Asymmetric Horner-Wadsworth-Emmons (HWE) reaction of prochiral cyclic ketones is of current interest.1-4) Several useful chiral HWE reagents such as phosphonates, [5][6][7][8][9] phosphonoamides, 10) and phosphonoamidates 11) have been developed for the synthesis of olefins possessing an axis of chirality. However, most of these reagents are restricted to the compounds with non-stereogenic phosphorus atom. Although Motoyoshiya et al. reported geometrical selectivity of HWE reactions of aldehydes with racemic phosphonoacetates, 12) the asymmetric HWE reaction of P-stereogenic phosphonoacetates has never been established. Herein we describe a facile synthesis of novel chiral phosphonoacetates bearing a stereogenic phosphorus atom utilizing the enzymecatalyzed kinetic resolution of racemic phosphonoacetates derived from two kinds of Z-selective HWE reagents, methyl bis(2,2,2-trifluoroehtyl)phosphonoacetate (Still's reagent,
1)13) and ethyl diphenylphosphonoacetate (2).
14)Recently, we reported a new and efficient stereoselective HWE reaction of aldehydes and ketones with bis(2,2,2-trifluoroehtyl)phosphonoacetic acid and found oxophilicity of a phosphorus atom of phosphonoacetate 1. 15,16) That is to say, the phosphonate moiety of 1 was found to be more easily hydrolyzed than the ester moiety of 1 under aqueous alkaline conditions. Thus, the phosphonoacetic acid was readily prepared by enzymatic hydrolysis of 1 with porcine liver esterase (PLE). Although attempts to hydrolyze the ester moiety of 1 under aqueous alkaline conditions were unsuccessful, reactions of 1 with various alcohols in the presence of triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) gave the corresponding phosphonoacetate rac-3a-d as the major product (Chart 1). The similar transformation of 2 using various alcohols gave rac-4a-d as shown in Chart 2. Attempts to hydrolyze 2 under aqueous alkaline conditions were also unsuccessful, though phosphonoacetates 4a and 5-7 were obtained (Chart 2). It can be concluded that the high oxophilicity of phosphorus atoms of these HWE reagents 1 and 2 appears to be necessary for Z-selective HWE reaction with aldehydes. [17][18][19] The phosphonoacetates rac-3a-d were subjected to enzymatic hydrolysis utilizing PLE (Sigma, E-2884), as follows. Phosphonoacetates rac-3a-d were dissolved in 1/15 M phosphate buffer solution (pH 7.4) and acetone (9 : 1). After addition of PLE (800 units/mmol), the mixture was stirred at room temperature for the appropriate time. The reaction mixture was treated with 10% HCl and then extracted with AcOEt. After evaporation of the extraction in vacuo, the residue was purified on a silica gel column with CHCl 3 -MeOH as eluent to give the corresponding carboxylic acid 8 and unreacted ester 3. The enantiomeric excess of resolution product 8 was determined by means of HPLC analysis with chiral-stationary-phase (CSP) after methylation with (trimethylsilyl)diazomethane (TMSCHN 2 ). 20) Unreacted resolution compound 3 was also subjected to HPLC analysis with CSP. As the result of enz...
In the imine aldol reactions of 1 with aromatic aldehydes using magnesium salts in the presence of amines, the threo/erythro ratios of products increased in the order Mg(ClO4)2>MgI2>MgBr2>MgCl2>Mg(OTf)2 and N,N,N',N'-tetramethylethylenediamine (TMEDA)>Et3N. This increase in the threo/erythro ratios of products was estimated to be caused by a retro-imine aldol reaction under thermodynamic control.
Stereochemistry O 0030Effects of Magnesium Salts and Amines on the Stereoselectivity in the Imine Aldol Reaction. -The ratio of threo-and erythro-products (III)/(IV) in the reaction of imine (I) with aromatic aldehydes, e.g. benzaldehyde (II), depends on the nature of the magnesium salt and amine used. -(HAYASHI*, K.; KUJIME, E.; KATAYAMA, H.; SANO, S.; NAGAO, Y.; Chem.
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