The First Catalytic Asymmetric Domino Claisen Rearrangement/Intra­molecular Carbonyl Ene Reaction

Abstract

The first catalytic asymmetric domino Claisen rearrangement/carbonyl ene reaction is reported. Chiral copper(II) bis(oxazolines) efficiently serve as catalysts for the transformation of an achiral allyl vinyl ether into a substituted 1-hydroxy-cyclohexane carboxylic acid ester. Starting from achiral substrates, two new C-C-bonds and three chirality centers are formed. The transformation proceeds with high catalyst-induced diastereo- and enantioselectivities.

asymmetric catalysis - rearrangements - ene reactions - Lewis acids - domino reactions

References

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Catalysis of the Claisen rearrangement, see:

4a Abraham L. Czerwonka R. Hiersemann M. Angew. Chem. Int. Ed.  2001,  40:  4700 

4b Hiersemann M. Abraham L. Eur. J. Org. Chem.  2002,  1461 

5 Catalysis of the ene reaction, see: Evans DA. Tregay SW. Burgey CS. Paras NA. Vojkovsky T. J. Am. Chem. Soc.  2000,  122:  7936 

6 Hiersemann M. Synthesis  2000,  1279 

7 Schlosser M. Jenny T. Guggisberg Y. Synlett  1990,  704 

8

Allyl vinyl ether E -7: ¹H NMR (CDCl₃, 300 MHz): δ = 5.35 (qt, J ₁ = 6.4 Hz, J ₂ = 0.9 Hz, 1 H), 5.24 (d, J = 2.4 Hz, 1 H), 5.11-4.97 (m, 2 H), 4.51 (d, J = 2.4 Hz, 1 H), 4.28 (d, J = 6.4 Hz, 2 H), 2.10-1.93 (m, 4 H), 1.61 (s, 6 H), 1.53 (s, 3 H), 1.24 (d, J = 6.2 Hz, 6 H); ¹³C NMR (CDCl₃, 75.5 MHz): δ = 162.8, 151.4, 140.6, 131.7, 123.8, 118.9, 93.7, 68.9, 65.5, 39.4, 26.2, 25.6, 21.7, 17.6, 16.6; IR(neat): 2979-2858, 1725, 1178 cm^-1. Allyl vinyl ether Z -7: ¹H NMR (CDCl₃, 300 MHz): δ = 5.43 (dt, J ₁ = 6.5 Hz, J ₂ = 1.4 Hz, 1 H), 5.29 (d, J = 2.3 Hz, 1 H), 5.14-5.05 (m, 2 H), 4.56 (d, J = 2.3 Hz, 1 H), 4.29 (d, J = 6.5 Hz, 2 H), 2.08 (d, J = 3.2 Hz, 4 H), 1.75 (s, 3 H), 1.67,1.59 (2 × s, 2 × 3 H), 1.28 (d, J = 6.2 Hz, 6 H); ¹³C NMR (CDCl₃, 75.5 MHz): δ = 162.7, 151.5, 141.1, 132.1, 123.6, 119.8, 93.6, 68.9, 65.1, 32.4, 26.4, 25.6, 23.4, 21.7, 17.6; IR(neat): 2955-2872, 1725, 1177 cm^-1.

9

General procedure: All reactions were performed in flame dried septum sealed round bottom flasks under an atmosphere of argon. 10 mol% Cu(OTf)₂ and 12 mol% of the bis(oxazoline) were dissolved in CH₂Cl₂ (5 mL/mmol of allyl vinyl ether). The green solution was stirred for 1 h at room temperature. A solution of the allyl vinyl ether in CH₂Cl₂ (5 mL/mmol of allyl vinyl ether) was then added. The reaction mixture was stirred for the appropriate time at room temperature and then filtered through a silica gel column (4 × 0.5 cm). The solvents were removed under reduced pressure to afford a colorless oil which was analytically pure without further purification. The diastereomers may be separated by flash chromatography (heptane/ethyl acetate, 20:1).

10

8: ¹H NMR (CDCl₃, 500 MHz): δ = 6.21 (dd, J ₁ = 17.5 Hz, J ₂ = 11.1 Hz), 5.00 (sept, J = 6.2 Hz, 1 H), 4.97 (d, J = 5.9 Hz, 1 H), 4.94 (s, 1 H), 3.04 (s, 1 H), 2.39 (dd, J ₁ = 12.7 Hz, J ₂ = 3.3 Hz, 1 H), 2.04-1.95 (m, 1 H, 3H), 1.94-1.89 (m, 1 H), 1.78 (d, J = 13.5 Hz, 1 H), 1.70-1.66 (m, 1 H), 1.68 (s, 3 H), 1.44-1.35 (m, 2 H), 1.25 (t, J = 6.2 Hz, 6 H), 0.99 (s, 3 H); ¹³C NMR (CDCl₃, 125 MHz): δ = 175.9, 146.9, 145.9, 113.1, 109.6, 77.3, 69.6, 50.1, 47.7, 36.5, 35.7, 31.5, 23.3, 22.1, 21.7; IR(neat): 3507, 3078-2867, 1719, 1103 cm^-1; C₁₆H₂₆O₃, M = 266.38 g/mol: calculated: C = 71.14%, H = 9.84%; found: C = 72.16%, H = 9.79%; [α]_D ²⁵ -30.5 (c = 0.095, CHCl₃); chiral GC: R_t 32.5 min, 25 m 6-O-TBDMS-2,3-di-O-methyl-β-cyclodextrin (50% in OV 1701, w/w). 9: ¹H NMR (CDCl₃, 500 MHz): δ = 6.21 (dd, J ₁ = 17.5 Hz, J ₂ = 11.1 Hz, 1 H), 5.00 (sept, J = 6.2 Hz, 1 H), 4.97 (d, J = 5.9 Hz, 1 H), 4.94 (s, 1 H), 3.04 (s, 1 H), 2.39 (dd, J ₁ = 12.7 Hz, J ₂ = 3.3 Hz, 1 H), 2.04-1.95 (m, 1 H), 1.94-1.89 (m, 1 H), 1.78 (d, J = 13.5 Hz, 1 H), 1.70-1.66 (m, 1 H), 1.68 (s, 3 H), 1.44-1.35 (m, 2 H), 1.25 (t, J = 6.2 Hz, 6 H), 0.99 (s, 3 H); ¹³C NMR (CDCl₃, 125 MHz): δ = 175.9, 146.9, 145.9, 113.1, 109.6, 77.3, 69.6, 50.1, 47.7, 36.5, 35.7, 31.5, 23.3, 22.1, 21.7; IR (neat): 3507 cm^-1 (OH), 3078-2867, 1719, 1103; C₁₆H₂₆O₃, M = 266.38 g/mol: calculated: C = 71.14%, H = 9.84%; found: C = 72.20%, H = 9.95%; [α]_D ²⁵ -25.5 (c = 0.855, CHCl₃); chiral GC: R_t 34.4 min.

11

The relative configuration was assigned based on NOESY experiments and an X-ray crystal structure analysis of compound 8. The absolute configuration was assigned based on the established rules for the topicity of [Cu(box)]-catalyzed Claisen rearrangements (see ref. [4] ).

12a For a review article, see: Mikami K. Shimizu M. Chem. Rev.  1992,  92:  1021 

12b Kocovsky P. Ahmed G. Srogl J. Malkov AV. Steele J. J. Org. Chem.  1999,  64:  2765 ; and references cited therein

13 Hiersemann M. Eur. J. Org. Chem.  2001,  483