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.     

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.     

Synthesis and properties of novel 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-triones: methodology for synthesizing cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates

Novel condensation reaction of tropone with N-substituted and N,N′-disubstitued barbituric acids in Ac₂O afforded 5-(cyclohepta-2′,4′,6′-trienylidene)pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (8a-f) in moderate to good yields. The ¹³C NMR spectral study of 8a-f revealed that the contribution of zwitterionic resonance structures is less important as compared with that of 8,8-dicyanoheptafulvene. The rotational barriers (ΔG^‡) around the exocyclic double bond of mono-substituted derivatives 8a-c were obtained to be 14.51-15.03 kcal mol⁻¹ by the variable temperature ¹H NMR measurements. The electrochemical properties of 8a-f were also studied by CV measurement. Upon treatment with DDQ, 8a-c underwent oxidative cyclization to give two products, 7 and 9-substituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborates (11a-c·BF₄⁻ and 12a-c·BF₄⁻) in various ratios, while that of disubstituted derivatives 8d-f afforded 7,9-disubstituted cyclohepta[b]pyrimido[5,4-d]furan-8(7H),10(9H)-dionylium tetrafluoroborate (11d-f·BF₄⁻) in good yields. Similarly, preparation of known 5-(1′-oxocycloheptatrien-2′-yl)-pyrimidine-2(1H),4(3H),6(5H)-trione derivatives (14a-d) and novel derivatives 14e,f was carried out. Treatment of 14a-c with aq. HBF₄/Ac₂O afforded two kinds of novel products 11a-c·BF₄⁻ and 12a,c·BF₄⁻ in various ratios, respectively, while that of 14d-f afforded 11d-f. The product ratios of 11a-c·BF₄⁻ and 12a-c·BF₄⁻ observed in two kinds of cyclization reactions were rationalized on the basis of MO calculations of model compounds 20a and 21a. The spectroscopic and electrochemical properties of 11a-f·BF₄⁻ and 12a-c·BF₄⁻ were studied, and structural characterization of 11c·BF₄⁻ based on the X-ray crystal analysis and MO calculation was also performed.     

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.     

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.     

The stereoselective synthesis of (E)-octafluoro-1,3,5-hexatriene and (3E,5E,7E)-dodecafluoro-1,3,5,7,9-decapentaene

(E)-(1,2-Difluoro-1,2-ethenediyl)bis[tributylstannane], 3, readily undergoes a Pd(PPh₃)₄/CuI-catalyzed cross-coupling reaction with iodotrifluoroethene to yield (E)-octafluoro-1,3,5-hexatriene, 4, in high isomeric purity. (1Z,3E,5Z)-(1,2,3,4,5,6-Hexafluoro-1,3,5-hexenetriyl)bis[tributylstannane], 7, was sequentially prepared from (1Z,3E,5Z)-(1,2,3,4,5,6-hexafluoro-1,3,5-hexenetriyl)bis[triethylsilane], 5, which was prepared via a Pd(PPh₃)₄/CuI-catalyzed cross-coupling reaction of 3 with (E)-1,2-difluoro-1-iodo-2-triethylsilylethene, 6. Pd(PPh₃)₄/CuI cross-coupling of 7 with iodotrifluoroethene gave (3E,5E,7E)-dodecafluoro-1,3,5,7,9-decapentaene, 8.     

SEAr-SNAr couplings of indolizines and related pyrrole derivatives with superelectrophilic nitrobenzoxadiazoles

The nucleophilic aromatic substitutions of 7-chloro-4,6-dinitrobenzofurazan (DNBZ-Cl) and 7-chloro-4,6-dinitrobenzofuroxan (DNBF-Cl) with a series of differently substituted indolizines (5a-f) and a series of dihyropyrroloisoquinolines (11a-f) have been investigated. In accord with previous reports emphasizing the superelectrophilic character of these compounds in σ-complexation processes, DNBZ-Cl and DNBF-Cl react very readily and quantitatively with the weak carbon nucleophiles 5a-f and 11a-f at room temperature in acetonitrile. In the case of DNBZ-Cl, the resulting products (7Z,a-f and 12Z,a-f) are those expected from the displacement of the chlorine atom through a S_EAr-S_NAr mechanism. A significant result is that these compounds, despite the lack of coplanarity of the two rings, are characterized by an intense intramolecular charge transfer between the donor pyrrole-type moiety and the electron-deficient acceptor DNBZ moiety. Contrasting with this behaviour, the DNBF-Cl reactions show a totally different pattern, proceeding with loss of the N-oxide functionality and expansion of the pyrrole moiety to afford stable zwitterionic spiro adducts (8F,a-f and 13F,a-f) of a so far unknown type. Rapid NMR recordings have revealed that the formation of these adducts occurs after initial formation of the expected substitution products 7F,a-f and 12F,a-f. A mechanism accounting for the overall rearrangement leading to the spirobenzofurazan adducts is suggested. It is based on an initial nucleophilic attack of the oxygen atom of the N-oxide functionality at the electron-deficient and strongly olefinic C-C coupling bond generated by the aforementioned intramolecular charge transfer. This results in the formation of an unstable five-membered isoxazole ring whose decomposition goes along with loss of the N-oxide functionality and enlargement of the pyrrole moiety into a pyridine one. Also discussed are the factors accounting for the high thermodynamic stability of the spiro adducts, and their relevance to the stability of previously reported spiro adducts.     

