A New, Highly Stereoselective Synthesis of β-Unsubstituted (Z)-γ-Alkylidenebutenolides Using Bromine as a Removable Stereocontrol Element

Abstract

Several β-unsubstituted (Z)-γ-alkylidenebutenolides have been prepared in highly stereocontrolled fashion by implementing a steric directing group stratagem in the vinylogous aldol condensation of butenolides with aldehydes. Applications to the synthesis of the antitumor heptene (S)-melodorinol and a thiophenelactone from Chamaemelum nobile L. are described.

aldol reaction - bromobutenolides - dehalogenation - 2-silyloxyfurans - stereoselectivity

References and Notes

Reviews on the synthesis of γ-alkylidenebutenolides:

1a Negishi E. Kotora M. Tetrahedron  1997,  53:  6707 

1b Brückner R. Chem. Commun.  2001,  141 

1c Brückner R. Curr. Org. Chem.  2001,  5:  679 

1d Rossi R. Bellina F. In Targets in Heterocyclic Systems: Chemistry and Properties   Vol. 5:  Attanasi OA. Spinelli D. Società Chimica Italiana; Roma: 2002.  p.169-198  

For more recent work, see:

2a Anastasia L. Xu C. Negishi E. Tetrahedron Lett.  2002,  43:  5673 

2b Rousset S. Abarbri M. Thibonnet J. Parrain J.-L. Duchêne A. Tetrahedron Lett.  2003,  44:  7633 

2c Olpp T. Brückner R. Angew. Chem. Int. Ed.  2005,  44:  1553 

2d Takayama H. Sudo R. Kitajima M. Tetrahedron Lett.  2005,  46:  5795 

2e Doroh B. Sulikowski GA. Org. Lett.  2006,  8:  903 

2f Albrecht U. Nguyen VTH. Langer P. Synthesis  2006,  1111 

2g Olpp T. Brückner R. Angew. Chem. Int. Ed.  2006,  45:  4023 

Natural melodorinol consists of a ca. 2.5:1 mixture of the R and S enantiomers:

3a Lu X. Chen G. Xia L. Guo G. Tetrahedron: Asymmetry  1997,  8:  3067 

3b See also: Pohmakort M. Tuchinda P. Premkaisorn P. Limpongpan A. Reutrakul V. Heterocycles  1999,  51:  795 

Synthesis of xerulin and its relatives:

4a Siegel K. Brückner R. Synlett  1999,  1227 

4b Negishi E. Alimardanov A. Xu C. Org. Lett.  2000,  2:  65 

4c Rossi R. Belina F. Catanese A. Mannina L. Valensin D. Tetrahedron  2000,  56:  479 

4d Sorg A. Siegel K. Brückner R. Chem. Eur. J.  2005,  11:  1610 

5a Hjelmgaard T. Persson T. Rasmussen TB. Givskov M. Nielsen J. Bioorg. Med. Chem.  2003,  11:  3261 

5b Piper S. Risch N. ARKIVOC  2003,  (i):  86 

High Z-selectivity has been obtained in some cases under equilibration conditions:

6a Pohmakort M. Tuchinda P. Premkaisorn P. Reutrakul V. Tetrahedron  1998,  54:  11297 

6b Sundar N. Kundu MK. Reddy PV. Mahendra G. Bhat SV. Synth. Commun.  2002,  32:  1881 

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

7b Sorg A. Blank F. Brückner R. Synlett  2005,  1286 

8 Vaz B. Alvarez R. Brückner R. de Lera AR. Org. Lett.  2005,  7:  545 

9a Boukouvalas J. Maltais F. Lachance N. Tetrahedron Lett.  1994,  35:  7897 

9b Boukouvalas J. Lachance N. Ouellet M. Trudeau M. Tetrahedron Lett.  1998,  39:  7665 

For recent synthetic applications, see:

10a Bellina F. Anselmi C. Viel S. Mannina L. Rossi R. Tetrahedron  2001,  57:  9997 

10b Wu J. Zhu Q. Wang L. Fathi R. Yang Z. J. Org. Chem.  2003,  68:  670 

10c Bellina F. Anselmi C. Martina F. Rossi R. Eur. J. Org. Chem.  2003,  2290 

10d Boukouvalas J. Pouliot M. Synlett  2005,  343 

In the absence of a β-substituent, stereoselectivities can vary both in magnitude and direction:

