3-Vinyl-2,5-dihydrofuran Derivatives via Enyne Metathesis

Abstract

Acyclic enynes having the alkyne moiety directly ­connected to the asymmetric carbon atom of an acetal were obtained in two steps. These reactive substrates were then subjected to ruthenium-catalyzed enyne metathesis to produce (5-ethoxy-4-­vinyl-2,5-dihydrofuran-2-yl)methanol derivatives in racemic and enantiomerically pure form. These products are useful glycosyl ­donors for the preparation of d4T analogues.

enyne - metathesis - carbohydrate - cyclization - furan

References and Notes

1 Len C. Mackenzie G. Tetrahedron  2006,  62:  9085 

2a Len C. Postel D. Curr. Org. Synth.  2006,  3:  261 

2b Lin TS. Schinazi RF. Prusoff WH. Biochem. Pharmacol.  1987,  36:  2713 

2c Balzarini J. Van Aerschot A. Herdewijn P. De Clercq E. Biochem. Pharmacol.  1989,  38:  869 

3a Ouma S. Kumamoto H. Kawato M. Tanaka H. Tetrahedron  2002,  58:  2497 

3b Kumamoto H. Tanaka H. J. Org. Chem.  2002,  67:  3541 

3c Haraguchi K. Itoh Y. Tanaka H. Miyasaka T. Tetrahedron  1993,  49:  1371 

3d Schmalz HG. Hebler E. Bats JW. Durner G. Tetrahedron Lett.  1994,  35:  4543 

3e Hebler E. Schmalz HG. Durner G. Tetrahedron Lett.  1994,  35:  4547 

3f Schlawe D. Majdalani A. Velcicky J. Hebler E. Wieder T. Prokop A. Schmalz HG. Angew. Chem. Int. Ed.  2004,  43:  1731 

4a Ewing DF. Fahmi NE. Len C. Mackenzie G. Ronco G. Villa P. Shaw G. Nucleosides Nucleotides  1999,  18:  2613 

4b Ewing DF. Fahmi NE. Len C. Mackenzie G. Pranzo A. J. Chem. Soc., Perkin Trans. 1  2000,  3561 

4c Belloli E. Len C. Mackenzie G. Ronco G. Bonte JP. Vaccher C. J. Chromatogr., A  2001,  943:  91 

4d Ewing DF. Len C. Mackenzie G. Ronco G. Villa P. Tetrahedron: Asymmetry  2000,  11:  4995 

4e Selouane A. Vaccher C. Villa P. Postel D. Len C. Tetrahedron: Asymmetry  2002,  13:  407 

4f Pilard S. Riboul D. Glacon V. Moitessier N. Chapleur Y. Postel D. Len C. Tetrahedron: Asymmetry  2002,  13:  529 

4g Egron D. Perigaud C. Gosselin G. Aubertin AM. Faraj A. Selouane A. Postel D. Len C. Bioorg. Med. Chem. Lett.  2003,  13:  4473 

5a Nicolaou KC. Bulger PG. Sarlah D. Angew. Chem. Int. Ed.  2005,  44:  4490 

5b Trnka TM. Grubbs RH. Acc. Chem. Res.  2001,  34:  18 

6a Poulsen CS. Madsen R. Synthesis  2003,  1 

6b Diver ST. Giessert AJ. Chem. Rev.  2004,  104:  1317 

6c Kinoshita A. Mori M. J. Org. Chem.  1996,  61:  8356 

6d Mori M. Adv. Synth. Catal.  2007,  349:  121 

7a Poulsen CS. Madsen R. J. Org. Chem.  2002,  67:  4441 

7b Marco-Contelles J. Arroyo N. Ruiz-Caro J. Synlett  2001,  652 

7c Boyer FD. Hanna I. Ricard L. Org. Lett.  2001,  3:  3095 

7d Leeuwenburgh MA. Appeldoorn CCM. van Hooft PAV. Overkleeft HS. van der Marel GA. van Boom JH. Eur. J. Org. Chem.  2000,  873 

7e Clark JS. Hamelin O. Angew. Chem. Int. Ed.  2000,  39:  372 

7f Leeuwenburgh MA. Kulker C. Duynstee HI. Overkleeft HS. van der Marel GA. van Boom JH. Tetrahedron  1999,  55:  8253 

