EPC Syntheses of Trifluorocitronellol and of Hexafluoropyrenophorin – A Comparison of Their Physiological Properties with the Nonfluorinated Analogs

Abstract

The natural products pyrenophorin (1a) and citronellol (2a), in which CH3 groups are replaced by CF3, were synthesized in enantiomerically pure form from simple four-carbon trifluorohydroxy acids (obtained by resolution). The cyclizations of analogous CH3 and CF3 seco acids (cf. 9) to give pyrenophorin derivatives require different methodologies; the F6 derivative 10a could be obtained in only very poor yield; in contrast to pyrenophorin. Most surprisingly, F6-pyrenophorin (1d) has an extremely poor solubility in common organic solvents, and has essentially no antimicrobial activity (see Table 2). The synthesis of F3-citronellol is the first application of an enantiopure F3-Roche acid (12) as a synthetic builiding block (see its derivatives 17–23). An olfactory comparison of F3-citronellol [(R)-(+)-2b] with citronellol and ent-citronellol (Scheme 6) shows that the fluorine derivative has a “very metallic, aggressive” character and lacks totally the “sweetness” of (R)-(+)- and (S)-(–)-2a. A number of generally useful, CF3-substituted electrophilic (iodides 4, 18, 37, tosylates 19, 33, aldehydes 5, 29, 39) and nucleophilic (Li dithiane precursor of 5, Li compounds 20, 38) reagents are described for the first time.