Efficient and regioselective chromium(0)-catalyzed reaction of 2-substituted furans with diazo compounds: stereoselective synthesis of (2E,4Z)-2-aryl-hexadienedioic acid diesters

Pentacarbonyl(η²-cis-cyclooctene)chromium(0) (1) catalyzes efficiently reactions of diazo compounds with electron-rich furans. The reaction of 2-methoxyfuran (2) with alkyl α-diazoarylacetate (3a-g) furnishes the (2E,4Z)-2-aryl-hexadienedioic acid diesters (4a-g) in excellent yields. These reactions are highly regioselective. The cyclopropanation intermediates formed from 1 and diazo compounds 3a-g always arise from a carbene addition to the less substituted CC bond of 2. The resulting cyclopropanation product undergoes a ring opening reaction to form the corresponding (2E,4Z)-2-aryl-hexadienedioic acid diesters (4a-g). The pentacarbonylchromium(0)-catalyzed reactions of 2-alkylfuran (5a-b) with ethyl α-diazophenylacetate (3a) and 9-diazo-9H-fluorene (3h) produce the 1(E),3(E)-butadienes (6a-d) in very good yields.     

Facile access to stereodefined dienoates and cyclopropylenoates containing a trifluoromethyl group

Ethyl (2E,4E)-3-trifluoromethyl-2,4-dienoates 1a-e and ethyl (E)-3-trans-alkylcyclopropyl-4,4,4-trifluoro-2-butenoates 2a-e were prepared from the trans-alkenylboronic acids 3a-e and the trans-cyclopropylboronic acids 4a-e with ethyl (Z)-3-iodo-4,4,4-trifluoro-2-butenoate (5) by the Suzuki cross-coupling reaction in high yields (88-95%). The configurations of both 3a-e or 4a-e and 5 were retained in the reaction.     

Application of chiral tetrahydropentalene ligands in rhodium-catalyzed 1,4-addition of (E)-2-phenylethenyl- and (Z)-propenylboronic acids to enones

Chiral tetrahydropentalenes (3aR,6aR)-1 have been prepared and used as ligands in the Rh-catalyzed 1,4-addition of 1-alkenylboronic acids to cyclic enones 5. It has been discovered that the stereochemistry of the reaction was controlled by the steric properties of the aryl groups in 1 rather than their electronic nature. In the vinylation with (E)-2-phenylethenylboronic acid 5, ligands (3aR,6aR)-1 provided enantioselectivity up to 87% ee and gave high yields of ethenylketones 6 in the presence of 1 (6.6 mol %). The configuration of all ketone products obtained with (3aR,6aR)-1 is (S). Rh-catalyzed reaction of cyclopentenone 4a and (Z)-propenylboronic acid 7 in the presence of ligands (3aR,6aR)-1 yielded at 50 °C an inseparable mixture of (Z)- and (E)-ketones 8 with (Z)-8 as the major product and both in only moderate enantiomeric excess.     

Convenient synthesis of 3-fluoro-4,5-diphenylfuran-2(5H)-one from benzoin ethers : Novel and efficient Z-E isomerisation and cyclisation of 2-fluoroalkenoate precursors, substitution of vinylic fluorine

Mixtures of ethyl (E)- and (Z)-4-alkoxy-2-fluoro-3,4-diphenylbut-2-enoates (6-8) prepared from benzoin ethers and ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate were transformed in high yields to the target 3-fluoro-4,5-diphenylfuran-2(5H)-one (14) using bromine in tetrachloromethane at room temperature. The non-cyclisable Z-isomers 6b-8b were gradually isomerised to the cyclisable E-isomers 6a-8a during the process. The reaction of the (E)-butenoates 6a-8a with boron trifluoride led to furanone 14, while in Z-isomers 6b-8b both alkoxy group and vinylic fluorine were substituted with bromine during the reaction. Mechanisms for both complex reactions have been proposed. Furanone 14 was transformed to 2-[tert-butyl(dimethyl)silyloxy]-3-fluoro-4,5-diphenylfuran (18) as a novel building block.     

