Catalytic Enantioselective Homoaldol Reactions Using Binol Titanium(IV) Fluoride Catalysts

Abstract

Titanium (IV) fluoride catalysts, prepared by the combination of (R)-2,2′-binaphthol and TiF₄, are effective for promoting the homoaldol addition of 1-ethoxy-1-(trimethylsilyloxy)cyclo­propane to aldehydes. The reactions proceed with ee’s of up to 72% and are effective with a range of aldehyde substrates. The reactions show greatly improved enantioselectivity when compared to those catalyzed by titanium(IV) triflates. The increase in selectivity is presumed to result from the elimination of deleterious silicon co-catalysis.

Key words

homoenolates - homoaldol additions - asymmetric catalysis - titanium(IV) fluorides

References

• For reviews on the homoaldol reaction, see:
• 1a Crimmins MT. Nantermet PG. Org. Prep. Proc.  1993,  25:  43 
• 1b Kuwajima I. Nakamura E. In Comprehensive Organic Synthesis   Vol 2:  Trost BM. Fleming I. Pergammon; Oxford.: 1991.  p.441 
• 2 Weber B. Seebach D. Tetrahedron  1994,  50:  7473 
• 3 Martins EO. Gleason JL. Org. Lett.  1999,  1:  1643 
• 4a Gauthier DR. Carreira EM. Angew. Chem., Int. Ed. Engl.  1996,  35:  2363 
• (b) Bode JW. Gauthier DR. Carreira EM. Chem. Commun.  2001,  24:  2560 
• 4c Pagenkopf BL. Carreira EM. Tetrahedron Lett.  1998,  39:  9593 
• 5 The absolute stereochemistry was established as R by comparison of the optical rotation of 4 with literature values: Gutman AL. Zuobi K. Bravdo T. J. Org. Chem.  1990,  55:  3546 

6

A survey of other ligands, including 3,3′-disubstituted binaphthols, F₈-Binol and TADDOL did not afford any increase in enantioselectivity.

7

Sample Experimental Procedure. A solution of titanium(IV) fluoride (12 mg, 0.095 mmol, 0.1 equiv) in acetonitrile (1.5 mL) was added to a solution of (R)-2,2′-binaphthol (56 mg, 0.195 mmol, 0.2 equiv) in acetonitrile (1.5 mL) in a flame dried Schlenk flask. The resulting red mixture was stirred at 21 °C for 1 h and then the solvent was removed in vacuo. The resulting oil was redissolved in acetonitrile (1.5 mL), allyltrimethylsilane (62 µL, 0.392 mmol, 0.4 equiv) was added and the resulting solution was allowed to stir for 3 h during which time a precipitate was observed to form. To this mixture was added 1-ethoxy-1-(trimethylsilyloxy)cyclopropane (300 µL, 1.50 mmol, 1.5 equiv), and after 10 min, benzaldehyde (100 µL, 0.99 mmol, 1 equiv) was added. This final solution was continuously stirred over 4 days. The reaction was quenched by addition of 1 M HCl (30 mL) and the products were extracted into ethyl acetate (2 × 30 mL). The organic layer was washed once with brine (30 mL), dried over Na₂SO₄, filtered and concentrated. The crude reaction mixture was dissolved in benzene (6 mL) and p-TsOH(cat) was added. The reaction mixture was stirred overnight. The reaction was quenched by addition of saturated NaHCO₃ (30 mL) and the product was extracted into ethyl acetate (2 × 30 mL). The organic layer was washed once with brine (30 mL), dried over Na₂SO₄, filtered and concentrated. Purification of the residue by column chromatography on silica gel using 30 % hexanes in methylene chloride as eluent afforded 128 mg of the lactone (66% yield, 72% ee). ¹H NMR (CDCl₃) δ 7.24-7.39 (m, 5 H), 5.46 (dd, 1 H, J = 7.9 Hz, 6.2 Hz), 2.54-2.67 (m, 3 H), 2.04-2.22 (m, 1 H); ¹³C NMR (CDCl₃) δ 176.8, 139.2, 128.5, 125.1, 81.0, 30.7, 28.7. Anal. Calcd for C₁₀H₁₀O₂: C, 74.06; H, 6.21. Found: C, 73.73; H, 6.02.