7g Dohlem F. Lievre C. Demailly G. Eur. J. Org. Chem.  2003,  2336 

8 Mori M. Sakakira N. Kinoshita A. J. Org. Chem.  1998,  63:  6082 

9a Kinoshita A. Sakakibara N. Mori M. J. Am. Chem. Soc.  1997,  119:  12388 

9b Kinoshita A. Sakakibara N. Mori M. Tetrahedron  1999,  8155 

9c Smulik JA. Diver ST. J. Org. Chem.  2000,  65:  1788 

9d Mori M. Tonogaki K. Nishiguchi N. J. Org. Chem.  2002,  67:  224 

10 Lloyd-Jones GC. Margue RG. de Vries JG. Angew. Chem. Int. Ed.  2005,  44:  7442 

11 Fürstner A. Langemann K. J. Am. Chem. Soc.  1997,  119:  9130 

12

RCEYM Reaction of rac -15 and rac -16 - Typical Procedure
The ruthenium catalyst 5 (3% mol) was dissolved in CH₂Cl₂ (26 mL) and ethylene gas was passed through the solution for 20 min. The enyne mixture of rac-15 and rac-16 (400 mg, 0.98 mmol) in CH₂Cl₂ (12 mL) was then added and the mixture was stirred under ethylene at 20 °C during 5 d. The volatiles were eliminated under reduced pressure and the residue was purified by flash chromatography (5% EtOAc in hexane) to give rac-cis-22 (100 mg, 25%) and rac-trans-22 (100 mg, 25%) in order of fractions eluted.

13a Hansen EC. Lee D. J. Am. Chem. Soc.  2003,  125:  9582 

13b Hansen EC. Lee D. J. Am. Chem. Soc.  2004,  126:  15074 

14

Selected physico-chemical data for compound cis-12: R _f = 0.50 (5% EtOAc-hexane). ¹H NMR (300 MHz, CDCl₃): δ = 7.71 (m, 4 H, Ph), 7.45 (m, 6 H, Ph), 6.48 (dd, 1 H, J = 12, 18 Hz, =CH), 6.18 (s, 1 H, H³), 5.87 (s, 1 H, H⁵), 5.46 (d, 1 H, J = 18 Hz, =CH), 5.23 (d, 1 H, J = 12 Hz, =CH), 4.80 (m, 1 H, J = 1 Hz, H²), 3.68 (m, 4 H, OCH ₂CH₃, CH₂OSi), 1.23 (t, 3 H, J = 8 Hz, CH₃), 1.06 (s, 9 H, 3 CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 138.9 (C⁴), 136.0 (Ph), 135.9 (Ph), 133.9 (C³), 133.8 (Ph), 130.4 (=CH), 128.1 (Ph), 118.0 (=CH₂), 107.6 (C⁵), 85.7 (C²), 67.6 (CH₂OSi), 62.6 (OCH₂), 27.2 (CH₃ of t-Bu), 19.6 (Cq of t-Bu), 15.8 (CH₃) ppm. ESI-HRMS: m/z calcd [M + Na⁺]: 431.2018; found: 431.2034.

15

Selected physico-chemical data for compound trans-12: R _f = 0.20 (5% MeOH-CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 7.65 (m, 4 H, Ph), 7.38 (m, 6 H, Ph), 6.43 (m, 1 H, J = 12, 18Hz, =CH), 5.98 (s, 1 H, H³), 5.96 (d, 1 H, J = 4 Hz, H⁵), 5.43 (d, 1 H, J = 18, =CH), 5.24 (d, 1 H, J = 12 Hz, =CH), 4.90 (m, 1 H, H²), 3.72 (m, 4 H, OCH ₂CH₃, CH₂OSi), 1.26 (t, 3 H, J = 8 Hz, CH₃), 1.04 (s, 9 H, 3 CH₃) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 138.8 (C⁴), 136.0 (Ph), 133.9 (Ph), 130.6 (C³), 130.0 (Ph), 129.0 (=CH), 128.1 (Ph), 118.0 (=CH₂), 107.6 (C⁵), 85.6 (C²), 66.6 (CH₂OSi), 62.1 (OCH₂), 27.2 (CH₃ of t-Bu), 19.6 (Cq of t-Bu), 15.8 (CH₃). ESI-HRMS: m/z calcd [M + Na⁺]: 431.2018; found: 431.2025.

16 Barfield M. Spear RJ. Sternhell S. J. Am. Chem. Soc.  1975,  97:  5160