A highly stereoselective preparation of CF3-substituted 1-aryl-1,2-diphenylethenes: application to the synthesis of panomifene

β-CF₃-α,β-diphenylvinyl sulfide 3a was prepared stereoselectively in 77% yield from the reaction of 2 with phenyllithium at room temperature for 5 h. Oxidation of 3a with MCPBA afforded the corresponding vinyl sulfone 4a, in which (E)-4a can be crystallized in a mixture of CH₂Cl₂ and hexane. The addition-elimination reaction of (E)-4a with phenyllithium having substituents on the benzene ring provided 5a-j in 51-82% yields stereospecifically. Similarly, the treatment of (E)-4a with p-chloroethoxyphenyllithium in the presence of 12-crown-4 (20 mol %) at −10 °C, followed by slowly warming to room temperature, resulted in the formation of the corresponding panomifene precursor 6 in 82% yield.     

Synthesis and photochemistry of pH-sensitive GFP chromophore analogs

GFP chromophore analogs (7a-e, 8, and 10a,b) containing 2-thienyl-, 5-methyl-2-furyl-, 2-pyrryl, and 6-methyl-2-pyridyl-groups were synthesized and their fluorescence spectra recorded in the pH range 1-7. NMR studies showed that protonation of 8 (2-thienyl system) inhibited photoisomerization (Z-E) about the exocyclic double bond but that protonation of 7c (E + Z) (2-pyrryl system) gave only 7cE. Fluorescence studies revealed enhancement of fluorescence intensity of 7c and 7b,e (furyl system) below pH 2.5 and gave a similar result for 10a (pyridyl system) below pH 6. Quantum yields at pH 1 were low, probably due to excited state proton transfer (ESPT).     

A New Alkylation-Elimination Method for Synthesis of Antiviral Fluoromethylenecyclopropane Analogues of Nucleosides

A new method for the synthesis of fluoromethylenecyclopropane nucleosides by alkylation-elimination procedure is described. Fluorination of methylenecyclopropane carboxylate 6 gave fluoroester 7. Treatment of 7 with phenylselenenyl bromide afforded the desired ethyl (E)-2-bromomethyl-1-fluoro-2-phenylselenenylcyclopropane-1-carboxylate 11 in 85% yield. DIBALH reduction of 11 gave 13, which after acetylation to 14 was reacted with 2-amino-6-chloropurine to give the 9-alkylated product 15 in 87% yield. Se-oxidation of 15 with hydrogen peroxide afforded 16, which underwent smooth elimination in a mixture of THF-DMF at 60 °C giving rise to a Z,E mixture of protected nucleosides 17. Deacetylation gave Z-1a and E-1a which were separated on a silica gel column. Both Z-1a and E-1a were converted into the respective guanine analogues Z-1b and E-1b.     

Synthesis of new tetracyclic 7-oxo-pyrido[3,2,1-de]acridine derivatives

A series of (±)3-hydroxyl- and 2,3-dihydroxy-2,3-dihydro-7-oxopyrido[3,2,1-de]acridines were synthesized for antitumor evaluation. These agents can be considered as analogues of glyfoline or (±)1,2-dihydroxyacronycine derivatives. The key intermediates, 3,7-dioxopyrido[3,2,1-de]acridines (15a,b or 24a,b), for constructing the target compounds were synthesized either from 3-(N,N-diphenylamino)propionic acid (14a,b) by treating with Eaton’s reagent (P₂O₅/MsOH) (Method 1) or from (9-oxo-9H-acridin-10-yl)propionic acid (23a-c) via ring cyclization under the same reaction conditions (Method 2). Compounds 15a,b and 24a,b were converted into (±)3-hydroxy derivatives (25a-d), which were then further transformed into pyrido[3,2,1-de]acridin-7-one (28a-d) by treating with methanesulfonic anhydride in pyridine via dehydration. 1,2-Dihydroxylation of 28a-d afforded (±)cis-2,3-dihydroxy-7-oxopyrido[3,2,1-de]acridine (29a-d). Derivatives of (±)3-hydroxy (25a,b) and (±)cis-2,3-dihydroxy (29a-d) were further converted into their O-acetyl congeners 26a,b and 30a-d, respectively. We also synthesized 2,3-cyclic carbonate (31, 32, and 33) from 29a-c. The anti-proliferative study revealed that these agents exhibited low cytotoxicity in inhibiting human lymphoblastic leukemia CCRF-CEM cell growth in culture.     