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.     

Regioselective Baeyer-Villiger lactonization of 2-substituted pyrrolidin-4-one. Synthesis of statine

Nine 2-substituted pyrrolidin-4-ones 4a-i were obtained via a series of functional group transformation of known prolinol 5 by facile six kinds of methodologies. The target structure of 1,3-amino alcohols 2a-i was constructed in the regioselective Baeyer-Villiger lactonization of ketones 4a-i and reduction of the resulting 4-substituted tetrahydro-1,3-oxazin-6-ones 3a-i. A new and straightforward synthesis of (3S,4S)-statine (6) has been established starting from trans-(2S,4R)-4-hydroxyproline (1).     

Alternative synthesis of cystothiazole A

Palladium-catalyzed methoxycarbonylation of (−)-(2R,3S)-1-tert-butyldimethylsiloxy-3-methyl-2-methoxypenta-4-yne 9 derived from (2R,3S)-epoxy butanoate 5 gave the acetylenic ester 10, which was treated with MeOH in the presence of Bu₃P to afford selectively (Z)-β-methoxy acrylate congener 11 in 86% yield. Treatment of (Z)-11 with 99.8% enrichment of CDCl₃ followed by consecutive desilylation and oxidation afforded the left-half aldehyde (+)-2. The overall yield (10 steps from 5; 23%) of (+)-2 via the present route was improved in comparison to that (10 steps from 5; 10%) of the previously reported route. By applying the modified Julia's coupling method, selectivity (E/Z=14:1) of the (E)-form (cystothiazole A 1) against the (Z)-form was improved in comparison to the Wittig method (E/Z=4:1 to 6.9:1).     

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.     

Salen-ligands based on a planar-chiral hydroxyferrocene moiety: Synthesis, coordination chemistry and use in asymmetric silylcyanation

Condensation of the O-protected hydroxyferrocene carbaldehyde (S_p)-1 with suitable diamines, followed by liberation of the hydroxyferrocene moiety leads to a new type of ferrocene-based salen ligands (3). While the use of ethylenediamine in the condensation reaction yields the planar-chiral ethylene-bridged ligand [(S_p,S_p)-3a], reaction with the enantiomers of trans-1,2-cyclohexylendiamine gives rise to the corresponding diastereomeric cyclohexylene-bridged systems [(S,S,S_p,S_p)-3b and (R,R,S_p,S_p)-3c], which feature a combination of a planar-chiral ferrocene unit with a centrochiral diamine backbone. Starting with the ferrocene-aldehyde derivative (R_p)-1, the enantiomeric ligand series (3d/e/f) is accessible via the same synthetic route.The (S_p)-series of these newly developed N₂O₂-type ligands was used for the construction of the corresponding mononuclear bis(isopropoxy)titanium (4a/b/c), methylaluminum (5a/b/c) and chloroaluminum-complexes (6a/b/c), which were isolated in good yields and identified by X-ray diffraction in several cases. The aluminum complexes (5/6) were successfully used in the Lewis-acid catalyzed addition of trimethylsilylcyanide to benzaldehyde, yielding the corresponding cyanohydrins in 45-62% enantiomeric excess.     

Rhodium(I) complexes with κP coordinated ω-phosphinofunctionalized alkyl phenyl sulfide, sulfoxide and sulfone ligands and their reactions with sodium bis(trimethylsilyl)amide and Ag[BF4]

