A concise total synthesis of (+)-deoxocassine and (−)-deoxoprosophylline from d-xylose

A concise total synthesis of (+)-deoxocassine (1) and (−)-deoxoprosophylline (2) has been achieved for the first time from d-xylose. The key steps involved in these synthesis are alkyl Grignard reaction, S_N2 substitution of mesylate by azide, Wittig reaction, and reductive amination.     

Regio- and stereoselective reactions of a rhodanine derivative with optically active 2-methyl- and 2-phenyloxirane

The reaction of a rhodanine derivative (=(Z)-5-benzylidene-3-phenyl-2-thioxo-1,3-thiazolidin-4-one; 1) with (S)-2-methyloxirane (2) in the presence of SiO₂ in dry CH₂Cl₂ for 10 days led to two diastereoisomeric spirocyclic 1,3-oxathiolanes 3 and 4 with the Me group at C(2) (Scheme 2). The analogous reaction of 1 with (R)-2-phenyloxirane (5) afforded also two diastereoisomeric spirocyclic 1,3-oxathiolanes 6 and 7 bearing the Ph group at C(3) (Scheme 3). The structures of 3, 4, 6, and 7 were confirmed by X-ray crystallography (Figs. 1 and 2). These results show that oxiranes react selectively with the thiocarbonyl group (CS) in 1. Furthermore, the nucleophilic attack of the thiocarbonyl S-atom at the SiO₂-activated oxirane ring proceeds with high regio- and stereoselectivity via an S_N2-type mechanism.     

Wittig reaction with ion-supported Ph3P

Ion-supported Ph₃P, 4-(diphenylphosphino)benzyltrimethylammonium bromide A and N-methyl-N-[4-(diphenylphosphino)benzyl]pyrrolidinium bromide B, were used for the Wittig reaction. Ion-supported phosphonium salts A1 and B1, which were prepared from the reactions of ion-supported Ph₃P A and B with ethyl bromoacetate, respectively, reacted with aromatic and aliphatic aldehydes in the presence of K₂CO₃ to give the corresponding α,β-unsaturated ethyl esters in good yields with high purity by simple filtration of the reaction mixture and subsequent removal of the solvent from the filtrate. Similarly, ion-supported phosphonium salts A2 and B2, which were prepared from the reactions of ion-supported Ph₃P A and B with p-methylbenzyl bromide, respectively, reacted with aromatic and aliphatic aldehydes in the presence of NaH to provide the corresponding p-methylstyrene derivatives in good yields with high purity by simple filtration of the reaction mixture and the subsequent removal of the solvent from the filtrate. In both reactions, the co-product, ion-supported Ph₃PO, could be obtained quantitatively by simple filtration, and was converted into the corresponding ion-supported Ph₃P A and B again in high yields using dimethyl sulfate, followed by the reduction with LiAlH₄. Recovered and regenerated ion-supported Ph₃P A and B could be reused for the same Wittig reaction while maintaining good yields of ethyl (E)-3-(4′-chlorophenyl)-2-propenoate and 1-(4′-chlorophenyl)-2-(4″-methylphenyl)ethene with high purity by simple filtration and removal of the solvent from the filtrate.     

Total synthesis of resolvin E2

Resolvin E2 (2) was synthesized stereoselectively using the C1-8 and C15-20 aldehydes 6 and 9, which were connected to the C9-14 fragment by using Wittig reactions. The aldehyde 6 was prepared from the γ-silyl alcohol (S)-20 by a sequence of reactions involving ozonolysis, oxidation with NaIO₄, and the Wittig reaction of the resulting aldehyde with Ph₃PCHCHO, whereas the aldehyde 9 was synthesized from the corresponding γ-silyl alcohol through epoxidation, reaction with Et₂AlCN, and reduction with DIBAL-H.     

Synthesis of polylactide using a zinc complex containing (S)-N-ethyl-N-phenyl-2-pyrrolidinemethanamine

The reaction between ZnCl₂ and (S)-N-ethyl-N-phenyl-2-pyrrolidinemethanamine (S-EPP) as a chiral ligand affords [ZnCl₂(S-EPP)], whose structure has been determined by X-ray crystallography. [ZnEt₂(S-EPP)] has demonstrated high activity toward the polymerization of rac-lactide with a maximum turnover frequency (TOF) of 121. Despite the intended stereocontrol by employing a chiral ligand, however, the observed heterotacticity was limited to under 0.6. The MWDs of the PLAs were found to be modulated by changing the solvent or controlling the concentration of the monomer in the solution. The glass transition temperature (T_g) was critically dependent on the MW within the narrow MWD regime, but the dependence became significantly shallow when the MWD was broadened.     

