Regio- and stereoselective cycloadditions of (1Z,4R,5R)-1-arylmethylidene-4-benzoylamino-3-oxo-5-phenylpyrazolidin-1-ium-2-ides to methyl methacrylate

[3+2] Cycloadditions of (1Z,4R^∗,5R^∗)-1-arylmethylidene-4-benzoylamino-3-oxo-5-phenylpyrazolidin-1-ium-2-ides 1a-e to methyl methacrylate gave the 1-CO₂Me regioisomers 3/3′, exclusively, in 1-67% yields. Stereocontrol was dependent on the ortho-substituents at the 1′-aryl group in dipole 1: ortho-unsubstituted dipoles 1a-c gave the major (1R^∗,3R^∗,5R^∗,6R^∗)-isomers 3a-c, whilst ortho-disubstituted dipoles gave the major (1R^∗,3S^∗,5R^∗,6R^∗)-isomers 3′d,e. The structures of cycloadducts were determined by NMR and X-ray diffraction.     

Synthetic studies directed toward amphidinol 2: elucidation of the relative configuration of the C1-C10 fragment

Model compounds (11 and 12) for the C1-C10 tetrahydropyran fragment of amphidinol 2 were prepared from (2S)-benzyloxypropanal in 9 steps. The synthetic route relied on diastereoselective diene-aldehyde cycloaddition, stereoselective C-allylation, and reagent based enantioselective aldehyde allylation. Comparison of the NMR spectra for models 11 and 12 with that for amphidinol 2 indicated that the C1-C10 segment of the natural product possesses the 2R^∗,4R^∗,6R^∗,7S^∗,8R^∗,10S^∗relative configuration.     

Unexpected cleavage of the N-N bond in the reactions of 3-pyrazolidinone-1-azomethine imines with HCN

Treatment of (1Z,4R^∗,5R^∗)-1-arylmethylidene-4-benzamido-5-phenylpyrazolidin-3-one 1-azomethine imines 4a-d with potassium cyanide in the presence of acetic acid resulted in addition of HCN to the exocyclic CN double bond followed by β-eliminative N-N single bond cleavage (ring opening) to give the N-[(1R^∗,2R^∗)-3-amino-2-benzamido-3-oxo-1-phenylpropyl]benzimidoyl cyanides 6a-d in 28-85% yields. Reaction of dipole 4e with HCN furnished stable intermediate, (1′S^∗,4R^∗,5R^∗)-4-benzamido-1-[cyano(mesityl)methyl]-5-phenylpyrazolidin-3-one (5e), in 76% yield. The structure of compound 6c was determined by X-ray diffraction.     

The intramolecular aromatic nucleophilic substitution as a route to tricyclic β-lactams. Synthesis of the novel 4-oxa-7-azabicyclo[4.2.0]octane skeleton

Sodium borohydride-carbonyl reduction of the novel 3-(2-fluoro-5-nitro) phenyl-4-benzoyl-2-azetidinones 3 and 7 gave quantitatively the stereoisomeric carbinols (4R^∗,5S^∗)-4 and (4R^∗,5R^∗)-5. Treatment of the latter with sodium hydride gave the title compounds 8 and 9, respectively, with good overall yield. The rationale of the stereochemical relationships outlined in the sequences 3 (or 7)→4→8 and 3 (or 7)→5→9 is given according to the conformational and keto-enol equilibria of the reactant(s).     

A mechanistic study on the intramolecular ionic Diels-Alder reaction of 2-methyl-3,9,11-tridecatriene-2-ol and 2,11-dimethyl-1,3,9,11-dodecatetraene

Intramolecular ionic Diels-Alder reaction of 2-methyl-3,9,11-tridecatriene-2-ol (1) was studied under acidic conditions. Treatment of 2-methyl-3,9,11-tridecatriene-2-ol (1) with trifluoromethanesulfonic acid yielded 7-methyl-8-isopropenyl-1,2,3,4,4aR^∗,7R^∗,8R^∗,8aS^∗-octahydronaphthalene (4) and (1Z)-1-((E)-but-2-enylidene)-2-(2-methylpropenyl)cyclohexane (5) through regioselective intramolecular ionic Diels-Alder reaction. The reaction appeared to proceed partly through a stepwise mechanism involving a carbocation intermediate. However, a concerted pathway rather than a stepwise one is suggested to be involved in the acid-catalyzed intramolecular Diels-Alder reaction of 2,11-dimethyl-1,3,9,11-dodecatetraene (13).     