Alkoxy substituted (E,E)-3,6-bis(styryl)pyridazine—a photosensitive mesogen for liquid crystals

(E,E)-3,6-Bis(styryl)pyridazines (3a-t) bearing 2, 4 or 6 alkoxy chains were prepared by applying the Siegrist reaction of 3,6-dimethylpyridazine (13) and the corresponding azomethines 10a-t. The transversal dipole moment of these calamitic compounds effects an extremely high tendency for self-organization in thermotropic LC phases (N, S_A, S_B, S_C, S_E, S_I/F, and Cub). The conjugated core structure represents moreover a chromophore with a high photosensitivity for (E,E)?(E,Z) isomerization reactions: this property makes the compounds interesting for optical imaging and switching techniques.     

Asymmetric synthetic study of macrolactin analogues

We designed two aromatic analogues 1a and 1b of macrolactin A with expectation of enhancing biological activity and metabolical stability. As a result of retrosynthetic analysis of these compounds 1a-b, two synthetic strategies have been examined. The first strategy includes the enantioselective addition of nonadienyl anion, derived from 3, to aldehyde 4 as a key step. The second one includes epimerization of ynone 7 to (E,E)-conjugated dienone 31 and subsequent diastereoselective hydride-reduction of 31. Although the former route furnished no desired target, the latter one was revealed to work well for the synthesis of 1. Unfortunately, the aimed (2Z,4E)-analogue 1a could not be synthesized due to an epimerization of the (2Z)-olefin into the (2E)-olefin. However, these methods could be applied to the total asymmetric synthesis of the (2E,4E)-analogue 1b. Overall, control of all of the four stereocenters was achieved by means of asymmetric and diastereoselective reactions without using any chiral natural sources.     

Diastereoselective route to (2R,5S)- and (2S,5S)-2-methyl-1,6-dioxaspiro[4.5]decane, a pheromone component of the wasp Paravespula vulgaris

A diastereoselective approach to (2R,5S)- and (2S,5S)-2-methyl-1,6-dioxaspiro[4.5]decane 1 and 1a is described. The route starts with an alkylation reaction among the cyclopentanone N,N-dimethylhydrazone 6 and the chiral iodides (R)-3 or (S)-3, derived from the enantiomers of ethyl β-hydroxybutyrate, controlling the estereocenter at C-2 of the molecules. The alkylated products 7 and 7a were easily transformed into the 1,8-O-TBS-1,8-dihydroxy-5-nonanones 9 and 9a in four steps, and a subsequent stereoselective spiroketalization, in acidic media, afforded a Z:E mixture (1:2) of compounds 1 and 1a.     

Stereoselective synthesis of 2-methylenepyrrolizidines by tandem cyclization of N-propargylaminyl radicals

Tandem cyclization of N-propargylaminyl radicals, generated by N-chlorination of (E)-alk-4-enylamines 2a-d and 2f followed by treatment with tributyltin radical, afforded 2-methylenepyrrolizidines 3a-d and 3f in a highly stereoselective manner. A similar radical cyclization of (Z)-N-propargyl-1-methyl-5-phenylpent-4-enylamine (2e) gave pyrrolizidine 3b having the same stereochemistry as that obtained from the E isomer 2b.     

