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We describe herein a method providing access to both enantiomers of 3-acetylthio-2-benzylpropionic acid via enzymatic desymmetrization of 2-benzyl-1,3-propanediol. These compounds are respectively the starting materials for the synthesis of ecadotril, and dexecadotril, which are powerful inhibitors of NEP (EC 3.4.24.11) and have been developed as therapeutic agents.

A three-step synthesis of (2 Z ), (4 E )-polyenic acids 6 is described. Condensation of aldehydes 1 with potassium prenal enolate led to dihydropyranols 3 which were oxidized into dihydropyrones 5 , precursors of (2 Z) , (4 E )-polyenic acids 6 . The procedure was applied to a synthesis of 13- cis -retinoic acids from β-ionylidene acetaldehydes.

Functionalized dienol ethers 6 were obtained in one pot from hydroxyacetal 3, via hydroxydienol ether 1 and anion 5, when treating 3 with n-butyllithium. It was shown that the transient organometallic species 5 occured only when the electrophile was added.

Aldol 5b, easily obtained from dihydrocarvone 6b, reacts with organolithium and Grignard reagents leading to enantiomerically enriched alcohols 8 (ee up to 35%). Thus, aldol 5b is a synthetic equivalent of benzaldehyde with a masked prochiral face.

Vinylic lithium reagents 1 and 2 could be obtained by the title procedure from their chloro precursors 5 and 6 instead of the less stable corresponding bromo derivatives 3 and 4 . Condensation with carbonyl compounds leads to interesting synthetic applications such as a two steps synthesis of retinal 13 from β-cyclocitral 10 .

The use of chiral alkoxides obtained from ephedrines for enantioselective proton abstraction is described in full. These reagents allow the practical obtention of axially dissymmetric 1,3-dioxanes via highly enantioselective dehydrohalogenation reactions. The conditions for a catalytic use of these chiral alkoxides are defined.

After halogen-metal exchange reaction followed by condensation with carbonyl compounds, ene diiodo acetal 1 allow the stereoselective synthesis of ene hydroxy acetals 2 with Z configuration, in a two step procedure. Moreover, after dehydration, the intermediate diene acetals 3–4 , via an appropriated hydrolysis procedure, lead to pure non conjugated dienals 5 .

The reactions of methyl or ethyl 4-tert-butylcyclohexylidene bromoacetates 3-Me or 3-Et with amines afford various products depending on the experimental conditions and the nature of the amine. When the starting ester 3 is treated with benzylamine in refluxing methanol, the ester 5 and the corresponding amide 6 are isolated as the main reaction products. By contrast, the same reaction at room temperature and under high pressure leads to a spiro aziridine derivative 4 in good yield and high stereoselectivity. On the other hand, when ester 3 reacts with secondary amines in refluxing alcohol, the corresponding α-amino β,γ-unsaturated ester 7 is isolated as the sole product of the reaction in good yield. In toluene, the same reaction produces, in addition to the deconjugation–substitution compound 7, the isomeric γ-amino α,β-unsaturated ester 8. Finally, the hetero-Michael type addition of alcohol is the main reaction when substrate 3 is treated with methanol in the presence of a secondary or tertiary amine under high pressure, leading to β-substituted ester 9.

A general and efficient preparation of epimeric optically pure γ-butyrolactones 2 and 3 is described starting from l-tartaric acid (1). These lactones are well-known to be important building blocks in the syntheses of natural products. l-Tartaric acid (1) was transformed into carbonylated chirons (ketones 4 and aldehyde 5). These chirons, when submitted to highly stereoselective reactions (reduction or organometallic addition), led to epimeric dihydroxy γ-butyrolactones 2 and 3 after lactonization and deprotection steps. The resulting optically pure lactones are precursors of biological compounds and have allowed a total synthesis of l-biopterin and formal syntheses of quercus lactone, dodecanolactone, avenaciolide, and tetrahydrocerulenin.