Studies on the factors controlling the stereoselectivity in electrophilic iodocyclization of alkylidenecyclopropyl ketones

An efficient electrophilic iodocyclization of alkylidenecyclopropyl ketones with N-iodosuccinimide (NIS) or I₂ in aqueous CH₃CN affording 3-oxabicyclo[3.1.0]hexan-2-ols is described. NIS is a better electrophilic iodocyclization reagent than I₂. Four chiral centers were formed within one step. The stereochemistry was established by the X-ray diffraction studies of compounds 2e-2h, 2n, and 2c. It is quite interesting to observe that the substituent of the cyclopropane ring plays an important role in determining the relative stereochemistry at the 4-position: with R² being an acyl or ester group a mixture of (1S^∗,2R^∗,4S^∗,5R^∗)-2 (major) and (1R^∗,2R^∗,4R^∗,5R^∗)-2 (minor) was formed with moderate selectivity while the reaction of the substrates with R² being sulfonyl and p-methylphenylsulfonyl or R¹ being phenyl afforded (1R^∗,2R^∗,4S^∗,5S^∗)-2 or (1S^∗,2R^∗,4S^∗,5R^∗)-2f as the only product. The reaction is general for a range of different substrates to afford the products in moderate to high yields.     

Synthesis of butenolides recently isolated from marine microorganisms

The syntheses and ¹³C NMR analyses of four diastereomeric butenolides, two of which were recently isolated from the marine microorganisms Streptomycete B 5632 and Streptoverticillium luteoverticillatum 11014 are described. The two isolated butenolides were found to be one of the two diastereomers (4S,10R^∗,11R^∗)-4,11-dihydroxy-10-methyl-dodec-2-en-1,4-olide (RRS-1 or SSS-1) and one of the two diastereomers (4S,10S^∗,11R^∗)-4,11-dihydroxy-10-methyl-dodec-2-en-1,4-olide (SRS-1 or RSS-1). An asymmetric 1,3-dipolar cycloaddition of a thiocarbonyl ylide with a dipolarophile attached to camphorsultam and a ring-opening of an enantiomerically pure vinyloxirane by lithiated dithiane served as key steps for the construction of the three stereogenic centres. Further elaborations including ring-closing metathesis and Mitsunobu inversion furnished the four diastereomeric butenolides.     

Synthesis and stereochemical studies of 1- and 2-phenyl-substituted 1,3-oxazino[4,3-a]isoquinoline derivatives

Starting from the 1′- or 2′-phenyl-substituted 1-(2′-hydroxyethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline diastereomers 3 and 6, 4-unsubstituted and 4-(p-nitrophenyl)- and 4-oxo-substituted 1-phenyl- and 2-phenyl-9,10-dimethoxy-2H,4H-1,6,7,11b-tetrahydro-1,3-oxazino[4,3-a]isoquinolines (7-12) were prepared. The relative configurations and the predominant conformations of the products were determined by NMR spectroscopy, by quantum chemical calculations and, for (2R^∗,4S^∗,11bR^∗)-9,10-dimethoxy-4-(p-nitrophenyl)-2-phenyl-2H,4H-1,6,7,11b-tetrahydro-1,3-oxazino[4,3-a]isoquinoline (11), by X-ray diffraction.     

Total synthesis of (±)-luminacin D

A 15-step synthesis of (±)-luminacin D from ethyl pent-2-ynoate is reported. The pivotal step involves the formation of the central C-2′/C-3′ bond of the natural product by condensation of the titanium enolate derived from aromatic ketone 1 with aldehyde 2a. A remote asymmetric centre in aldehyde 2a exerts control over the stereochemical course of this reaction, with the major adduct (3a, 54% yield) possessing the required (2′S^∗,3′R^∗,5′R^∗)-stereochemistry. This assignment was unambiguously established by X-ray crystallography of late stage synthetic intermediate, 17. Further manipulation of 3a (six steps) yielded synthetic (±)-luminacin D spectroscopically identical to material isolated from Streptomyces sp. Mer-VD1207 by Naruse et al.     