Synthesis of arylated highly congested indans using a domino sequence

A novel and efficient regioselective synthesis of various arylated highly congested 7-aryl-5-methylsulfanylindan-4-carbonitriles (3a-f), methyl 7-aryl-5-methylsulfanylindan-4-carboxylates (10a-e) and 7-aryl-5-methylsulfanylindan-4-carboxylic acids (11a-e) through base-catalyzed reaction of 6-aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carbonitriles (1a-f) and methyl 6-aryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carboxylates (9a-e) by cyclopentanone (2) has been delineated. The synthetic potential of 2-pyranone was explored further to generate molecular diversity using 6-aryl-4-sec-amino-2-oxo-2H-pyran-3-carbonitriles (7a-h), 5,6-diaryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carbonitriles (5a,b) and methyl 5,6-diaryl-4-methylsulfanyl-2-oxo-2H-pyran-3-carboxylates (12a,b) as precursors for the ring transformation by cyclopentanone to assess the effects of substituents on the course of the reaction to obtain highly congested indans, 6,7-diaryl-5-methylsulfanylindan-4-carbonitriles (6a,b), 7-aryl-5-(piperidin-1-yl)indan-4-carbonitriles (8a-h) and methyl 6,7-diaryl-5-methylsulfanylindan-4-carboxylates (13a,b).     

Formation of chiral tertiary homoallylic alcohols via Evans aldol reaction or enzymatic resolution and their influence on the Sharpless asymmetric dihydroxylation

Enantioenriched tertiary homoallylic alcohol derivatives (S)-2c and (S)-2a were obtained via Evans aldol methodology and enzymatic resolution of racemic tertiary acetate 2e, respectively. In order to study asymmetric 1,3-induction of the stereogenic center present in 2, congener (R)-2a as well as its O-protected derivatives (R)-2b-d were submitted to Sharpless asymmetric dihydroxylation to yield the diastereomeric 1,2,4-triol derivatives (2R,4R)- and (2S,4R)-3a-d, revealing that neither the substrate nor the Sharpless catalyst exert any stereocontrol. Similar observations were made for the less bulky alkynyl-substituted derivative 12b. However, by using a directed dihydroxylation, the anti product (2R,4R)-3a was favored.     

A non-catalytic regioselective approach to the synthesis of (E)-stilbenes from suitably functionalized 2H-pyran-2-ones

Highly functionalized (E)-stilbenes 3a-m and 4-aryl-6-styryl-pyran-2-ylidineacetonitriles 4a-b have been prepared and delineated through the ring transformation of 6-aryl-3,4-disubstituted-2H-pyran-2-ones 1 with commercially available (E/Z)-4-phenyl-3-buten-2-one 2 without the use of any catalyst.     

Synthesis and evaluation of new chiral diols based on the dicyclopentadiene skeleton

The resolution by Lipase PS of rac-5 (from reduction of ketone 6, obtained from dicyclopentadiene with a new environment-friendly synthesis) gives (2S)-5, which was further reduced to the endo(2R)-1a alcohol. The endo(2S)-1b alcohol was obtained from camphor with a multistep synthesis. Pinacol couplings of 3a,b, carried out with Mg/Hg or Corey's general procedure respectively, afforded with high diastereoselectivity the C₂ symmetry diols (2R,2′R)-2a and (2S,2′S)-2b, with endo oriented OH functions. The enantiogenic power of the endo alcohol (2R)-1a and (2S)-1b and of the diols (2R,2′R)-2a and (2S,2′S)-2b was tested towards the LiAlH₄ reduction of acetophenone. The C₂ symmetry appears to play a fundamental role.     

Solid-state and solution photocycloadditions of 4-acyloxy-2-pyrones with maleimide

Solid-state photosensitized reactions of 4-acyloxy-2-pyrones (1b,c) with maleimide (2) afforded endo-endo double-[4+2] cycloadducts (3b,c) with high stereoselectivity. Sensitized photoreactions of 1a-d with 2 in solution gave exo-endo double-[4+2] cycloadducts (4a-d). 2-Pyrones 1a-d were photolyzed to give carboxylic acids (5a-d) via their valence isomerization in the solid state and in solution. Such kinds of photoreaction of the 4-acyloxy-2-pyrones were dramatically different from regio- and stereoselective [2+2] cycloadditions of 4-alkyloxy-2-pyrones. The photoreaction mechanisms of 1 with 2 and 1 itself were analyzed by powder X-ray diffraction analysis and MO calculations.     