Syntheses of 5-halogeno-2,4-dienals 1a–c are described starting either from the glutaconaldehyde potassium salt or from furan. The 5-bromopenta-2,4-dienal 1b can be transformed efficiently into homologous ω-bromo polyenals 2–4, precursors of ω-bromo polyenol ethers 5b,d, 6 and 7. After bromine–lithium exchange, followed by condensation with carbonyl compounds, 1-bromo-6-methoxyhexa-1,3,5-triene 5b, 1-bromo-8-methoxyocta-1,3,5,7-tetraene 6 and 1-bromo-10-methoxydeca-1,3,5,7,9-pentene 7 lead to various conjugated tri-, tetra- and penta-enals in good yields, in a one-pot procedure.

Condensation of enol ether 6 with methyl vinyl ketone led easily to ketoaldehyde 7 whose cyclisation afforded the azaspiranic enone 8, a key intermediate for the synthesis of the title alkaloids.

γ-Amino α,β-unsaturated dimethyl acetals are direct precursors of (E)-1-methoxy-2-methylamino-1,3-butadiene and of the corresponding bis-dienes, which are useful partners in cycloadditions.

The preferred conformation of thiorphan during the inhibitor-neprilysin docking process was investigated. A series of achiral inhibitors were tested. This study led to the design of a potent inhibitor, in which the ethylenic bond bears the aryl residue of P′1.

Chiral lithio enol ethers 1 obtained from corresponding Z-bromo enol ethers react with alkyliodides, acylchlorides, leading to new chiral enol ethers of controlled configuration 5–8.

2,2-Di(ethoxy)vinyllithium 2 generated from bromo ketene acetal 1 reacts with carbonyl compounds to give either β-hydroxy esters 5 or conjugated esters 6 or hydroxy ketene acetals 7 according to the work up.

γ-Functionalized α,β-unsaturated dimethyl acelals undergo a methanol δ-elimination upon basic treatment, leading to 1,4-disubstituted 1,3-dienes in good yields and, in several cases, with high stereocontrol of the newly formed double bonds.

Optically active (S)-2-bromo- and 2-chloro-alkanoic acids 6 and 7 have been obtained via the diastereoselective halogenation of chiral silyl ketene acetals 3a-f , and subsequent saponification of the resulting crude esters. Examples characterized by e.e. values up to 95% are reported. The diastereoface selectivity is independent of the silyl ketene acetal E Z configuration.

Semiempirical and ab initio calculations on (di)allylic alcohols indicate that the efficiency of their acid-catalyzed condensation with dienol ethers depends on their protonation-dehydration energies.

We describe one synthesis of ( S )-fenfluramine and several syntheses of its precursors ( R )- and ( S )-1-(metatrifluoromethylphenyl) propan-2-ols. They were obtained from the asymmetric epoxidation of the primary allylic alcohol 5 and from the kinetic resolution with asymmetric epoxidation of the secondary allylic alcohol 6 .

β-Trimethylsilyl enol ethers 1 ( Z ) obtained from β-bromoenolethers 2 were condensed with aliphatic and aromatic aldehydes in the presence of a catalytic quantity of trimethylsilyl triflate leading to ethylenic aldehydes 3 ( E ) with good yields (79–90%).

Functionalized dienol thioethers reacts with 3 eq. of thiophenol at room temperature in presence of dioxygen to give directly corresponding ketene dithiacetals in high yields.

2, 6-Dimethyl-8-methoxy-1-lithio-octatetra-1, 3, 5, 7-ene 4 is prepared by bromine-lithium exchange from its readily accessible bromo precursor 8 . The lithio reagent 4 reacts with carbonyl compounds to give in one pot, after a mild acidic hydrolysis, the retinoid aldehydes 2 .

Carbonyl compounds 2 are converted into conjugated dienals 3. in a one pot reaction, by a condensation with lithio-4 trimethylsiloxybutadiene, followed by a mild acidic hydrolysis.

