Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

3-Fluorofuran-2(5H)-one (1) and three 3,4-difluorofuran-2(5H)-ones 2–4, α,β-unsaturated lactones possessing fluorinated double bonds, were applied as dienophiles in Diels–Alder reactions with normal electron demand using diphenylisobenzofuran or cyclopentadiene as dienes. In the same reactions, furan or 2,3-dimethylbuta-1,3-diene were completely unreactive. Three structural factors of furan-2(5H)-ones appeared to have an effect on the reactivity, regioselectivity and diastereoselectivity of the [4+2] cycloadditions: the number of fluorine atoms attached to the double bond and the number and the bulkiness of alkyl substituents at the 5-position of the furan-2(5H)-one system. The monofluorinated furan-2(5H)-one 1 was generally more reactive than the difluorinated furan-2(5H)-ones 2–4. While the reactions of the furan-2(5H)-ones 2–4 with isobenzofuran exclusively gave exo products, those of the monofluorinated lactone 1 led to mixtures of endo and exo diastereoisomeric [4+2] cycloadducts. All fluorinated furan-2(5H)-ones 1–4 formed mixtures of diastereoisomeric 1:1 and 1:2 adducts with cyclopentadiene. DFT calculations of the transition states of the above Diels–Alder reactions using the BMK functional, a third-generation hybrid functional tailored for transition state calculations, together with the polarization consistent aug-pc-2 basis set, confirmed the preferential formation of the exo adducts from difluorinated furan-2(5H)-ones, while for nonfluorinated analogues a small but significant preference for the endo adducts was confirmed.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

A new practical method for the regioselective synthesis of the N-benzoyl-4-(polyfluoroalkyl)anilines 5a–g by thermal Diels–Alder cycloaddition of 5-substituted 3-(benzoylamino)-6-(polyfluoroalkyl)pyran-2-ones 1a–e with fluorostyrenes 2 and 7, acetylenes 8a–c or vinyl ethers 10 and 13a and 13b is described. In the case of the reactions of pyrone 1a with cyclic vinyl ethers 13a and 13b, the dihydrobenzenes 14a and 14b were obtained. Free 4-(polyfluoroalkyl)anilines 16a–c were smoothly formed in good yields by DBU-assisted benzoyl deprotection. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Two diastereomeric enantiopure 4-fluoro-4,5-dihydroceramides with the natural D-erythro configuration at the 2- and 3-carbon atoms have been synthesized in an enantioselective eleven-step sequence. The key step of the synthesis was a diastereoselective asymmetric Sharpless dihydroxylation of ethyl trans-4-fluorooctadec-2-enoate (8) with AD-mix-β to afford the D-erythro arrangement. The diastereomers of the other enantiomeric series were synthesized analogously with the use of AD-mix-α. In all cases, the nitrogen heteroatom was introduced into the 2-position by regio- and stereoselective ring opening of cyclic sulfates 13 and 14 with azide. Staudinger reduction, acylation of the intermediary formed amino group, chromatographic separation of the diastereomers and chemoselective reduction of the ester functionality with sodium borohydride in the presence of methanol afforded both title compounds in an enantiopure form. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Mixtures of endo,endo-9-oxabicyclo[4.2.1]nonane-2,5-diol (meso-2) and endo,endo-9-oxabicyclo[3.3.1]nonane-2,6-diol [(±)-3] were prepared from cycloocta-1,5-diene (1) upon treatment with peracids by transannular O-heterocyclization and subsequent saponification of the formed diol monoesters such as (±)-4 and (±)-5. The corresponding diacetates, meso-6 and (±)-7, were formed by acetylation of either meso-2 and (±)-3 or (±)-4 and (±)-5 with acetic anhydride/pyridine. These diacetates were enantioselectively hydrolyzed by microbial enzymes such as the lipases from Candida antarctica (CAL) or Candida rugosa (CRL). The corresponding enantiomers were formed by lipase-catalyzed acetylation of the diols meso-2 and (±)-3 with vinyl acetate. The skeletal isomers can also be separated in this way because the enantiopure monoacetates 4 were formed from the meso-compounds 2 or 6, while one enantiomer of the racemic diacetate (±)-7 [or the diol (±)-3] was transformed into the enantiopure diol 3 (or the enantiopure diacetate 7, respectively) via the corresponding enantiomers of the monoacetate 5. The other enantiomer remained untouched in both cases. The lipases reacted enantioselectively to give the R isomer. Cycloocta-1,5-diene (1) was also used to synthesize 2-oxa-6-thiatricyclo[3.3.1.1^3,7]decane-4,8-diol [(±)-11] in a four-step sequence. This racemic diol was also acetylated selectively (R isomer) with vinyl acetate and CRL. Reductive desulfuration of (±)-11 gave exo,exo-9-oxabicyclo[3.3.1]nonane-2,6-diol [(±)-12], which was acetylated selectively (S isomer) with CRL under the same conditions. The similarity in size and particularly in shape is responsible for the observed stereoselectivity of the lipases for the racemic endo,endo compounds (±)-3 and (±)-7 on the one hand and the exo,exo compound (±)-12 on the other hand. The absolute configuration and crystal packing of the products was determined by X-ray structural analysis. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