Synthesis of naturally occurring diene and trienes by Te/Li exchange on (1Z,3Z)-butyltelluro-4-methoxy-1,3-butadiene

(1Z,3Z)-Butyltelluro-4-methoxy-1,3-butadiene 2 was obtained by the hydrotelluration of (Z)-1-methoxy-but-1-en-3-ynes 1. The butadienyllithium 3 obtained by the Te/Li exchange reaction in the (1Z,3Z)-1-butyltelluro-4-methoxy-1,3-butadiene 2 reacted with aldehydes to form the corresponding alcohols 4a-d with total retention of configuration. The alcohols formed undergo hydrolysis, resulting in the α,β,γ,δ-unsaturated aldehydes of (E,E) configuration, which are precursors of trienes obtained from natural sources. The products of this reaction were employed in the synthesis of methyl-(2E,4E)-decadienoate 7, which is a component of the flavor principles of ripe Bartlett pears. Performing the Wittig reaction of the methyl triphenylphosphorane with the deca-(2E,4E)-dienal 5a, we were able to synthesize the undeca-(1,3E,5E)-triene 6a. This compound is a sex-pheromone component of the marine brown algae Fucus serratus, Dictyopteris plagiograma, and Dictyopteris australis. Performing the Wittig reaction of methyl triphenylphosphorane with the octa-(2E,4E)-dienal 5c, the nona-(1,3E,5E)-triene 6b was synthesized. The compound obtained is a sex-pheromone component of the marine brown alga Sargassum horneri. The octa-(1,3E,5E)-triene 6c was easily obtained from hepta-(2E,4E)-dienal 5d by the Wittig reaction with methyl triphenylphophorane. This compound is a sex-pheromone component of the marine brown alga Fucus serratus.     

Effect of α-fluorination on asymmetric epoxidation of trans-olefins using α-fluorinated cyclohexanone dioxiranes

Epoxidations of trans-β-methylstyrene, trans-stilbene and trans-methyl p-methoxycinnamate using chiral dioxiranes derived from both enantiopure diastereomers of α-fluoro cyclohexanones, (2S, 5R)-3a-6a and (2R, 5R)-3e-6e are studied and compared. From ab initio calculations at the HF/6-31G^∗ level of conformational inter-conversion for (2S, 5R)-D5a and (2R, 5R)-D5e dioxiranes it was found that, due to the α-fluorine atom, conformer K1 is more stable in the case of (2S, 5R)-D5a while conformer K2 is more stable in the case of (2R, 5R)-D5e. However, in both cases, the more stable conformers, K1 and K2, undergo rapid inter-conversion. Therefore, based on slow epoxidation reactions and rapid ring inversion of six-membered ring dioxiranes the Curtin-Hammett principle holds. Conformation K2 with axial fluorine having been found to be more reactive, the inversion of configuration observed for the epoxides obtained with ketones 3e-6e (compared with ketones 3a-6a) could be rationalized from competitive reactions of K2 and K1 conformations leading to simultaneous production of both (−) and (+) epoxides in the case of ketones 3e-6e.     

Manganese(III) acetate based oxidative cyclizations of 3-oxopropanenitriles with conjugated alkenes and synthesis of 4,5-dihydrofuran-3-carbonitriles containing heterocycles

4,5-Dihydrofuran-3-carbonitriles 3a-i were obtained through oxidative cyclizations of 3-oxo-3-phenylpropanenitrile 1a, 3-oxo-3-thien-2-ylpropanenitrile 1b, 3-(2-furyl)-3-oxopropanenitirle 1c, 3-(1-benzofuran-2-yl)-3-oxopropanenitrile 1d, and 4,4-dimethyl-3-oxopropanenitrile 1e mediated manganese(III) acetate with 1,1-diphenyl-1-butene 2a and 1,2-diphenyl-1-pentene 2b. The treatments of these 3-oxopropanenitriles with 2-thienyl substituted alkenes such as 2-[(E)-2-phenylvinyl]thiophene 2c, 2-[(E)-1-methyl-2-phenylvinyl]thiophene 2d, and 2-(1-phenylvinyl)thiophene 2e formed 5-(2-thienyl)-4,5-dihydrofuran-3-carbonitriles 3j-r in good yields (45-93%). As a result, 2-thienyl substituted alkenes formed products in higher yields than phenyl substituted derivatives.