Domino Metathesis Reactions for the Synthesis of Fused Tricyclic Frameworks

Abstract

A domino metathesis strategy has been successfully applied to the straightforward stereocontrolled construction of functionalized tricyclic systems of different ring sizes starting from readily available precursors.

domino reactions - metathesis - ring-opening metathesis - fused-ring systems - polycycles

References

For recent reviews:

1a Fürstner A. Angew. Chem. Int. Ed.  2000,  39:  3012 

1b Grubbs RH. Trnka RR. Acc. Chem. Res.  2001,  34:  18 ; and references cited therein

2 For a review on cross-metathesis: Connon ST. Blechert S. Angew. Chem. Int. Ed.  2003,  42:  1900 

3 Tietze LF. Chem. Rev.  1996,  96:  115 

4 Zuercher WJ. Hashimoto M. Grubbs RH. J. Am. Chem. Soc.  1996,  118:  6634 

5 Stragies R. Blechert S. Synlett  1998,  169 

6 Schrock RR. Hoveyda AH. Angew. Chem. Int. Ed.  2003,  42:  4592 ; and references cited therein

7 For a recent account see: Arjona A. Csákӱ AG. Murcia MC. Plumet J. Eur. J. Org. Chem.  2003,  611 

8 Hagiwara H. Katsumi T. Endou S. Hoshi T. Suzuki T. Tetrahedron  2002,  58:  6651 

9 Wrobleski A. Sahasrabudhe K. Aubé J. J. Am. Chem. Soc.  2004,  126:  5475 

10 Rosenblum M. J. Am. Chem. Soc.  1957,  79:  3179 

11 Lipshutz BH. Ellsworth EL. Dimock SH. Smith RAJ. J. Am. Chem. Soc.  1990,  112:  4404 

12 Schwab P. Grubbs RH. Ziller JW. J. Am. Chem. Soc.  1996,  118:  100 

13 Scholl M. Ding S. Lee CW. Grubbs RH. Org. Lett.  1999,  1:  953 

14

Under these conditions, compound 2 did not lead to any tricyclic adduct.

15

Typical Procedure for Domino Metathesis with Ethylene:
Ketone 3 (100 mg, 0.54 mmol) was dissolved in dry CH₂Cl₂ so that the concentration reached approximately 0.035 M (15 mL). This solution was degassed under argon using the freeze-pump-thaw technique (3 times). Ethylene was then bubbled through the solution for 5 min and 2nd generation Grubbs catalyst was added (22 mg, 5 mol%). Ethylene was again passed through the solution for 5 more minutes. The solution was stirred under an ethylene atmosphere (fitted balloon) at 20 °C until TLC revealed completion of the reaction (2 h). Silica gel was added and the mixture concentrated to dryness. Purification was achieved by flash chromatography on silica gel (8:1 petroleum ether-Et₂O) to afford 7 (64 mg, 64%) as a colorless oil. Analytical data for compound 7: ¹H NMR (400 MHz, CDCl₃): δ = 5.89-5.86 (m, 1 H), 5.80 (dd, J = 10.2, 5.6 Hz, 1 H), 5.72 (ddd, J = 17.2, 10.2, 1.2 Hz, 1 H), 5.00 (dt, J = 17.2, 1.2 Hz, 1 H), 4.97 (dt, J = 10.2, 1.2 Hz, 1 H), 3.12-3.10 (m, 1 H), 2.81 (dd, J = 12.0, 7.6 Hz, 1 H), 2.66-2.60 (m, 1 H), 2.30-2.28 (m, 2 H), 2.27-2.23 (m, 1 H), 2.17 (dt, J = 13.0, 8.0 Hz, 1 H), 2.01-1.93 (m, 3 H), 1.56 (dt, J = 13.0, 10.8 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 218.2, 139.3, 130.1, 128.0, 114.0, 55.0, 51.1, 46.2, 45.1, 40.1, 38.0, 35.2, 30.1. IR (thin film): 3078, 3018, 2904, 1738, 1635, 1418, 1149 cm^-1. MS (GC, CI NH₃): m/z = 206 [M + NH₄ ⁺], 189 [M + H⁺], 169. HRMS: m/z calcd for C₁₃H₁₆O + H⁺: 189.1279. Found: 189.1275.

16

Typical Procedure for Domino Metathesis with Homogeneous Cross-Metathesis Partner:
To a degassed solution (3 freeze-pump-thaw cycles) of ketone 3 (50 mg, 0.27 mmol) in CH₂Cl₂ was added allyltrimethylsilane (85 µL, 0.54 mmol, 2.0 equiv) followed by the addition of 11 mg (5 mol%) of 2nd generation Grubbs catalyst. The mixture was stirred at reflux for 2.5 h. It was then concentrated in vacuo. Purification by flash chromatography on silica gel (15:1 petroleum ether-Et₂O) afforded 61 mg (88%) of the expected tricyclic compound 10 as a colorless oil. Analytical data for compound 10: ¹H NMR (400 MHz, CDCl₃): δ = 5.87 (dd, J = 10.0, 4.4 Hz, 1 H), 5.79 (ddd, J = 10.0, 5.6 Hz, 1 H), 5.38 (ddd, J = 15.4, 8.0, 0.8 Hz, 1 H), 5.08 (dd, J = 15.4, 8.8 Hz, 1 H), 3.07-3.04 (m, 1 H), 2.75 (dd, J = 12.4, 7.6 Hz, 1 H), 2.65-2.56 (m, 1 H), 2.30-2.21 (m, 3 H), 2.16 (dt, J = 13.0, 5.6 Hz, 1 H), 2.02-1.91 (m, 3 H), 1.49 (dt, J = 13.0, 2.0 Hz, 1 H), 1.41 (d, J = 8.0 Hz, 2 H), -0.02 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 218.7, 130.5, 129.7, 127.8, 126.4, 55.3, 51.4, 45.9, 45.2, 40.1, 39.4, 35.2, 30.3, 22.5, -2.0. IR (thin film): 3019, 2837, 1739, 1418, 1247 cm^-1. MS (GC, CI NH₃): m/z = 292 [M + NH₄ ⁺], 275 [M + H⁺]. Anal. Calcd for C₁₇H₂₆OSi: C, 74.39; H, 9.55. Found: C, 74.59; H, 9.39.

17

See ref.⁵ and ref.⁷

For detailed studies of this aspect in the opening of related norbornene systems see:

18a

Ref.⁷

18b Mayo P. Tam W. Tetrahedron  2002,  58:  9513 

18c Weeresakare GM. Liu Z. Rainier JD. Org. Lett.  2004,  6:  1625