Organocatalytic Mukaiyama Aldol Reaction
Ξ | → | ∇ Aldol Reaction, Mukayama reaction |
Asymmetric Mukaiyama Aldol Reaction of Nonactivated Ketones Catalyzed by allo-Threonine-Derived Oxazaborolidinone
Shinya Adachi and Toshiro Harada
Org Lett (ASAP)
Chiral tertiary alcohols are important frameworks frequently found in biologically active compounds and catalytic asymmetric aldol addition to ketone acceptors has received growing attention since the resulting tertiary aldols are valuable building blocks for these subunits.
They have recently reported that allo-threonine-derived oxazaborolidinone (OXB) 1 is an efficient catalyst for the asymmetric Michael reaction and Diels-Alder reaction, of acyclic unsaturated ketones. The characteristic feature of the OXB catalyst for the enantioselective activation of the less reactive ketone carbonyl groups prompted us to employ it in the ketone aldol reaction. Herein, they wish to report the first example of the asymmetric Mukaiyama aldol reaction of nonactivated ketones by employing a dimethylsilyl ketene S,O-acetal as a nucleophile with OXB 1.
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The potential of OXB catalyst 1 in ketone aldol reaction was first evaluated in the reaction of p-bromoacetophenone with silyl ketene S,O-acetals 3. The reaction with 20% of 1 gave the alcohol 4 in 20% yield and 84% ee. When they use dimethylsilyl derivative rather than trimethylsilyl, they obtain 4 in 90% ee toghether with reduction product 5.
The scope of the OXB-catalyzed ketone aldol reaction was examined in toluene at -10 °C. A variety of acetophenone derivatives bearing substituents at the para-, meta-, or ortho-position underwent reaction with 3b to give the corresponding aldol products 4 in high enantioselectivity (91-98% ee) and in satisfactory yield.
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The scope of the OXB-catalyzed ketone aldol reaction was examined in toluene at -10 °C . A variety of acetophenone derivatives bearing substituents at the para-, meta-, or ortho-position underwent reaction with silyl ketene S,O-acetal to give the corresponding aldol products 4 in high enantioselectivity (91-98% ee) and in satisfactory yield.
The absolute stereochemical course of the present reaction is rationalized in terms of an activated complex model, in which nucleophile 3 attacks selectively from the open re face of a ketone.
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The attack of ketene silyl acetal 3 to activated enone 6 first generates unstable intermediate 7. A pathway involving direct silyl-group migration of 7 to give 4 is less likely. However, prolonged reaction time and higher temperature were required for the reaction to proceed in a catalytic manner, leading to the formation of the silyl derivatives 4.
The result can be rationalized by assuming a stepwise silyl-group migration via silyl ester 8; initial rapid migration to form 8 followed by slow formation of 4 with regeneration of OXB 1. According to this pathway, at the low temperature, the reaction stopped at 8 to give silylated species after hydrolysis as an exclusive aldol product. At higher temperature, transformation of 8 to 4 proceeded slowly to afford the observed mixture of products after workup.