Reactions of ω-diphenylphosphinofunctionalized alkyl phenyl sulfides Ph₂P(CH₂)_nSPh (n = 1, 1a; 2, 2a; 3, 3a), sulfoxides Ph₂P(CH₂)_nS(O)Ph (n = 1, 1b; 2, 2b; 3, 3b) and sulfones Ph₂P(CH₂)_nS(O)₂Ph (n = 1, 1c; 2, 2c; 3, 3c) with dinuclear chlorido bridged rhodium(I) complexes [(RhL₂)₂(μ-Cl)₂] (L₂ = cycloocta-1.5-diene, cod, 4; bis(diphenylphosphino)ethane, dppe, 5) afforded mononuclear Rh(I) complexes of the type [RhCl{Ph₂P(CH₂)_nS(O)_xPh-κP}(cod)]¹ (n/x = 1/0, 6a; 1/1, 6b; 1/2, 6c; 2/0, 8a; 2/1, 8b; 2/2, 8c; 3/0, 10a; 3/1, 10b; 3/2, 10c) and [RhCl{Ph₂P(CH₂)_nS(O)_xPh-κP}(dppe)] (n/x = 1/0, 7a; 1/1, 7b; 1/2, 7c; 2/0, 9a; 2/1, 9b; 2/2, 9c; 3/0, 11a; 3/1, 11b; 3/2, 11c) having the P^S(O)_x ligands κP coordinated. Addition of Ag[BF₄] to complexes 6-11 in CH₂Cl₂ led with precipitation of AgCl to cationic rhodium complexes of the type [Rh{Ph₂P(CH₂)_nS(O)_xPh-κP,κS/O}L₂][BF₄] having bound the P^S(O)_x ligands bidentately in a κP,κS (13a-18a, 15b-18b) or a κP,κO (13b, 14b, 13c-18c) coordination mode. Unexpectedly, the addition of Ag[BF₄] to 6a in THF afforded the trinuclear cationic rhodium(I) complex [Rh₃(μ-Cl)(μ-Ph₂PCH₂SPh-κP:κS)₄][BF₄]₂·4THF (12·4THF) with a four-membered Rh₃Cl ring as basic framework. Addition of sodium bis(trimethylsilyl)amide to complexes 6-11 led to a selective deprotonation of the carbon atom neighbored to the S(O)_x group (α-C) yielding three different types of organorhodium complexes: a) Organorhodium intramolecular coordination compounds of the type [Rh{CH{S(O)_xPh}CH₂CH₂PPh₂-κC,κP}L₂] (22a-c, 23a-c), b) zwitterionic complexes [Rh{Ph₂PCHS(O)_xPh-κP,κS/O}L₂] having κP,κS (21a, 21b) and κP,κO (20b/c, 21c) coordinated anionic [Ph₂PCHS(O)_xPh] ligands, and c) the dinuclear rhodium(I) complex [{Rh{μ-CH(SPh)PPh₂-κC:κP}(cod)}₂] (19). All complexes were fully characterized spectroscopically and complexes 15b, 15c, 12·4THF and 19·THF additionally by X-ray diffraction analysis. DFT calculations of zwitterionic complexes gave insight into the coordination mode of the [Ph₂PCHS(O)Ph] ligand (κP,κS versus κP,κO).     

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).     

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.     

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).     

An efficient microwave assisted synthesis of novel class of Rhodanine derivatives as potential HIV-1 and JSP-1 inhibitors

(Z)-5-(2-(1H-Indol-3-yl)-2-oxoethylidene)-3-phenyl-2-thioxothiazolidin-4-one (7a-q) derivatives have been synthesized by the condensation reaction of 3-phenyl-2-thioxothiazolidin-4-ones (3a-h) with suitably substituted 2-(1H-indol-3-yl)-2-oxoacetaldehyde (6a-d) under microwave condition. The thioxothiazolidine-4-ones were prepared from the corresponding aromatic amines (1a-e) and di-(carboxymethyl)-trithiocarbonyl (2). The aldehydes (6a-h) were synthesized from the corresponding acid chlorides (5a-d) using HSnBu₃.     

Synthesis of (3′R,5′S)-3′-hydroxycotinine using 1,3-dipolar cycloaddition of a nitrone

To synthesize (3′R,5′S)-3′-hydroxycotinine [(+)-1], the main metabolite of nicotine (2), cycloaddition of C-(3-pyridyl)nitrones 3a, 3c, and 15 with (2R)- and (2S)-N-(acryloyl)bornane-10,2-sultam [(2R)- and (2S)-8] was examined. Among them, l-gulose-derived nitrone 15 underwent stereoselective cycloaddition with (2S)-8 to afford cycloadduct 16, which was elaborated to (+)-1.     

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.     

First total synthesis of fumaridine

The first total synthesis of the alkaloid fumaridine 1a is reported. The key step is the assemblage of the arylmethylene isoindolinone 2a (E) by Horner reaction between the phosphorylated isoindolinone 3a and the suitably substituted benzaldehyde 4. N-Lactam deprotection and concomitant E→Z isomerization complete the synthesis of the title compound.