The bislactones rac-tetrahydro-2,2′-bifuranyl-5,5′-dione (rac-12) and its diastereomer meso-25 were prepared from endo-5-hydroxy-9-oxabicyclo[4.2.1]nonan-2-one (endo-10) and endo-6-hydroxy-9-oxabicyclo[3.3.1]nonan-2-one (endo-11) or exo-5-hydroxy-9-oxabicyclo[4.2.1]nonan-2-one (exo-23), respectively, under the conditions of a Baeyer−Villiger oxidation with trifluoroperacetic acid. The latter compounds were obtained by O-heterocylization of cis,cis-cycloocta-1,5-diene (1) by either reaction with peracids followed by hydrolysis and Jones oxidation or ruthenium tetraoxide oxidation, respectively. The optically active bislactone (R,R)-(−)-12 was prepared in a similar manner from (1S,5R,6R)-(+)-10 and (1R,5R,6R)-(+)-11, which, in turn, were obtained by lipase-catalyzed asymmetric acetylation of the corresponding diols meso-2 and rac-3 and subsequent Jones oxidation of the formed hydroxy esters (1S,2S,5R,6R)-(+)-4 and (1R,2R,5R,6R)-(+)-5. Since the regioisomeric hydroxy-9-oxabicyclo[4.2.1]- and -[3.3.1]nonan-2-ones (1S,5R,6R)-(+)-10 and (1R,5R,6R)-(+)-11 yielded the same bislactone [(R,R)-(−)-12] it is presumed that the sequence proceeds via open-chain intermediates. Applying this strategy to the enantiopure acetoxy ketones (1S,5R,6R)-(+)-8 and (1R,5R,6R)-(+)-9, followed by Kolbe electrolysis of the formed (R,R)-5-acetoxy-7-carboxyheptan-4-olide [(R,R)-27], (R,R)-5-acetoxydecan-4-olide [(R,R)-29] was accessible in a five-step synthesis. The absolute configuration of (+)-8 was determined by X-ray analysis of the dithiepane derivative 14. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Location makes a difference. Fluorinated analogues of the antidepressive tranylcypromine (see structures) are much stronger inhibitors of different monoamine oxidases such as microbial tyramine oxidase or human liver mitochondrial-outer-membrane monoamine oxidases A and B. Regiochemistry, as well as relative and absolute stereochemistry of the fluorine substituent at the cyclopropane ring, has a strong influence on the effectiveness of inhibition and on the physicochemical data, such as pK_a values, permeability, and log D values.

The biotransformation of tricyclo[2.2.1.0^2,6]hept-3-yl N-phenylcarbamate (8) by a standard procedure using Beauveria bassiana gave a 7:1 mixture of optically active exo,exo- and exo,endo-5-hydroxytricyclo[2.2.1.0^2,6]hept-3-yl N-phenylcarbamates 15 and 16 in 19% isolated yield. No ring opening of the three-membered ring was observed. Substitution with a fluorine atom at the 5-endo- or 5-exo-position prevented hydroxylation of any alicyclic position of the molecules, p-hydroxylation of the aromatic ring occurring to a small extent instead. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

The asymmetric ring opening of five meso- and three racemic epoxides with different fluorinating reagents in the presence of stoichiometric or slightly sub-stoichiometric amounts of Jacobsen's enantiopure (salen)chromium chloride complex A gave the corresponding optically active vicinal fluorohydrins. Silver fluoride was used as one of the fluoride sources either in the presence of Bu₄N⁺H₂F₃⁻ in diethyl ether or in acetonitrile. The latter reactions starting from cyclohexene oxide (1) showed maximum 72% ee in the formed fluorohydrin 2 isolated in 90% yield. From other meso-epoxides such as cyclopentene oxide and cycloheptene oxide the corresponding fluorohydrins were isolated in 80% and 82% yield with 65% and 62% ee, respectively. In case of ring opening under similar conditions of the racemic styrene oxide or phenyl glycidyl ether 83% and 75% of the fluorohydrins with fluorine in the primary position were isolated with 74% ee and 65% ee, respectively. Tetrahydronaphthalene oxide yielded a 2:1 mixture of trans- (23% ee) and cis-2-fluoro-3,4-benzocyclohexenol (2% ee) suggesting competing S_N2 and S_N1 type ring openings. Other epoxides such as cyclooctene oxide, cis-stilbene oxide and α-methylstyrene oxide did not react or gave the fluorohydrins with very small enantiomeric excess.

