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In 2‐ und 3‐Stellung verzweigte, enantiomerenreine 4,4,4‐Trifluor‐3‐hydroxy‐buttersäure‐Derivate aus 6‐Trifluormethyl‐1,3‐dioxan‐und ‐dioxin‐4‐onen
Author(s) -
Gautschi Markus,
Schweizer W. Bernd,
Seebach Dieter
Publication year - 1994
Publication title -
chemische berichte
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.667
H-Index - 136
eISSN - 1099-0682
pISSN - 0009-2940
DOI - 10.1002/cber.19941270317
Subject(s) - chemistry , trifluoromethyl , substituent , electrophile , adduct , stereochemistry , medicinal chemistry , bromide , crystal structure , alkyl , organic chemistry , catalysis
Preparation of Enantiomerically Pure 4,4,4‐Trifluoro‐3‐hydroxy‐butanoic Acid Derivatives, Branched in the 2‐ or 3‐Position, from 6‐Trifluoromethyl‐1,3‐dioxan‐ and ‐dioxin‐4‐ones Enantiomerically pure 3‐hydroxy‐3‐trifluoromethyl‐propionic acid and esters, substituted in the 2‐ or 3‐position, are prepared (13 examples) from ( R )‐ or ( S )‐4,4,4‐trifluoro‐3‐hydroxy‐butanoic acid. Key intermediates 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, nitroolefins, Br 2 , I 2 ) with predominant formation of trans,trans ‐2,5,6‐trisubstituted dioxanones (9 examples). Elimination of HBr from the 5‐Br‐substituted dioxanone gives the ( R )‐ or ( S )‐dioxinone, a chiral derivative of 4,4,4‐trifluoro‐3‐oxo‐butanoic acid (trifluoro‐acetoacetate). Michael additions of cuprates or of CuCl‐doped Grignard reagents to the dioxinone produce 6,6‐disubstituted dioxanones (10 examples) bearing a CF 3 group in the 6‐position. In most cases this addition is highly diastereoselective, with the new substituent winding up in the trans position. 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 trisubstituted dioxanones bearing CF 3 groups are determined by X‐ray crystal structure analysis (Figure 1, Table 1), one of them including the absolute configuration (by anomalous diffraction). Besides the well‐known sofa , a twist‐boat conformation of dioxanones appears to be favorable. The solution conformations of the different types of CF 3 ‐substituted dioxanones are derived from Nuclear Overhauser NMR measurements and compared with the crystal structures (Figure 3).