Highly Enantioselective Synthesis of α-Diazo-β-hydroxy Esters Using a Bifunctional Titanium Complex

Abstract

A bifunctional titanium catalyst system has been developed for the asymmetric direct-type aldol reaction of ethyl diazo­acetate with aldehydes, which produced the desired products in good yields (up to 83%) with excellent enantioselectivities (up to 94% ee). A wide range of aromatic, heteroaromatic and aliphatic aldehydes were found to be suitable substrates in the presence of (S)-BINOL (5 mol%), cinchonine (5 mol%), Ti(Oi-Pr)₄ (5 mol%) and H₂O (15 mol%). On the basis of the experimental results and previous reports, a possible working model has been proposed to explain the origin of the activation and asymmetric induction.

Key words

asymmetric catalysis - combinational chemistry - titanium - aldol reaction - diazo esters

References and Notes

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10

The catalyst prepared from 5 mol% (S)-BINOL-Ti(Oi-Pr)₄ complex gave the expected product in 40% yield with 29% ee after 72 h.

13

General Procedure for the Asymmetric Aldol Reaction of Ethyl Diazoacetate with Benzaldehyde Ti(Oi-Pr)₄ (1.0 M in toluene, 7.5 µL, 0.0075 mmol) was added to a soln of 1a (2.2 mg, 0.0075 mmol), 2a (2.2 mg, 0.0075 mmol) in THF (0.5 mL), and the mixture was stirred at 25 ˚C under Ar. This was followed by the addition of H₂O (1.0 M in THF, 22.5 µL, 0.0225 mmol). Benzaldehyde (0.15 mmol) was added after the contents were stirred for 30 min at 25 ˚C. To this solution, ethyl diazoacetate (0.45 mmol) was added under 0 ˚C. The reaction was vigorously stirred at 0 ˚C under Ar atmosphere and monitored by TLC, after 6 d, the residue was purified by flash SiO₂ chromatography
(PE-acetone, 10:1) to afford the corresponding α-diazo-β-hydroxy ester 5a (20.5 mg, 62% yield) as a yellow oil with 91% ee; HPLC [Chiralpak AD-H column, hexane-2-PrOH (90:10), 254 nm, 1.0 mL min^-¹]: t _R(minor) = 6.906 min, t _R(major) = 7.774 min; [α]_D ^²5 +21.9 (c 0.42, CH₂Cl₂). Lit.^6a [α]_D ^²0 -9.5 (c 3.2, CH₂Cl₂) for R enantiomer in 87% ee. ^¹H NMR (400 MHz, CDCl₃): δ = 7.28-7.45 (m, 5 H), 5.94 (s, 1 H), 4.31 (q, J = 7.2 Hz, 2 H), 2.99 (br s, 1 H), 1.32 (t, J = 7.2 Hz, 3 H) ppm.