The synthesis of racemic 2-fluoro-3-hexadecyloxy-2-methylprop-1-yl 2′-(trimethylammonio)ethyl phosphate (10), a fluorinated analogue of the anticancer active and blood platelet activating ether lipids 8 and 9, has been achieved in a six-step sequence from methallyl alcohol (11). Etherification of 11 with hexadecyl bromide gave allylic ether 12, bromofluorination of which afforded the bromo-substituted fluoride 13, which was subsequently transformed into the acetate 14. Hydrolysis of 14 gave the key intermediate 2-fluoro-2-(hexadecyloxymethyl)propanol (15), which was attached to the phosphocholine residue in the final step. Enzyme-catalyzed deracemization of the fluorohydrin 15 by acetylation with several lipases gave optically active compounds 14 and 15, with a maximum ee of 61% for 15 with Candida antarctica lipase catalysis after 74% conversion. An enantioselective synthesis of 10, based on a planned eight-step synthesis starting from α-methylstyrene, failed. The anticancer activity of racemic 10 has been observed in an in vivo model of methylcholanthrene-induced mouse fibrosarcoma.

(+)-(S)-2-Amino-4-fluorobutanoic acid (5a) (> 96% ee), its α-methylated derivative (+)-(S)-5b (85% ee), and (−)-(S)-2-amino-4-fluoro-4-pentenoic acid (10) (81% ee) were synthesized by diastereoselective alkylation in the presence of LDA at low temperatures. Alkylation of (+)-(R,R,R)-2-hydroxy-3-pinanone based imines of glycine tert-butyl ester 1a or alanine isopropyl ester 1b with 1-bromo-2-fluoroethane (2) or 3-bromo-2-fluoropropene (7), respectively, followed by stepwise deprotection was used. The selectivity of the alkylation increased by lithium/magnesium exchange or for 1b also by addition of DMPU. Differences in the reactivity of enolate alkylations of enantiomerically pure or racemic Schiff base 1a with 2 or 7, respectively, can be explained by the formation of structurally different aggregates of the enolates in solution, caused by diastereomeric interactions between enantiomers in the transition state of alkylation.

Lipase-catalyzed ring-opening polymerization of 10-fluorodecan-9-olide (1a), 11-fluoroundecan-10-olide (1b), 12-fluorododecan-11-olide (1c) and 14-fluorotetradecan-13-olide (1d) gave optically active products with M_w of 3.000 to 8.000, while 10-fluoroundecan-11-olide (3a) gave an optically inactive polymer with M_w = 11.000. On the other hand, Candida antarctica lipase-catalyzed polymerization of 10- to 14-membered ω-fluoro-(ω-1)-hydroxyalcanoic acids gave optically inactive oligomers with M_w of 3.000 to 11.000 in the presence of molecular sieves, while reactions without molecular sieves gave oligomers with lower molecular weight, but with small optical rotations. 9-Fluoro-10-hydroxydecanoic acid, on the other hand, gave an optically inactive polyester with M_w = 7400. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 2004–2012, 2000

(R)-(−)-2-Amino-4-fluorobutyric acid (4c) (32% ee) and six of its homologues 9 have been synthesized by diastereoselective alkylation (54–72% yield) of (R)-(+)-camphor-based glycine ester imines 1 with 1-bromo-2-fluoro-alkanes 6, at low temperature, followed by deprotection. Similarly 1-bromo-3-fluoropropane was used for the preparation of (R)-(−)-5-fluornorvaline (4d) (42% ee). With 1-bromo-2-fluoropropane (6a) and its homologues (prepared by bromofluorination of 1-alkenes) partial resolution occurs in the alkylation step, yielding mixtures of four diastereomers. Using (R)-1-bromo-2-fluoro-4-methylpentane two diastereomeric alkylation products are formed (58% de). The overall yield of the three-step procedure varied from 10% to 32%.