Preparation of both enantiomers of β-(3,4-dihydroxybenzyl)-β-alanine, higher homologues of Dopa

β²-(3,4-Dihydroxybenzyl)-β-alanine [β²-Homo-Dopa, 1] is a novel β-amino acid homologue of Dopa, the most successful therapeutic agent in the treatment of Parkinson's disease. Enantioenriched (R)-1 and (S)-1 were obtained via the diastereoselective alkylation of enantiopure pyrimidinone (R)- and (S)-3, chiral derivatives of β-alanine, with veratryl iodide. The major diastereomeric products (2S,5R)-4 and (2R,5S)-4 were hydrolyzed with 57% HBr, and the desired β-amino acids were purified by silica gel chromatography. Alternatively, enantioenriched (R)- and (S)-1 were prepared by means of the highly diastereoselective alkylation (3,4-dimethoxybenzyl iodide) of open-chain β-aminopropionic acid derivatives (R,R,S)-8 and (S,S,R)-8 containing the chiral auxiliary α-phenylethylamine. Finally, nearly enantiopure (R)- and (S)-1 were obtained by resolution of racemic N-benzyloxycarbonyl-2-(3,4-dibenzyloxybenzyl)-3-aminopropionic acid, rac-12, with (R)- or (S)-α-phenylethylamine, followed by catalytic hydrogenolysis.     

New isomers of 4,1-benzothiazepines. The first evidence for the desmotropy of seven-membered heterocycles

A novel procedure was developed for the preparation of 2,3-disubstituted 4,1-benzothiazepines, via the ring transformation of (2R^∗,2aS^∗)-2-chloro-2a-phenyl-2,2a-dihydro-2H,4H-azeto[1,2-a][3,1]benzothiazin-1-one (1) with sodium ethoxide in ethanol. The tautomeric products (R^∗)-3-ethoxycarbonyl-2-phenyl-3,5-dihydro-4,1-benzothiazepine (4) and 3-ethoxycarbonyl-2-phenyl-1,5-dihydro-4,1-benzothiazepine (5) exhibit the rare phenomenon of desmotropy of the condensed seven-membered heterocycles. Surprisingly, these desmotropes could be separated by column chromatography. The products are unexpectedly stable in solution and their structures were proved by means of NMR and mass spectrometry.     

Reactions of hafnocene stannyl complexes with stannanes: implications for the mechanism of the metal-catalyzed dehydropolymerization of secondary stannanes

Reactions of the hydrostannyl complexes CpCp^∗Hf(SnHMes₂)Cl (2), [Me₂C(C₅H₄)₂]Hf(SnHMes₂)NMe₂ (3) and CpCp^∗Hf(SnHMes₂)OMe (4) with Ph₂SnH₂ or ⁿBu₂SnH₂ afforded poly- and oligostannanes of varying molecular weights. The reaction of 2 with 1.2 equiv. of Ph₂SnH₂ produced the oligostannyl complexes CpCp^∗Hf(SnPh₂SnHMes₂)Cl (6, 68%), CpCp^∗Hf(SnPh₂SnHPh₂)Cl (7, 15%), and CpCp^∗Hf(SnPh₂SnPh₂SnHPh₂)Cl (8, 7%), which may be intermediates in the dehydropolymerization process. Compounds 7 and 8 were observed in higher yields in the reaction of CpCp^∗Hf(H)Cl (1) with 2 equiv. of Ph₂SnH₂. Possible mechanisms for the formation of 6, 7, and 8 are discussed. Two trialkylstannyl complexes, CpCp^∗Hf(SnMe₃)Cl (11) and CpCp^∗Hf(SnⁿBu₃)Cl (12), were synthesized in good yields from the reaction of 1 with R₃SnH (R=Me, ⁿBu). When a solution of 11 was heated to 100 °C for 1 h, CpCp^∗Hf(SnMe₂SnMe₃)Cl (13) and CpCp^∗Hf(SnMe₂SnMe₂SnMe₃)Cl (14) were formed, probably via Me₂Sn insertion into Hf-Sn bonds. Based on the known influence of catalyst structure on the molecular weight of polystannanes, and the observations reported herein, it is proposed that the Sn-Sn bond-forming mechanism may involve R₂Sn insertions into M-Sn bonds.     

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.     