11a Takayama H. Kuwajima T. Kitajima M. Nonato MG. Aimi N. Heterocycles  1999,  50:  75 

11b Takayama H. Ichikawa T. Kuwajima T. Kitajima M. Seki H. Aimi N. Nonato MG. J. Am. Chem. Soc.  2000,  122:  8635 

11c Barbosa LCA. Demuner AJ. de Alvarenga ES. Oliveira A. King-Diaz B. Lotina-Hennsen B. Pest Manag. Sci.  2006,  62:  214 

Bromine has previously performed this role in CBS-reduction and TADA reactions:

12a Nicolaou KC. Bertinato AD. Piscopio AD. Chakraborty TK. Minowa N. Chem. Commun.  1993,  619 

12b He F. Bo Y. Altom JD. Corey EJ. J. Am. Chem. Soc.  1999,  121:  6771 

12c Parker KA. Fokas D. J. Org. Chem.  2006,  71:  449 

12d Frank SA. Roush WR. J. Org. Chem.  2002,  67:  4316 

13 Jas G. Synthesis  1991,  965 

14a López CS. Álvarez R. Vaz B. Faza ON. de Lera R. J. Org. Chem.  2005,  70:  3654 

14b Boeckman RK. Pero JE. Boehmler DJ. J. Am. Chem. Soc.  2006,  128:  11032 

15

The major isomers (syn) of all aldol products described herein (5 and 10a-d) were clearly distinguished from their anti counterparts by the upfield shift of their γ-proton
(Δδ ≈ 0.2-0.3 ppm). Their stereochemistry was deduced by debromination of syn-10a/anti-10a to the corresponding butenolides syn-13a/anti-13a whose stereostructures were unambiguously assigned from the diagnostic shift of the β-proton [5a] (Scheme [4] ).

16 Uenishi J. Kawahama R. Yonemitsu O. Tsuji J. J. Org. Chem.  1998,  63:  8965 

17

Typical Procedure: To a solution of 8 [13] (147 mg, 0. 903 mmol) in anhyd CH₂Cl₂ (3 mL) at 0 °C were successively added TBSOTf (207 µL, 0. 903 mmol) and Et₃N (125 µL, 0. 903 mmol). The mixture was stirred for 30 min at 0 °C, then cooled to -78 °C, and then p-anisaldehyde (100 µL, 0.821 mmol) was added. After stirring at -78 °C for 1 h, DBU (251 µL, 1.64 mmol) was added and the resulting dark purple solution was allowed to warm to r.t. and stirred for an additional 1.5 h before quenching with 15% aq tartaric acid. The aqueous phase was extracted with CH₂Cl₂ (3 ×) and the combined organic layers were washed with sat. aq NaHCO₃, dried over MgSO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel; EtOAc-CH₂Cl₂-hexanes, 1:3:10) to afford 6b (196 mg, 85%) as a pale red-brown solid; mp 129-130 °C. ¹H NMR (400 MHz, CDCl₃): δ = 3.86 (s, 3 H), 6.33 (s, 1 H), 6.35 (s, 1 H), 6.95 (d, J = 8.6 Hz, 2 H), 7.79 (d, J = 8.6 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 55.2, 113.5, 114.3, 117.4, 124.8, 132.7, 138.1, 145.0, 160.9, 167.3. MS (CI): m/z = 281 [MH⁺]. Anal. Calcd for C₁₂H₉BrO₃: C, 51.27; H, 3.23. Found: C, 51.29; H, 2.99.
Data for 6c: yellow solid; mp 138-139 °C. ¹H NMR (400 MHz, CDCl₃): δ = 2.55 (br d, J = 1.0 Hz, 3 H), 6.33 (s, 1 H), 6.55 (s, 1 H), 6.78 (dq, J = 3.7, 1.0 Hz, 1 H), 7.26 (d, J = 3.7 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 15.7, 107.6, 117.7, 126.6, 133.0, 133.5, 136.7, 144.2, 147.8, 166.8. MS (CI): m/z = 271 [MH⁺]. Anal. Calcd for C₁₀H₇BrO₂S: C, 44.30; H, 2.60; S, 11.83. Found: C, 44.25; H, 2.43; S, 12.19.
Compounds 6a (white solid; mp 84-85 °C) and 6d (yellow oil) exhibited NMR data commensurate with those reported by Brückner. [7a]

18a Negishi E. Xu C. Tan Z. Kotora M. Heterocycles  1997,  48:  209 ; and references cited therein

18b von der Ohe F. Brückner R. New J. Chem.  2000,  24:  659 

18c

See also ref. 6b.

