Tandem reduction-olefination for the stereoselective synthesis of (Z)-α-fluoro-α,β-unsaturated esters

A tandem stereoselective reduction-olefination reaction of ethyl 2-acyl-2-fluoro-2-diethylphosphonoacetate employing NaBH₄ in EtOH was developed. The one-pot reaction gave α-fluoro-α,β-unsaturated esters with excellent (Z)-selectivity. A plausible mechanism involving a diastereoselective reduction predicted by the Felkin-Anh model, followed by olefination similar to the Horner-Wadsworth-Emmons reaction, has been proposed.     

Convenient procedure of Horner-Wadsworth-Emmons olefination for the synthesis of simple and functionalized α,β-unsaturated nitriles

A mild and practical procedure of Horner-Wadsworth-Emmons olefination promoted by lithium hydroxide and α-cyano phosphonates has been set up for the synthesis of α,β-unsaturated nitriles. The reaction conditions are tolerated by functionalized ketones and the exclusive formation of E-γ-hydroxy α,β-unsaturated nitriles has been observed.     

(E)-Selective Wittig reactions of Garner's aldehyde with nonstabilized ylides

In the Wittig olefination reactions of Garner's aldehyde with certain nonstabilized ylides, the (E)-alkenes could be produced as a major product by simply quenching the reactions with a large excess of MeOH at −78 °C. Even under the salt-free conditions, more than a 10:1 ratio of the (E)- to (Z)-alkene was resulted consistently from the ylides of a linear alkyl chain. Without addition of MeOH, usual selectivity for the (Z)-alkene was obtained in a ratio of 94:6.     

Z/E Stereoselective synthesis of β-bromo Baylis-Hillman ketones using MgBr2 as promoter via a one-pot three-component reaction

The first time steroselective synthesis of (Z)-β-bromo Baylis-Hillman ketones has been achieved using a one-pot three-component reaction. The new system uses MgBr₂ as both the Lewis acidic promoter and the bromine source for the Michael-type addition with α,β-acetylenic ketones to form an active β-bromo allenolate intermediate, which in turn attacks various aldehydes to afford β-bromo Baylis-Hillman adducts in good yields and Z-selectivity.     

Synthetic application of fluorinated vinamidinium salts: Synthesis of fluorinated 1,3-butadienylphosphonates by the reaction with Horner-Wadsworth-Emmons reagents

The reaction of β-fluoro vinamidinium salt 1 with Horner-Wadsworth-Emmons reagents (HWE) such as diethyl(ethoxycarbonyl)methylphosphonate (2a), diethyl(methoxycarbonyl)methylphosphonate (2b), diethyl-2-oxopropylphosphonate (2c), diethyl benzylphosphonate (2d), tetraethyl methylenediphosphonate (2e) and diethyl cyanomethylphosphonate (2f) under basic conditions gave the fluorinated 1,3-butadienylphosphonates 3 in moderate to good yields. The phosphonates 3 could be hydrolyzed with a 10% HCl aqueous solution to afford the corresponding γ-(diethylphosphono)-α-fluoro-α,β-unsaturated aldehydes 7 in good yields. The treatment of the phosphonate 3c with an NH₃ aqueous solution at 70 °C produced the pyridine derivative 8 in 60% yield.     

Synthesis of poly(phenyltrifluoroethoxyphosphazene) by direct reaction of trimethylsilyl azide with bis(2,2,2-trifluoroethyl) phenylphosphonite

The reaction between bis(2,2,2-trifluoroethyl) phenylphosphonite and trimethylsilyl azide at temperatures from 70 to 120°C provides a mixture of bis(2,2,2-trifluoroethoxy)phenylN-(trimethylsilyl) phosphoranimine and poly(phenyl-2,2,2-trifluoroethoxyphosphazene). The polymer is probably formed by phosphine azide intermediates because the phosphor-animine is thermally stable up to 200°C. The polyphosphazene is an amorphous stereo-random polymer with a glass transition temperature at ?31°C.     