Synthesis and characterization of half-sandwich Rh, Ir complexes containing mono-thiolate-ortho-carborane ligand

Two binuclear complexes [Cp^∗M(Cl)Carb^S]₂ (Cp^∗ = η⁵-C₅Me₅, M = Rh (1a), Carb^S = SC₂(H)B₁₀H₁₀, Ir (1b)) were synthesized by the reaction of LiCarb^S with the dimeric metal complexes [Cp^∗MCl(μ-Cl)]₂ (M = Rh, Ir). Four mononuclear complexes Cp^∗M(Cl)(L)Carb^S (L = BuⁿPPh₂, M = Rh (2a), Ir (2b); L = PPh₃, M = Rh (4a), Ir (4b)) were synthesized by reactions of 1a or 1b with L (L = BuⁿPPh₂ (2); PPh₃ (4)) in moderate yields, respectively. Complexes 3a, 3b, 5a, 5b were obtained by treatment of 2a, 2b, 4a, 4b with AgPF₆ in high yields, respectively. All of these compounds were fully characterized by IR, NMR, and elemental analysis, and the crystal structures of 1a, 1b, 2a, 2b, 4a, 4b were also confirmed by X-ray crystallography. Their structures showed 3a, 3b and 5a, 5b could be expected as good candidates for heterolytic dihydrogen activation. Preliminary experiments on the dihydrogen activation driven by these half-sandwich Rh, Ir complexes were done under mild conditions.     

Diastereoselective synthesis of new polyhydroxylated indolizidines from (l)-glutamic acid

A diastereoselective synthesis of two new swainsonine's analogues 1a and 1b with the piperidine ring fused to a phenyl nucleus at C6-C7, namely (1R, 2S, 10R, 10aR)-(+)-1,2,10-trihydroxy-1,2,3,5,10,10a-hexahydrobenzo[f] indolizine (1a) and (1S, 2R, 10R, 10aR)-(+)-1,2,10-trihydroxy-1, 2, 3, 5, 10, 10a-hexahydrobenzo[f] indolizine (1b), is described. Throughout this work, the effectiveness of the tricyclic indolizidine dione 5, readily available in three steps from the cheap l-glutamic acid, as an attractive platform for chemo- and stereodivergent transformations is illustrated. The key steps involved totally diastereoselective ketone reduction of compound 5 and catalytic cis-dihydroxylation of the unsaturated amide 10. The synthetic strategy also allowed for the diastereoselective synthesis of benzoanalogues of the 1,8a-di-epi-lentiginosine 3a ((1R, 2S, 10aR)-(+)-1,2-dihydroxy-1, 2, 3, 5, 10, 10a-hexahydrobenzo[f]indolizine) and 2,8a-di-epi-lentiginosine 3b ((1S, 2R, 10aR)-(+)-1,2-dihydroxy-1,2,3,5,10,10a-hexahydrobenzo[f]indolizine).     

Design, synthesis and conformational analysis of turn inducer cyclopropane scaffolds: microwave assisted amidation of unactivated esters on catalytic solid support to obtain γ-turn mimic scaffolds

Novel constrained 1-aroyl-cyclopropane-2,3-cis-dicarboxylic acid bis-[(2-hydroxy-ethyl)-amides] (17a-e) with varied torsional angles have been synthesized in high yield from unactivated esters of 1-aroyl-2,3-cis-diethoxycarbonylcyclopropanes (15a-e) on a catalytic solid support with reduced reaction times by using the monomode-microwave irradiation; 15a-e were obtained by diastereoselective ethoxycarbonylmethylene transfer from a sulfur ylide to ethyl β-aroylacrylates (10a-e). Torsional angles and interatomic distance measurements on the energy minimized structures of the obtained molecules (17a-e, DFT, B3LYP/6-31G^∗ level) have established these molecules as valuable γ-turn mimic scaffolds.     

Syntheses and coordination behaviour of 2-(ortho-phosphinophenyl)-functionalised 1,3-dioxolanes and 1,3-dioxanes towards a [(COD)Rh]-complex fragment - models for immobilised complexes