19 Xu D. Sharpless KB. Tetrahedron Lett.  1994,  35:  4685 

20

Silyloxyfuran 9 was prepared in 98% yield by silylation (TBSOTf, Et₃N, CH₂Cl₂, r.t.) of the readily available β-bromo-α-methylbutenolide: Svendsen, J. S.; Sydnes, L. K. Acta Chem. Scand. 1990, 44, 202.
Data for 9: colorless oil. ¹H NMR (300 MHz, CDCl₃): δ = 0.22 (s, 6 H), 0.97 (s, 9 H), 1.80 (s, 3 H), 6.86 (s, 1 H).). ¹³C NMR (75 MHz, CDCl₃): δ = -4.5, 7.4, 17.9, 25.4, 94.0, 104.3, 129.2, 152.4. HRMS (EI): m/z calcd for C₁₁H₁₉BrO₂Si: 290.0338; found: 290.0331.

21

Data for 11a: orange oil. ¹H NMR (400 MHz, CDCl₃): δ = 0.93 (t, J = 7.3 Hz, 3 H), 1.37 (m, 2 H), 1.49 (m, 2 H), 2.41 (q, J = 7.6 Hz, 2 H), 5.62 (dt, J = 0.5, 8.0 Hz, 1 H), 6.34 (d, J = 0.5 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 13.7, 22.3, 26.1, 30.8, 117.3, 119.6, 136.9, 148.1, 167.0. HRMS (EI): m/z calcd for C₉H₁₁BrO₂: 229.9942; found: 229.9938.
Data for 11b: orange oil. ¹H NMR (300 MHz, CDCl₃): δ = 0.90 (t, J = 7.1 Hz, 3 H), 1.31-1.50 (m, 4 H), 1.96 (s, 3 H), 2.37 (q, J = 7.4 Hz, 2 H), 5.47 (t, J = 7.9 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 10.2, 13.7, 22.3, 25.8, 31.0, 114.5, 128.1, 132.2, 147.0, 167.9. HRMS (EI): m/z calcd for C₁₀H₁₃BrO₂: 244.099; found: 244.0098.
Data for 11c: yellow oil. ¹H NMR (300 MHz, CDCl₃): δ = 2.65 (m, 2 H), 2.72 (m, 2 H), 5.54 (t, J = 7.6 Hz, 1 H), 6.25 (s, 1 H), 7.11-7.25 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ = 28.0, 34.7, 115.7, 119.8, 126.2, 128.2, 128.4, 136.9, 140.3, 148.3, 166.8. HRMS (EI): m/z calcd for C₁₃H₁₁BrO₂: 277.9942; found: 277.9938.
Data for 11d: white solid; mp 66-67 °C. ¹H NMR (300 MHz, CDCl₃): δ = 3.74 (d, J = 8.1 Hz, 2 H), 5.76 (t, J = 8.1 Hz, 1 H), 6.40 (s, 1 H), 7.22-7.36 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ = 32.6, 114.9, 120.3, 126.8, 128.6, 128.8, 137.1, 137.9, 148.2, 166.8. Anal. Calcd for C₁₂H₉BrO₂: C, 54.55; H, 3.44. Found: C, 54.76; H, 3.53.
Data for 11e: white solid; mp 29-31 °C; [α]_D ²³ +32.5 (c = 1.03, CHCl₃). ¹H NMR (300 MHz, CDCl₃): δ = 1.40 (s, 3 H), 1.47 (s, 3 H), 3.73 (dd, J = 6.7, 8.2 Hz, 1 H), 4.23 (dd, J = 6.7, 8.2 Hz, 1 H), 5.12 (dt, J = 6.7, 8.2 Hz, 1 H), 5.64 (d, J = 8.2 Hz, 1 H), 6.43 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 25.4, 26.5, 69.0, 70.6, 110.0, 112.8, 121.2, 137.0, 148.9, 165.9. HRMS (CI): m/z calcd for C₁₀H₁₁BrO₄: 274.9919; found: 274.9915.

22 Boukouvalas J. Côté S. Ndzi B. Tetrahedron Lett.  2007,  48:  105 ; and references cited therein

23 Ma Z. Morris TW. Combrink KD. Ann. Rep. Med. Chem.  2004,  39:  197 

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