Enantiomeric products formed via different mechanisms: asymmetric hydrogenation of an α,β-unsaturated carboxylic acid involving a Ru(CH3COO)2[(R)-binap] catalyst

Hydrogenation of (Z)-3-phenyl-2-butenoic acid with a Ru(CH₃COO)₂[(R)-binap] (BINAP=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) catalyst in methanol gives (S)-3-phenyl-2-butanoic acid and its R enantiomer in a 97:3 (4 atm) to 94:6 (100 atm) ratio in quantitative yield. Both hydrogen gas and protic methanol participate in the saturation of the olefinic bond. Analysis of the products obtained using (Z)-3-phenyl-2-butenoic acid-3-¹³C and either H₂, a 1:1 H₂-D₂ mixture, or D₂ in CH₃OD indicates that several catalytic cycles are operative, showing different reactivity and stereoselectivity. The major S enantiomer was formed primarily by the standard Ru monohydride mechanism, whereas the minor R isomer is produced via more complicated routes.     

Development of radical addition-cyclization-elimination reaction of oxime ether and its application to formal synthesis of (±)-martinelline

Radical addition-cyclization-elimination (RACE) reaction of oxime ether carrying unsaturated ester provides a novel method for the construction of pyrroloquinoline. Treatment of oxime ethers with Bu₃SnH and AIBN gave N-norpyrroloquinoline as a major product, which was also obtained by the radical reaction of the corresponding hydrazone and imine. The radical reaction of aldehyde and ketone carrying unsaturated ester proceeded stereoselectively to give cis-furoquinolines and cis-hydroxyesters. The RACE reactions by using each of Bu₃SnNMe₂, Bu₃SnD, and/or D₂O were also examined in order to propose a reaction pathway to N-norpyrroloquinoline. Furthermore, the synthetic utility of RACE reaction is demonstrated by preparation of a key intermediate for the synthesis of (±)-martinelline.     

Reactions of (Z)-3-aryl-3-chloropropenals with nucleophiles: stereoselective formation of (E)-vinylogous esters, (E)-vinylogous amides, and vinamidinium salts

The highly stereoselective conversions of (Z)-3-aryl-3-chloropropenals to (E)-3-alkoxy-3-arylpropenals, to (E)-3-aryl-3-morphorlinopropenals, and to vinamidinium salts are reported. The stereochemical assignments were based on 2D-NMR experiments.     

Design and synthesis of (E)-4-((3-ethyl-2,4,4-trimethylcyclohex-2-enylidene)methyl)benzoic acid

(E)-4-((3-Ethyl-2,4,4-trimethylcyclohex-2-enylidene)methyl)benzoic acid, 6, was synthesized in 87% starting from β-cyclocitral. The target compound 6 was synthesized starting from 1 via a Grignard reaction to form alcohol 2. Compound 2 was converted to Wittig salt 3 by treatment with aldehyde 4 in butyllithium and hexane at −78 °C to form ester 5. Ester 5 was saponified and, following acidification, acid 6 was isolated as white solid yield 87%.     

A simple procedure for the synthesis of γ-hydroxy-α,β-(E)-alkenoic esters: formal synthesis of (+)-macrosphelides A and B

A highly trans-selective conjugate reduction of γ-hydroxy-α,β-alkynoic esters to produce γ-hydroxy-α,β-(E)-alkenoic esters using LiAlH₄ is reported. The application of this methodology is demonstrated by a formal synthesis of the potent cell-cell adhesion inhibitors (+)-macrosphelides A and B.     

Preparation of (1R,1′R)-1,1′-(anthracene-9,10-diyl)bis(2,2,2-trifluoroethanamine): a chiral diamine with low basicity

A new chiral diamine with low basicity was synthesized in enantiopure form. (1R,1′R)-1,1′-(Anthracene-9,10-diyl)bis(2,2,2-trifluoroethanamine) was obtained by means of several stereochemically controlled reactions. The structures of the title compound and several intermediates were studied.     

Conjugate addition of indoles and thiols with electron-deficient olefins catalyzed by Bi(OTf)3

Conjugate addition of indoles and thiols with a variety of electron-deficient olefins mediated by a catalytic amount of Bi(OTf)₃ at ambient temperature to afford the corresponding Michael adducts in good to excellent yields with high selectivity is reported.     

4-Formylazetidin-2-ones, synthon for the synthesis of (2R,3S) and (2S,3R)-3-amino-2-hydroxydecanoic acid (AHDA)

An efficient synthesis of 3-amino-2-hydroxydecanoic acid (AHDA), a nonproteinogenic amino acid, using enantiopure 3-benzyloxy-4-formylazetidin-2-one as a building block is described. Both the enantiomers of AHDA have been synthesized from the corresponding enantiomer of 3-benzyloxy-4-formylazetidin-2-one in good yield and optical purity.     

