1,2-syn-Selective and Enantioselective Michael Reactions of Acyclic Enones with a Propionate-Derived Nucleophile Catalyzed by Oxazaborolidinone

Abstract

allo-Threonine-derived oxazaborolidinone 1b is demonstrated to be an effective catalyst for the stereoselective Michael reaction of simple acyclic enones with propionate-derived silyl ketene acetals. The reaction affords the corresponding Michael adducts with two contiguous asymmetric centers with high syn selectivity and enantioselectivity.

asymmetric - boron - catalysis - Lewis acids - Michael additions

References

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9

In this reaction, a racemic enolsilane, EtO₂CCH(Me)CH(Ph)CH=(OTBS)Me, was obtained as a major product in 49% yield.

10

Reaction of 3a with Me₂C=C(OTMS)OEt under similar conditions gave the corresponding Michael adducts in only 6% ee (60% yield). These results suggest that the extent of the Si ⁺-catalyzed pathway depends significantly on the structure of the nucleophiles.

11

Typical experimental procedure (Table 1, entry 8). To a solution of O-(4-biphenoyl)-N-tosyl-(l)-allo-threonine [7c] (136 mg, 0.30 mmol) in CH₂Cl₂ (3 mL) under an argon atmosphere at r.t. was added dichlorophenylborane (39 µL, 0.30 mmol). After being stirred for 30 min, the mixture was concentrated in vacuo. To a solution of the resulting OXB 1b, silyl ketene acetal (E)-4b (523 mg, 3.0 mmol), tert-butyl methyl ether (0.48 mL, 4.0 mmol) in CH₂Cl₂ (2 mL) at
-78 °C were added a CH₂Cl₂ (2 mL) solution of 3a (146 mg, 1.0 mmol) and 2,6-diisopropylphenol (535 mg, 3.0 mmol) over 6 h by syringe pump. After the completion of the addition, the mixture was quenched by the addition of a sat. aq soln of NaHCO₃ and filtered. The filtrate was extracted three times with hexane, dried (MgSO₄), and concentrated in vacuo. The residue was dissolved in 1 N HCl (2 mL) and THF (10 mL) and the resulting solution was stirred at r.t. for 30 min. The mixture was poured into aq NaHCO₃ and extracted three times with Et₂O. The organic layers were dried (MgSO₄) and concentrated in vacuo. Purification of the residue by flash chromatography (SiO₂, 4-20% EtOAc in hexane) gave 158 mg (64%) of adduct syn-5a (syn/anti = 16:1, 86% ee): ¹H NMR (500 MHz, CDCl₃): δ = 0.94 (3 H, d, J = 7.0 Hz), 1.27 (3 H, t, J = 7.1 Hz), 1.98 (3 H, s), 2.65 (1 H, qd, J = 7.0, 9.9 Hz), 2.75 (1 H, dd, J = 4.8, 16.2 Hz), 2.85 (1 H, dd, J = 9.6, 16.2 Hz), 3.38 (1 H, dt, J = 4.8, 9.7 Hz), 4.15 (2 H, q, J = 7.1 Hz), 7.16-7.30 (5 H, m) [minor anti isomer resonated at δ = 1.15 (3 H, d, J = 7.0 Hz), 1.05 (3 H, t, J = 7.1 Hz), 3.94 (2 H, m)]; ¹³C NMR (125.8 MHz, CDCl₃): δ = 14.2, 15.8, 30.3, 44.1, 45.5, 48.4, 60.5, 126.9, 128.1, 128.6, 141.4, 175.6, 206.7. Anal. Calcd for C₁₅H₂₀O₃: C, 72.55; H, 8.12. Found: C, 72.69; H, 8.34. HPLC, Daicel Chiralpak AD-H, 1.0 mL/min, 0.7% 2-PrOH in hexane (S) t _R 26.8 min, (R) t _R 19.9 min.

12

The low diastereoselectivity observed in the reaction using B-methyl OXB 1f (Table [1] , entry 10) might support this rationale.