359 

21b Farina V. Kapadia S. Krishnan B. Wang C. Liebeskind LS. J. Org. Chem.  1994,  59:  5905 

22 Prepared by a procedure analogous to: Betzer J.-F. Delaloge F. Muller B. Pancrazi A. Prunet J. J. Org. Chem.  1997,  62:  7768 

23 Betzer J.-F. Pancrazi A. Synlett  1998,  1129 

24

The reaction of Z-8 with 35 under the hitherto used conditions [Pd(dba)₂, AsPh₃, CuI] was troublesome, leading to inseparable isomeric mixtures of 36 with up to 15% of its 1′-E-isomer. Running the same reaction in the absence of CuI increased the Z:E-ratio to 94:6.

25

(Z )-5-( trans -4-Hydroxy-2-butenylidene)-3-[( Z )-3-hydroxy-1-methyl-1-propenyl]-2(5 H )-furanone (32; 95:5 mixture with the E-isomer): Yellow solid; mp 154-156 °C. ¹H NMR (499.9 MHz, CD₃OD-D₂HCOD): δ = 1.93 (d, ⁴ J _{1 ′′ -Me,2 ′′} = 1.1 Hz, 1′′-H₃), 4.20 (dd, J _{4 ′ ,3 ′} = 5.2 Hz, ⁴ J _{4 ′ ,2 ′} = 1.7 Hz, 4′-H₂), 4.30 (d, J _{3 ′′ ,2 ′′} = 6.5 Hz, 3′′-H₂), 6.00 (d, J _{1 ′ ,2 ′} = 11.4 Hz, 1′-H), 6.16 (dtd, J _{3 ′ ,2 ′} = 15.4 Hz, J _{3 ′ ,4′} = 5.3 Hz, ⁴ J _{3 ′ ,1 ′} = 0.9 Hz, 3′-H), 6.76 (ddt, J _{2 ′ ,3 ′} = 15.5 Hz, J _{2 ′ ,1 ′} = 11.4 Hz, ⁴ J _{2 ′ ,4 ′} = 1.9 Hz, 2′-H), 6.96 (incompletely resolved br tq, J _{2 ′′ ,3 ′′} = 6.5 Hz, ⁴ J _{2 ′′ ,1 ′′ -Me} = 1.1 Hz, 2′′-H), 7.41 (s, 4-H). ¹³C NMR (125.7 MHz, CD₃OD-D₂HCOD): δ = 14.71 (1′′-CH₃), 59.79 (C-3′′), 63.14 (C-4′), 114.39 (C-1′), 123.89 (C-2′), 128.10 (low intensity; C-1′′), 134.75 (C-2′′), 135.80 (C-4), 140.29 (C-3′), 148.53 (C-5), 169.18 (C-2). HRMS (EI, 70 eV): m/z calcd for C₁₂H₁₂O₃, 204.078645; found, 204.078238 (M⁺ - H₂O).

26

(Z )-5-( trans -4-Hydroxy-2-methyl-2-butenylidene)-3-( trans -3-hydroxy-1-propenyl)-2(5 H )-furanone (37; 92:8 mixture with the E-isomer): Yellow solid; mp 111-113 °C. ¹H NMR (499.9 MHz, CD₃OD-D₂HCOD): δ = 2.06 (d, ⁴ J _{Me,1 ′} = 1.1 Hz, 2′-Me), 4.22 (dd, J _{3 ′′ ,2 ′′} = 5.1 Hz, ⁴ J _{3 ′′ ,1 ′′} = 1.9 Hz, 3^′′-H₂), 4.26 (d, J _{4 ′ ,3 ′} = 6.5 Hz, 4′-H₂), 5.83 (br s, 1′-H), 5.99 (incompletely resolved tqd, J _{3 ′ ,4 ′} = 6.6 Hz, ⁴ J _{3 ′ ,2 ′ -Me} = ⁴ J _{3 ′ ,1 ′} = 1.1 Hz, 3′-H), 6.45 (dt, J _{1 ′′ ,2 ′′} = 16.0 Hz, ⁴ J _{1 ′′ ,3 ′′} = 1.9 Hz, 1′′-H), 6.90 (dt, J _{2 ′′ ,1 ′′} = 16.0 Hz, J _{2 ′′ ,3 ′′} = 5.0 Hz, 2′′-H), 7.38 (s, 4-H). ¹³C NMR (125.7 MHz, CD₃OD-D₂HCOD): δ = 15.46 (2′-CH₃), 59.56 (C-4′), 63.18 (C-3′′), 118.89 (C-1′), 119.13 (C-1′′), 138.38 (C-2′′), 138.51 (C-4), 139.14 (C-3′), 148.09 (very low intensity, C-5), 170.50 (very low intensity, C-2); the signals of C-3 and C-2′ were not identified unambiguously. Anal. calcd for C₁₂H₁₄O₄ (204.1): C 64.85; H 6.35. Found: C 64.55; H 6.32.

27

(Z )-5-( trans -4-Hydroxy-2-butenylidene)-3-( trans -3-hydroxy-1-propenyl)-2(5 H )-furanone (38): Stannane 34 (586 mg, 1.69 mmol, 2.20 equiv) was added to a degassed solution of dibromobutenolide Z-8 (192 mg, 0.768 mmol), Pd(dba)₂ (20.2 mg, 35.1 µmol, 5 mol%), and AsPh₃ (37.2 mg, 0.122 mmol, 0.16 equiv) in THF (2.0 mL). The resulting solution was heated at 50-60 °C for 1.5 h, cooled to room temperature, and concentrated in vacuo. Flash chromatography (cyclohexane-EtOAc, 2:1→1:1; tert-butylmethylether-EtOAc, 1:1) provided the title compound (105.0 mg, 66%) as a yellow solid; mp 124-126 °C (Ref. [28] 126-127 °C).

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33a Two-dimensional structure: Strain HH. Svec WA. Aitzetmüller K. Grandolfo MC. Katz JJ. Kjøsen H. Norgård S. Liaaen-Jensen S. Haxo FT. Wegfahrt P. Rapoport H. J. Am. Chem. Soc.  1971,  93:  1823 

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34b Three-dimensional structure: Aakermann T. Liaaen-Jensen S. Phytochemistry  1992,  31:  1779