The syntheses are reported of the ether-phosphine ligands: 2-(ortho-diphenylphosphinophenyl)-1,3-dioxolane (1a), 2-(ortho-diisopropylphosphinophenyl)-1,3-dioxolane (1b), 2-(ortho-diphenylphosphinophenyl)-1,3-dioxane (1c), 2-(ortho-diisopropylphosphinophenyl)-1,3-dioxane (1d). Their reaction with [(COD)RhCl]₂ (COD: 1,5-cyclooctadiene) results in the formation of the mononuclear complexes: {chloro(COD)[2-(ortho-diphenylphosphinophenyl)-1,3-dioxolane]rhodium(I)} (2a), {chloro(COD)[2-(ortho-diisopropylphosphinophenyl)-1,3-dioxolane]rhodium(I)} (2b), {chloro(COD)[2-(ortho-diphenylphosphinophenyl)-1,3-dioxane]rhodium(I)} (2c), and {chloro(COD)[2-(ortho-diisopropylphosphinophenyl)-1,3-dioxane]rhodium(I)} (2d). The chloride ligands of compounds 2a and 2b were abstracted with TlPF₆, with accompanied insertion of an acetal oxygen atom of the ligands 1a and 1b into the coordination sphere of the metal centre, producing {(COD)[η²-P,O-2-(ortho-diphenylphosphinophenyl)-1,3-dioxolane]rhodium(I)}PF₆ (3a∗PF₆) and {(COD)[η²-P,O-2-(ortho-diisopropylphosphinophenyl)-1,3-dioxolane]rhodium(I)}PF₆ (3b∗PF₆). In contrast the dioxane analogues of 3, 3c∗BF₄ and 3d∗BF₄, were formed by reacting the ligands 1c, 1d with [Rh(COD)₂]BF₄. The ligands 1 and the complexes 2 serve as model compounds for their via acetalation to a polyvinylalcohol resin bound analogues. The complexes synthesised were employed as pre-catalysts in the hydroformylation reaction of 1-octene.     

H and C NMR assignments of the three dicyclopenta-fused pyrene congeners

Complete ¹H and ¹³C NMR assignments of the (di-)cyclopenta-fused pyrene congeners, cyclopenta[cd]- (2), dicyclopenta[cd,fg]- (3), dicyclopenta[cd,jk]- (4) and dicyclopenta[cd,mn]pyrene (5), respectively, are achieved using two-dimensional (2D) NMR spectroscopy. The experimental ¹³C chemical shift assignments are compared with computed ab initio CTOCD-PZ2/6-31G^∗∗13C chemical shifts; a satisfactory agreement is found. Substituent-induced chemical shifts in the pyrene core induced by annelation of cyclopenta moieties are discussed. Effects of dicyclopenta topology on electronic structure are illustrated for 3-5.     

Insertion of nitrene and chalcogenolate groups into the Ir-C σ bond in a cyclometalated iridium(III) complex

Treatment of [Cp∗Ir(ppy)Cl] (Cp∗ = η⁵-C₅Me₅, ppyH = 2-(2-pyridyl)phenyl) with Ag(OTf) (OTf⁻ = triflate) in MeOH and MeCN gave the solvento complexes [Cp∗Ir(ppy)(solv)][OTf] (solv = MeOH (1) and MeCN (2)). Complex 1 is capable of catalyzing oxidation and azirdination of styrene with PhIO and PhINTs (Ts = tosyl), respectively. Treatment of 2 with a stoichiometric amount of PhINTs resulted in the insertion of the NTs group into the Ir-C(ppy) bond and formation of [Cp∗Ir(η²-ppy-NTs)(MeCN)][OTf] (3). Treatment of 1 with R₂E₂ afforded [Cp∗Ir(ppy)(η¹-R₂E₂)][OTf] (E = S (4), Se (5), Te (6)). Reactions of 4 and 5 with Ag(OTf) resulted in cleavage of the E-E bond and insertion of an ER group into the Ir-C(ppy) bond. The crystal structures of complexes 2-6 and [Cp∗Ir(η²-ppy-S-p-tol)(H₂O)][OTf]₂ have been determined.     

Synthesis and characterization of binuclear μ-oxo and μ-telluro molybdenum(V) complexes, [CpMo(O)(μ-Te)]2

Pyrolysis of an in-situ generated intermediate, produced in the reaction of [Cp^∗MoCl₄], 1, (Cp^∗ = η⁵-C₅Me₅) with [LiBH₄·THF], with an excess of difuryl ditelluride in toluene at 90 °C yielded syn and anti isomers of [Cp^∗Mo(O)(μ-Te)]₂ (2, 3) and [Cp^∗₂Mo₂O₂(μ-O)(μ-Te)] (4, 5). In a similar fashion, dibenzyl diselenide yielded syn and anti isomers of [Cp^∗Mo(O)(μ-Se)]₂ (6, 7), along with the known nido-[(Cp^∗Mo)₂B₄H₈Se₂]. Note that in parallel with 2-7, [(Cp^∗Mo)₂B₅H₉] was isolated as the major product in both cases. Compounds 2-7 have been isolated in modest yield as orange to brown crystalline solids. All the new compounds have been characterized in solution by mass, IR, ¹H, ¹³C, ⁷⁷Se and ¹²⁵Te NMR spectroscopy, and the structural types were unequivocally established by crystallographic analysis of 2-4 and 7.