PREPARATION OF ENANTIOMERICALLY PURE 4,4, 4-TRIFLUORO-3-HYDROXY-BUTANOIC ACID-DERIVATIVES, BRANCHED IN THE 2-POSITION OR 3-POSITION, FROM 6-TRIFLUOROMETHYL-1,3-DIOXAN AND DIOXIN-4-ONES

Enantiomerically pure 3-hydroxy-3-trifluoromethyl-propionic acid and e sters, substituted in the 2- or 3-position, are prepared (13 examples) from (R)- or (S)-4,4,4-trifluoro-3-hydroxy-butanoic acid. Key interme diates are the 2-t-butyl-6-trifluoromethyl-1 ,3-dioxan- and -dioxin-4- ones. The Li enolate of the cis-dioxanone is generated with t-BuLi and reacts with electrophiles (alkyl halides, aldehydes, imines, nitroole fins, Br-2, I-2) with predominant formation of trans,trans-2,5,6-trisu bstituted dioxanones (9 examples). Elimination of HBr from the 5-Br-su bstituted dioxanone gives the (R)- or (S)-dioxinone, a chiral derivati ve of 4,4,4-trifluoro-3-oxo-butanoic acid (trifluoro-acetoacetate). Mi chael additions of cuprates or of CuCl-doped Grignard reagents to the dioxinone produce 6,6-disubstituted dioxanones (10 examples) bearing a CF3 group in the 6-position. In most cases this addition is highly di astereoselective, with the new substituent winding up in the trans pos ition. There are, however, surprising exceptions, such as the product formed with benzylmagnesium chloride which is an abnormal adduct with a p-quinoid structure (26) and with the newly introduced group in the cis position with respect to the t-Bu group. The structures of four tr isubstituted dioxanones bearing CF3 groups are determined by X-ray cry stal structure analysis (Figure 1, Table 1), one of them including the absolute configuration (by anomalous diffraction). Besides the well-k nown sofa, a twist-boat conformation of dioxanones appears to be favor able. The solution conformations of the different types of CF3-substit uted dioxanones are derived from Nuclear Overhauser NMR measurements a nd compared with the crystal structures (Figure 3).