Pd-catalyzed cross-coupling reaction of (Z)- and (E)-bromoenyne: unusual stereochemical outcome

Pd-catalyzed cross-coupling reaction of (E)-bromoenyne 1Z with 1-alkyne and tributylvinyl-stannane occurs with retention of the configuration in benzene but with an inversion of the configuration in DMF or CH₂Cl₂. On the other hand, that of (Z)-bromoenyne 1E occurs with retention of the configuration in these solvents.     

Synthesis of (S)-(+)-enantiomers of food-relevant (n-5)-monoenoic and saturated anteiso-fatty acids by a Wittig reaction

We developed an enantioselective synthesis for the food-relevant anteiso-fatty acids a15:0, a16:0, and a17:0. Different (carboxyalkyl)triphenylphosphonium bromide salts were coupled with (S)-3-methylpentanal in a Wittig reaction. Mixtures of the obtained cis-/trans-isomers were separated by Ag⁺-HPLC to give the novel cis-isomers of (S)-(+)-a15:1n-5, (S)-(+)-a16:1n-5, and (S)-(+)-a17:1n-5. Hydrogenation of the monoenoic products led to (S)-(+)-a15:0, (S)-(+)-a16:0, and (S)-(+)-a17:0, which are essential for the assessment of the bioactivity of tests with standards of anteiso-fatty acids.     

The stereoselective total synthesis of (+)-18-(6S,9R,10R)-bovidic acid

An expedient stereoselective total synthesis of 18-carbon (+)-(6S,9R,10R)-bovidic acid, isolated from the pelage and skin of a gaur B. frontalis is described using l-proline catalysed sequential α-aminoxylation and Horner-Wadsworth-Emmons olefination of aldehyde, cross metathesis and tandem Sharpless asymmetric dihydroxylation-S_N2 cyclization reaction as the key steps.     

Stereoselective synthesis of (Z)-β-fluoro-α,β-unsaturated esters from (Z)-2-fluoro-1-alkenyliodonium salts

(Z)-β-Fluoro-α,β-unsaturated esters were stereoselectively synthesized from (Z)-2-fluoro-1-alkenyliodonium salts by the Pd-catalyzed methoxycarbonylation reaction. The reaction proceeded at room temperature and various functional groups on the substrate can tolerate the reaction conditions.     

Stereoselective synthesis of (Z)-γ-cyano-β-perfluoroalkyl-β,γ-unsaturated esters

(Z)-γ-Cyano-β-perfluoroalkyl-β,γ-unsaturated esters have been synthesized by the reaction of perfluoroacylated phosphonates with organozinc reagent in 50-71% (three steps) yields.     

Synthesis of (E)-2-(1-ferrocenylmethylidene)malonic acid derivatives by a cobalt-catalyzed domino reaction of ethyl diazoacetate, carbon monoxide and ferrocenylimines

The domino reaction of ethyl diazoacetate, carbon monoxide and ferrocenylimines was investigated in the presence of Co₂(CO)₈ as catalyst. In most cases the main products are 2-(1-ferrocenylmethylidene) malonates formed by an N(1)-C(4) cleavage of the primarily derived β-lactams. The latter compounds could only be isolated when the reaction was carried out at relatively low CO pressure, using an excess of ethyl diazoacetate. trans-N-(tert-Butyl)-3-ethoxycarbonyl-4-ferrocenyl-β-lactam proved to be the most stable one among these compounds and could be isolated in 55% yield. N-alkyl β-lactams were shown to undergo acidic cleavage leading to the E isomers of 2-(1-ferrocenylmethylidene) malonates as the main products. The structures of the two new compounds, (E)-2-ethoxycarbonyl-3-ferrocenyl-N-((R)-1-phenylethyl)-2-propenamide and trans-N-(tert-butyl)-3-ethoxycarbonyl-4-ferrocenyl-β-lactam were confirmed by X-ray crystallography. The relative thermodynamical stability of the products as well as the energetics of the acid-mediated cleavage of the β-lactam ring was elucidated with DFT calculations.