Synthesis of N-tosyl-3,3,4-trisubstituted pyrrolidine derivatives starting from the Baylis-Hillman adducts via radical cyclization

N-Tosyl-3,3-disubstituted-4-vinylpyrrolidine derivatives 3a-c were synthesized via radical cyclization from the modified Baylis-Hillman adducts 2. The required starting materials 2a-c were prepared in moderate yields from the Baylis-Hillman adducts in three steps: (i) acetylation of the Baylis-Hillman adducts, (ii) S_N2′ reaction with tosylamide to prepare 1, and (iii) alkylation with 1,4-dibromo-2-butene.     

A facile access to natural and unnatural dialkylsubstituted maleic anhydrides

A facile new route to the potential building blocks 2-bromomethyl-3-alkylmaleic anhydrides 15a/b for the synthesis of natural and unnatural dialkylsubstituted maleic anhydrides has been demonstrated, starting from dimethyl citraconate (9) via NBS-bromination, S_N2′ Grignard coupling reactions, hydrolysis, molecular bromine addition and dehydrative ring closure reactions pathway with 49-51% overall yield in 5-steps. Chemoselective allylic substitution of bromoatom in 15a/b with Grignard reagents has been described to obtain the unsymmetrical maleic anhydride 16 and symmetrically dialkylsubstituted maleic anhydrides 25a/b in 55% yield. The naturally occurring 2-carboxymethyl-3-hexylmaleic anhydride (1) has been synthesized from 16 via esterification, ozonolysis and an oxidation route. The synthesis of two naturally occurring 2-(β-carboxyethyl)-3-alkylmaleic anhydrides 2a/b have been completed via a chemoselective diethylmalonate coupling reaction followed by acid induced hydrolysis. In our hands the S_N2 or S_N2′ coupling of Grignard reagent with 21 to obtain 1 and Reformatsky reaction with 15a/b to obtain 2c/d met with failure.     

The first synthesis of (±)-brevione B, an allelopathic agent isolated from Penicillium sp.

Breviones A∼E (1∼5), allelopathic agents isolated from Penicillium brevicompactum Dierckx, are structurally unique pentacyclic or hexacyclic diterpenoid derivatives. The first synthesis of brevione B (2) was achieved by employing the double S_N2′-type tandem reaction as a key step.     

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.     

Reactions of P4S10 and pyPS2Cl with N,N′-diphenylurea and N,N′-diphenylthiourea

The reaction of P₄S₁₀ (1) with N,N′-diphenylurea (PhNH)₂CO (2) results in new heterocyclic compounds: the pyridinium salt of 1,3-diphenyl-2-sulfido-2-thioxo-1,3-diaza-2λ⁵-phosphetidine (3) (with a P–N–C–N cycle) and the pyridinium salt of 1,4-diphenyl-2,5-disulfido-2,5-dithioxo-1,4-dithiadiaza-2λ⁵,5λ⁵-diphosphinane (4), containing the (P–S–N)₂ cycle and the cyclic thiophosphates [pyH]₂[P₂S₈] (5), [pyH]₂[P₂S₇] (6) and [pyH]₃[P₃S₉] (7). A similar reaction, but carried out with N,N′-diphenylthiourea (PhNH)₂CS (8), leads to the formation of 4 and 6. pyPS₂Cl (9), used as an alternative starting material, also yields compounds 3, 4, 5, and further [pyH][PS₂Cl₂] (10) and S₈ after reaction with 2. Compound 3 reacts with Pd(CH₃COO)₂, with the formation of the complex [Pd(Ph₂N₂COPS₂)₂] (11). The crystal structures of 3 and 7 were determined by single-crystal X-ray diffraction.     

Synthesis and absolute configuration of brevione B, an allelochemical isolated from Penicillium sp.

Breviones A-E (1-5), allelochemicals isolated from Penicillium brevicompactum Dierckx, are structurally unique diterpenoid derivatives. The first synthesis of both enantiomers of brevione B (2) was accomplished by employing the double S_N2′-type tandem reaction as a key step, and the absolute configuration of the naturally occurring 2 was established.     

