No abstract

Surprisingly stable synperiplanar conformers of CFTA esters have led us to develop a new and very reliable method for assigning absolute configurations of even secondary alcohols having minimal structural differences, such as chiral benzhydrols and alpha-monodeuterated benzyl alcohols.

Surprisingly stable anti‐periplanar conformers of CFTA amides form the basis of a new and very reliable method for determining the absolute configuration of chiral primary amines by 1H NMR spectroscopy (see picture). CFTA=α‐cyano‐α‐fluoro‐p‐tolylacetic acid.

2-Arylpropionic acids 1 are used clinically as nonsteroidal anti-inflammatory drugs (NSAIDs) (Fig. 1). The (S)-enantiomers have been considered to be pharmacologically more active than the (R)-enantiomers of these acids. 1)Nonetheless, these agents are normally marketed as racemates. This is possible because it has been shown [1][2][3][4] that an in vivo inversion at the stereogenic center converts the pharmacologically less active (R)-enantiomers into the more active (S )-enantiomers, thereby obviating a prior separation of enantiomers.Owing to this in vivo epimerization, it is difficult to examine and clarify the medicinal actions or metabolism of each enantiomer closely. The replacement of hydrogen with fluorine can produce isosteric analogues (pseudologues) that often mimic the parent with respect to biological behavior. Therefore, to provide tools to study the in vivo behavior of the individual enantiomers of these NSAIDs, we have prepared a series of chiral non-epimerizable 2-fluorinated 2-arylpropionic acids 2 (Fig. 2).Some other groups have reported the synthesis of 2-aryl-2-fluoropropionic acid derivatives 2a, b, and 4a (RϭMe) by nucleophilic fluorination of the corresponding 2-hydroxy acids or 2-aryl epoxides with (diethylamino)sulfur trifluoride (DAST) or Et 3 N · 3HF, respectively (Eqs. 1, 2), 5,6) or electrophilic fluorination of the enol silyl ether of 3a with acetyl hypofluorite (Eq. 3).7) Laurent et al. reported the synthesis of 2-fluorinated ester 4a (RϭEt) by electrochemical oxidation in fluorinating media (Eq. 4).8) However, all of these methods require rather delicate conditions and/or many steps, and therefore, they lack synthetic generality (Chart 1).In this paper, we report an efficient and practical synthesis of 2-aryl-2-fluoropropionic acids 2 by direct fluorination of readily available 2-arylpropionic acid methyl esters 3 with diluted perchloryl fluoride (FClO 3 ), according to the convenient procedure we have reported previously.9-11) A simple and general procedure for optical resolution of the 2-fluoro acids 2 is also described. Results and DiscussionWe first attempted direct fluorination of carbanions derived from methyl ester 3a using selectfluor 12) and N-fluorobenzenesulfonimide.13) However, the yields seemed sensitive to the amount and kind of bases employed for the reaction and the results were found not to be reproducible. We then focused on fluorination using diluted FClO 3 , 9-11) considering the successful results obtained in the preparation of the structurally similar 2-cyano-2-fluoro-p-tolylacetic acid ethyl ester. 14,15) We first examined bases and temperatures for the fluorination of ibuprofen methyl ester 3a with FClO 3 in order to optimize reaction conditions (Table 1). The best result was obtained when a solution of the lithium enolate of 3a in tetrahydrofuran (THF), formed by treatment with lithium diisopropylamide (LDA) by usual procedure, was subjected to slow introduction of diluted FClO 3 , at Ϫ40°C for 1 h, to give a-fluoroibuprofen methyl ester 4a in 93% yield ...