Massimo Frigerio

EPC synthesis of gem-difluorocyclopentane derivatives

Abstract gem-Difluorocyclopentane derivatives were obtained in optically pure form by thermal or photochemical radical cyclization of the coresponding haloalkenes. Reductive or thermal elimination of the chiral auxiliary and appropriate elaborations afforded some difluoromethyl-cyclopentanols and -cyclopentantriols. The structure of the compounds was elucidated on the basis of 1H, 13C and 19F NMR data and of NOE difference experiments.

A new versatile fluorinated C4 chiron

Abstract Optically pure 2-(fluoromethyl)-2-[(4-methylphenylsulphinyl)methyl]oxirane has been obtained in good yield and with high d.e. by reacting diazomethane with optically pure 1-fluoro-3-(4-methylphenylsulphinyl)propan-2-one. Regio- and stereo-selective openings of oxirane ring performed with selected nucleophiles afforded several useful derivatives.

Synthesis of four homochiral 3,4-dideoxy-3-fluoro-hexoses from a non-carbohydrate precursor

Abstract The asymmetric synthesis of the 2-O-benzyl-3,4-dideoxy-3-fluoro-[α]-D- lyxo -hexopyranose (11), the -L- ribo -, the -D- arabino -, and the -L- xylo - analogues (12 - 14) has been realized through dihydroxylation of the double bond of (5S)-5-benzyloxy-4-fluoro-6-[(R)-(4-methylphenyl)sulphinyl]-hex-1-ene (4) followed by oxidative removal of the chiral auxiliary sulphinyl group. A detailed spectroscopic analysis of the four fluorocarbohydrates 11 - 14 has also been performed.

Synthesis of fluorinated chirons: Stereoselective oxirane formation by reaction of diazomethane on 1-fluoro-3-arylsulfinyl-2-propanone and ring opening by selected nucleophiles

Abstract (R)-1-fluoro-3-[(4-methylphenyl)sulfinyl]-2-propanone (1) reacts with diazomethane affording (S)-2-(fluoromethyl)-2-[(R)-(4-methylphenyl)sulfinyl]methyl oxirane (2) as the main product. The influence of reaction conditions (solvent, temperature) on the chemo-and stereoselectivity has been studied. Several elaborations of 2, including reactions on the chiral auxiliary and opening of the oxirane ring by carbon, nitrogen, oxygen, phosphorus and halogen nucleophiles, are described. Full structural elucidation of the products is provided.

Synthesis of optically pure fluoro- and gem-chlorofluoro-cyclohexane derivatives by intramolecular trapping of dihaloalkyl radicals.

Abstract gem -Chlorofluorocyclohexanols 8 bearing a methyl and a p-tolylsulphinyl substituent have been obtained in optically pure form by radical cyclization of the corresponding halo-alkenes 4 . Reductive dechlorination of both (6R)- and (6S)- 8 gave fluoroderivative (6R)- 9 , which through functional group elaborations gave the hydroxyfluoro- and trihydroxyfluoro-cyclohexane derivatives 12 and 15 .

Synthesis of optically pure difluoro- or chloro,fluoro-cyclohexanols and cyclopentanols

Abstract Starting from the secondary alcohols 1, cyclohexanols 2 having three (Xue5fbF) of four (Xue5fbCl) chiral centres on the ring can be obtained in optically pure form by intramolecular trapping of difluoroalkyl or chlorofluoroalkyl radicals (tributyltin hydride method). The diastereoselection of the process seems to be determined mainly by the stereochemistry at the carbons bearing the sulfinyl and the hydroxyl substituents. Optically pure difluoro- or chloro, fluoro-cyclopentanols can be obtained in the same way.

Synthesis of (−)-(1S,5R)- and (+)-(1R,5S)-trifluoroanalogues of frontalin

Abstract The synthesis of enantiomerically pure (−)-(1 S ,5 R )-1-trifluoromethyl frontalin 7 starting from (−)-(1 R )-menthyl ( S )-toluene-4-sulfinate, 5-pentenylmagnesium bromide and methyl trifluoroacetate is described. The synthetic procedures to obtain the enantiomer (+)-(1 R ,5 S )- 7 are also mentioned. Absolute stereochemistry was unambiguously assigned by X-ray analysis of intermediates 3 and 5 .

Stereoselective Synthesis of Both Enantiomers of Trifluoro-γ-valerolactone and Pentafluoro-γ-caprolactone

Both enantiomers of 5-(trifluoromethyl)dihydrofuran-2-one (1a) and 5-(pentafluoroethyl)dihydrofuran-2-one (1b) have been synthesised stereoselectively, in four steps, starting from chiral (R)- or (S)-3-[(4-methylphenyl)sulfinyl]propionic acid (2) and commercially available perfluorinated esters. Compound (+)-(S)-1b is the pentafluoro analogue of the aggregation pheromone of Trogoderma glabrum. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Synthesis of 2-Fluoro Analogues of Frontalin

The synthesis of enantiomerically and diastereomerically pure (−)-(1R,2R,5R)- and (−)-(1R,2S,5R)-2-fluoro frontalin (7) starting from (+)-(1S)-menthyl-(R)-toluene-4-sulfinate, methylmagnesium bromide, methyl fluoroacetate, 4-pentenyl bromide and diazomethane is described. The absolute stereochemistry was unambiguously determined by X-ray analysis of (+)-(1S,2R,5S,RS)-5, an intermediate in the synthesis of the enantiomeric (+)-(1S,2R,5S)-2-fluoro frontalin (7).

Asymmetric synthesis of trifluoro- and difluorochloro- methyl-containing epoxides

Abstract One of the inherent limitations of the well established chiron approach to the synthesis of fluoroorganic compounds of biological interest remains the limited number of chiral and enantiomerically pure starting materials, which should be both readily available and easily adaptable. An improved high yield procedure for transferring a methylene group from diazomethane to β-keto-γ-fluoro sulphoxides has been found, giving the corresponding epoxides as main compounds [G. Cavicchio, P. Bravo, V. Marchetti and C. Zappala, J. Fluorine Chem., 54 (1991) 244]. The reaction has been now extended to polyhalogenated derivatives ( 1 ). Although those compounds are present as an equilibrium mixture of keto and gem-diol form, they react fast to give mainly the corresponding epoxides ( 2 ) along with minor amounts of methyl enolethers ( 3 ). Chemical yields range from 35 to 60%. When a substituent is present on the α position, a crude mixture of diastereoisomers ( 1 ) can be used since partial equilibration occurs during the reaction and the epoxidcs ( 2 ) are still the predominant products. The reaction medium does not influence diastereoselection but greatly influences the final epoxides ( 2 )/enolethers ( 3 ) ratio. The mechanism of epoxide formation, stereochemical details and the possibilities of employing epoxides ( 2 ) in the synthesis of natural product analogues will be discussed.