Syntheses of methylene-bridged ansa-zirconocene complexes and copolymerization studies of ethylene and norbornene

Methylene-bridged ansa-metallocene complexes bearing substituents on the cyclopentadienyl (Cp) and fluorenyl (Flu) moieties, namely methylene[9-(2,7-di-tert-butyl)fluorenyl(2-(1,3-dimethylcyclopentadienyl))]zirconium dichloride (1a) and its analogue, methylene[(9-(2,7-di-tert-butyl)fluorenyl(2-(1-methyl-3-phenyl)cyclopentadienyl))]zirconium dichloride (2a), have been prepared from (2,7-di-tert-butyl)-9-prop-2-ynyl-9H-fluorene (2). This procedure includes the use of 3-bromo-1-propyne which affords the methylene bridging unit by way of an intermolecular Pauson-Khand reaction in which norbornadiene and a pendant alkyne cyclize to form a ring that later becomes a substituted cyclopentadienyl group. Ethylene-norbornene (E-N) copolymerization was then carried out using these new complexes (1a and 1b) in the presence of methylaluminoxane (MAO) as a cocatalyst; these activities can be compared to that of isopropylene[9-fluorenyl-cyclopentadienyl]zirconium dichloride (3a). The activity of catalyst 1a was comparable to that of 3a but much higher than that of 2a. In addition, 1a shows higher norbornene insertion performance, and gives an E-N copolymer with a higher glass transition temperature (T_g) than 2a under identical conditions; both 1a and 2a give a lower T_g polymer than 3a does.     

Unsymmetrical double Wittig olefination on the syntheses of insect pheromones. Part 1: Synthesis of 5,9-dimethylpentadecane, the sexual pheromone of Leucoptera coffeella

An expeditious three-step synthesis of a mixture of stereoisomers of 5,9-dimethylpentadecane 1, the sexual pheromone of the coffee leaf miner Leucoptera coffeella, is described. The route employs an unsymmetrical double Wittig olefination to build the carbon skeleton of the molecule, as the key reaction. The bis-phosphonium salt 3, derived from 1,3-dibromopropane 2, reacted ‘one-pot’ with the ketones 2-octanone and 2-hexanone, affording the asymmetric diene 4. This was readily hydrogenated over Pd/C, furnishing pheromone 1 in 54% overall yield. Synthetic 1 showed high biological activity when tested in field experiments.     

Enantioselective synthesis of (1S,2S)-1,2-di-tert-butyl and (1R,2R)-1,2-di-(1-adamantyl)ethylenediamines

An enantioselective synthesis of sterically congested 1,2-di-tert-butyl and 1,2-di-(1-adamantyl)ethylenediamines has been developed. Thus, diastereomerically pure trans-1-apocamphanecarbonyl-4,5-dimethoxy-2-imidazolidinones 6 and 7 were successfully prepared by optical resolution of (±)-trans-4,5-dimethoxy-2-imidazolidinone using apocamphanecarbonyl chloride (MAC-Cl) followed by stereospecific and stepwise substitution of the dimethoxyl groups using tert-butyl or 1-adamantyl cuprates to provide (4S,5S)-4,5-di-tert-butyl and (4R,5R)-4,5-di-(1-adamantyl)-2-imidazolidinones 12 and 15, respectively. Furthermore, N-acetyl 4,5-di-tert-butyl and 4,5-di-(1-adamantyl)-2-imidazolidinones 16a,b were enantioselectively deacetylated using a catalytic oxazaborolidine system to provide enantiopure 1-p-tolylsulfonyl-4,5-di-tert-butyl-2-imidazolidinones 12 and 19 and 1-p-tolylsulfonyl-4,5-di-(1-adamantyl)-2-imidazolidinones 18 and 20, respectively. Finally, N-p-tolylsulfonyl-2-imidazolidinones 12 and 15 were treated with 30 equiv of Ba(OH)₂·8H₂O to achieve ring cleavage and to provide (1S,2S)-1,2-di-tert-butylethylenediamine 3 and (1R,2R)-1,2-di-(1-adamantyl)ethylenediamine 4.     

Synthesis of an octasubstituted galactose zinc(II) phthalocyanine

4,5-Bis(1,2:3,4-di-O-isopropylidene-α-d-galactopyranos-6-yl)phthalonitrile (3) was prepared by S_NAr reaction of diacetone galactose 1 and 4,5-difluorophthalonitrile (2) in 96% yield. Cyclotetramerization of 3 was achieved via its isoindoline derivative 4, affording the peripherally octasubstituted galactose zinc(II) phthalocyanine 5 in 29% yield. Deprotection of 5 gave the highly water soluble octasubstituted galactose zinc(II) phthalocyanine 6 in 81% yield which will be applied as a photosensitizer in photodynamic therapy.     

New synthesis of 3-arylpyrrolines

We present an easy and straightforward synthesis of 3-arylpyrrolines 4a-g by repeated treatment of 4-aryl-1,2,5,6-tetrahydropyridines 2a-g with m-chloroperoxybenzoic acid (MCPBA) and boron trifluoride etherate (BF₃-OEt₂). The transformation proceeds via epoxidation, ring contraction, Baeyer-Villiger oxidation and elimination reaction and affords 3-arylpyrrolines 4a-g with 61-70% yield. This facile strategy was also used to synthesize racemic baclofen (6).     