Mono-, di- and trisubstituted tert-butyl 5-amino-4-alkenoates 3 and mono- or disubstituted tert-butyl 5-oxoalkanoates 4 are prepared in good overall yield by conjugate addition of β-lithiated enamines to enoates, followed by quenching with water or iodomethane. In all cases, only one stereoisomer of the polysubstituted enamino esters 3 is produced (de >98 %)

The enolate of prenal 1 prepared from the corresponding silyl enol ether 2 or enol acetate 3 led to a γ-regiospecific reaction with polyunsaturated aldehydes 4 yielding dihydropyrans 5 leading after hydrolysis to polyenals 7 . This process allows the introduction of the isoprenyl skeleton. A synthesis of retinal. from β-ionylidenacetaldehyde is reported.

A γ-condensation of the enolate of prenal 1 is observed with aldehydes and α,β-unsaturated aldehydes. In this last case, a conjugate addition is obtained. Intermediate dihydropyrans 4 yield dienals 5 by hydrolysis.

A simple and efficient synthesis of chiral cyclic imides with C2 symmetry based on smooth cyclisation of amides 4a-c obtained from (2R,3R) tartaric acid, is described.

Title products, lithiodienol ethers 6a and 7a , synthetic equivalents of 4-lithio pent-3-ene-2-one and 4-lithio-senecialdehyde were obtained by bromine-lithium exchange. They are choice reagents for the transformations l → 2 and L → 3 respectively.

Enantioselective dehydrohalogenation reactions with enantiomeric excesses (e.e.) as high as 90% are promoted by chiral alcoholates as bases.

2, 6-Dimethyl-8-methoxy-1-lithio-octatetra-1, 3, 5, 7-ene 4 is prepared by bromine-lithium exchange from its readily accessible bromo precursor 8 . The lithio reagent 4 reacts with carbonyl compounds to give in one pot, after a mild acidic hydrolysis, the retinoid aldehydes 2 .

Functionalized dienol thioethers reacts with 3 eq. of thiophenol at room temperature in presence of dioxygen to give directly corresponding ketene dithiacetals in high yields.

The OSM (oxidation state modification) concept for the elaboration of new synthetic pathways is demonstrated for the synthesis of β-ionylidene acetaldehyde 11 and retinal 13. According to this new scheme, electrophilic addition to ω-heterosubstituted enol ethers 5 of the cationic species 9, generated from β-ionol led to aldehydic intermediates 10 which undergo easy elimination to β-ionylidene acetaldehyde 11. Similarly, retinal 13 was obtained from vinyl-β-ionol 14 and dienol ethers 12, via aldehydes 16.

Condensation of 1-lithio-2-trimethylsiloxyethylene 1 with t-butyl(dimethyl)silyl triflate 2a leads to silylated enol ethers 4a or 4b according to the experimental conditions. The formation of 4b is due to a 1,3-migration of the trimethylsilyl group from oxygen to carbon of 1 . Condensation with chlorosilane 2b lead exclusively to 4b .

α-Trimethylsilyl and α-triethylsilyl aldehydes 6 were obtained from trimethylsilyl and triethylsilyl β-bromo enol ethers 1, using a bromine–lithium exchange and a 1–3 migration of the trialkylsilyl group.

As precursors of molecular wires, linear conjugated polyenes with protected hydroquinone terminal groups 1a–c have been obtained from gentisic aldehyde by condensation with 1-ethoxy-6-lithiohexa-1,3,5-triene 6, followed by reacting the resultant aldehydes 5 with the dianion of the bis-phosphonate 7.

We describe one synthesis of ( S )-fenfluramine and several syntheses of its precursors ( R )- and ( S )-1-(metatrifluoromethylphenyl) propan-2-ols. They were obtained from the asymmetric epoxidation of the primary allylic alcohol 5 and from the kinetic resolution with asymmetric epoxidation of the secondary allylic alcohol 6 .

β-Trimethylsilyl enol ethers 1 ( Z ) obtained from β-bromoenolethers 2 were condensed with aliphatic and aromatic aldehydes in the presence of a catalytic quantity of trimethylsilyl triflate leading to ethylenic aldehydes 3 ( E ) with good yields (79–90%).

Chiral alcoholates are efficient reagents to afford in optically pure form the cyclic acetal 1, thus demonstrating the potential of this clans of homochiral bases