A robust method for preparing (3S)-3-alkyl-3-phenyl-1,4-dioxane-2,5-diones was developed using an improved cyclocondensation reaction between (S)-a-alkylmandelic acids and 2-bromocarbonyl halides. Subtle differences in the reaction conditions, including separate additions of triethylamine, significantly increased the yield compared with Schöllkopf's original method.Racemic 1,4-dioxane-2,5-diones (±)-3 comprise useful precursors of biologically active compounds. 1,2 The nonchiral synthesis of (±)-3 was originally developed by Schöllkopf's group: 2 cyclocondensation between 2-alkyl-2-hydroxycarboxylic acids (±)-1 and 2-bromocarbonyl chlorides (±)-2 promoted by two equivalents of triethylamine as the HX (X = Cl and Br) binder (Scheme 1). The precursor (±)-3 was synthetically valuable for providing tetronic acids and 2-alkoxy-2¢-hydroxyketones utilizing a characteristic lactide-ring-contraction reaction.Scheme 1 Preparation of 1,4-dioxane-2,5-diones (±)-3 by Schöll-kopf's method and transformation into tetronic acids and 2-alkoxy-2¢-hydroxyketones Chiral 1,4-dioxane-2,5-diones 3 have recently attracted attention as the precursor for polylactides, which represent synthetically biocompatible or biodegradable polymers, 3 and as an antidiabetic drug. 4 Here, we present an improved and robust method for preparing chiral (3S)-3-alkyl-3-phenyl-1,4-dioxane-2,5-diones 6 from (S)-a-alkylmandelic acids 4 based on Schöllkopf's method. In our hands, however, a subtle difference in the reaction conditions sometimes affected the yield of the original method.The noteworthy features of the present method, compared with the original one, are as follows: (i) the method has led to the first preparation of chiral analogues 6, (ii) to significantly higher yields, and (iii) the method is more robust and reproducible. The advantages of the present approach are attributed to the one-pot procedure of separate addition of triethylamine in each step of the reaction sequence.Recently, we reported two robust preparative methods for the synthesis of chiral a-alkylmandelic acids, including atrolactic acid (a-methyl), 5 and its useful five-membered derivatives, Seebach and Fráter's chiral template 6 (cis-2,5-disubstituted 1,3-dioxolan-4-ones). 7 Thus, (S)-alkyl mandelic acids 4a-c were readily obtained in good yields with high optical purities. Based on the results, we extended our investigation to the preparation of a six-membered chiral analogue 6. Initial experiments were guided by a cyclocondensation reaction between (S)-atrolactic acid (4a) and 2-bromopropanoyl bromide to give (3S)-3,6-dimethyl-3-phenyl-1,4-dioxane-2,5-dione (6a) (Scheme 2). The optimized conditions increased the yield to 91%. Screening of various conditions revealed that the increase in yield was solventdependent [toluene (20%), acetone (30%), DMF (43%), NMP (58%), THF (60%), and MeCN (91%)].This reaction involved the following sequence: (i) formation of the mixed anhydride intermediate 5A; (ii) intramolecular acyl-transfer giving carboxylic acid intermediate 5B, and (iii) nuc...