Reactivity of 2,3-bis(2-pyridyl)pyrazine with [Re2(CO)8(CH3CN)2]: Molecular structures of [Re2(CO)8(C14H10N4)] and [Re2(CO)8(C14H10N4)Re2(CO)8]

The reaction of the labile compound [Re₂(CO)₈(CH₃CN)₂] with 2,3-bis(2-pyridyl)pyrazine in dichloromethane solution at reflux temperature afforded the structural dirhenium isomers [Re₂(CO)₈(C₁₄H₁₀N₄)] (1 and 2), and the complex [Re₂(CO)₈(C₁₄H₁₀N₄)Re₂(CO)₈] (3). In 1, the ligand is σ,σ′-N,N′-coordinated to a Re(CO)₃ fragment through pyridine and pyrazine to form a five-membered chelate ring. A seven-membered ring is obtained for isomer 2 by N-coordination of the 2-pyridyl groups while the pyrazine ring remains uncoordinated. For 2, isomers 2a and 2b are found in a dynamic equilibrium ratio [2a]/[2b]  =  7 in solution, detected by ¹H NMR (−50 °C, CD₃COCD₃), coalescence being observed above room temperature. The ligand in 3 behaves as an 8e-donor bridge bonding two Re(CO)₃ fragments through two (σ,σ′-N,N′) interactions. When the reaction was carried out in refluxing tetrahydrofuran, complex [Re₂(CO)₆(C₁₄H₁₀N₄)₂] (4) was obtained in addition to compounds 1-3. The dinuclear rhenium derivative 4 contains two units of the organic ligand σ,σ′-N,N′-coordinated in a chelate form to each rhenium core. The X-ray crystal structures for 1 and 3 are reported.     

Convenient synthesis of 7-aryl-3,4,5,6-tetrahydro-2H-pyrido[4,5-b]- and [2,3-b]-1,5-oxazocine-6-ones

A convenient and diversity-oriented method for synthesis of the novel 7-aryl-3,4,5,6-tetrahydro-2H-pyrido[4,5-b]-1,5-oxazocine-6-one skeleton 1 and the very rarely described 7-aryl-3,4,5,6-tetrahydro-2H-pyrido[2,3-b]-1,5-oxazocine-6-one skeleton 2, featuring cyclization using nucleophilic aromatic substitution (S_NAr) and Suzuki coupling, is described.     

Synthesis and characterizations of N,N,N′,N′-tetrakis (diphenylphosphino)ethylendiamine derivatives: Use of palladium(II) complex as pre-catalyst in Suzuki coupling and Heck reactions

Oxidation of N,N,N′,N′-tetrakis(diphenylphosphino)ethylendiamine (1) with elemental sulfur and selenium gives the corresponding sulfide and selenide, respectively, [(Ph₂P(E))₂NCH₂CH₂N(P(E)Ph₂)₂] (E: S 1a, Se 1b). Complexes of 1 [(M₂Cl₄){(Ph₂P)₂NCH₂CH₂N(PPh₂)₂}] (M: Ni(II) 1c, Pd(II) 1d, Pt(II) 1e) were prepared by the reaction of 1 with NiCl₂ or [MCl₂(COD)] (M = Pd, Pt). The new compounds were characterized by NMR, IR spectroscopy and elemental analysis. The catalytic activity of Pd(II) complex 1d was tested in the Suzuki coupling reaction and Heck reaction. The palladium complex 1d catalyses the Heck reaction between styrene and aryl bromides as well as Suzuki coupling reaction between phenylboronic acid and arylbromides affording stilbenes and biphenyls in high yield, respectively.     

Investigations of the stereoselectivity of the intramolecular Diels-Alder reaction of a spiculoic acid model system

Model linear precursors to the spiculoic acids were prepared and underwent thermally induced IMDA reactions. The configuration of C5 in the stereotriad was found to dominate any inherent endo/exo selectivity of the IMDA reaction. The isomer (2E,5S)-20 underwent the IMDA to give the spiculoic acid stereochemistry in 84% yield and 94% ds. The required stereotriads were synthesised using stereoselective substrate-controlled aldol reactions; an anti-boron aldol reaction, controlled by the π-facial preference of (S)-2-benzoyloxypentan-3-one ((S)-27) led to (5R)-(22) and a syn-titanium aldol reaction, under the stereocontrol of a chiral N-acylthiazolidinethione (42) led to (5S)-(22). Chain extension using standard Wittig, HWE and ‘modified’ Julia olefinations installed the diene and dienophile components giving the linear precursors to the IMDA reactions.