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The first binuclear Gd‐complex of the 12‐membered pyridine‐based polyaminocarboxylate macrocyclic ligand PCTA was synthesized by C−C connection of the pyridine units through two different synthetic procedures. A dimeric AAZTA‐ligand was also synthesized with the aim to compare the relaxometric results or the two ditopic Gd‐complexes. Thus, the 1H relaxometric study on [Gd2PCTA2(H2O)4] and on [Gd2AAZTA2(H2O)4]2− highlighted the remarkable rigidity and compactness of the two binuclear complexes, which results in molar relaxivities (per Gd), at 1.5 T and 298 K of ca. 12–12.6 mM−1 s−1 with an increase of ca. 80 % at 1.5 T and 298 K (+70 % at 310 K) with respect to the corresponding mononuclear complexes., Two novel binuclear PCTA2 and AAZTA2 ligands were synthesized with a multistep process. Their GdIII‐complexes results in molecular relaxivities at 1.5 T and 298 K of ca. 24–25 mM−1 s−1 thanks to the rigidity and compactness of the ligands. These values are remarkably higher that those found for the corresponding mononuclear complexes.

The synthesis and characterization of copper(I) complexes of the novel pyridine-containing macrocyclic ligand (PC-L) and their use as catalysts in the Henry reaction are reported. The pyridine-based 12-membered tetraaza macrocyclic (PC-L) ligand 1 can be obtained in good overall yield (85%) from commercially available starting materials. The Cu(I) complexes showed good catalytic activities in the Henry reaction of different aldehydes and nitroalkanes. Remarkable diastereoselectivity was observed when isatine was reacted with nitroethane under catalytic conditions. Copyright © 2011 John Wiley & Sons, Ltd.

Four new ligands for lanthanide ions based on the H3do3a (=1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid) structure and bearing one N-sulfonylacetamide arm were synthesized, i.e., H4dota-NHSO2R=10-{2-[(R)sulfonylamino]-2-oxoethyl}-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acids 1a–e. A 15N-NMR study of the 15N-labelled Eu3+ complex of one such ligands, 1d, showed that the coordination of the N-sulfonylacetamide arm involves the carbonyl O-atom rather than the N-atom. The relaxometric properties of the corresponding Gd3+ complexes were investigated as a function of pH and temperature. These complexes have relaxivities in the range 4.5–5.3 mM−1 s−1, at 20 MHz and 25°, and are characterized by a single H2O molecule in their inner coordination sphere. The mean residence lifetime of this molecule is relatively long (500–700 ns) compared to other anionic complexes. The slow rate of H2O exchange can be justified by the extensive delocalization of the negative charge on the N-sulfonylacetamide arm. The long residence time of the coordinated H2O allowed the observation of the effect of the prototropic exchange on the relaxivity. The study of the interaction between the complex [Gd(1e)]- and HSA revealed a weak affinity constant highlighting the importance of a localized negative charge on the complex to promote a strong interaction with the protein.

The new C 2 -symmetrical 1,2-diamine { N , N ′-bis[(1 R ,2 R ,4 R )-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl]-1,2-ethanediamine} 3 has been synthesized from commercial (1 R )-(+)-camphor 1 and scrutinized as ligand in the oxidative biaryl coupling of naphthol derivatives. Under the optimal conditions employing a Cu(I)- 3 triflate complex (10 mol%) in dichloroethane–MeCN and molecular sieves with air as the oxidant, aryl coupling of naphthol derivatives could be achieved in satisfactory yields (48–90% yield) and ees of up to 65%. The ester moiety at the 3-position of the substrate was found to be crucial for a satisfactory asymmetric induction in the present coupling reaction.

The three novel pyridine-containing 12-membered macrocyclic ligands 1–3 were synthesized. The coordinating arms are represented by three acetate moieties in 1 and 3 and by one acetate and two phosphonate moieties in 2. In all three ligands, the acetate arm in the distal position is substituted, with a benzyl group in 1 and 2 and with an arylmethyl moiety in 3. The relaxivities r1p (20 MHz, 25°) of GdIII complexes are: GD⋅1, r1p=8.3 mM−1 s−1; GD⋅2, r1p8.1 mM−1 s−1; Gd⋅3, r1p10.5 mM−1 s−1. 1H-NMRD and 17O-NMR T2 data show that Gd⋅1 and Gd⋅3 contain two H2O molecules in the inner sphere, whereas the presence of two phosphonate arms allows the coordination of only one H2O molecule in Gd⋅2. Interestingly, the exchange lifetime of coordinated H2O in the three complexes is similar in spite of the difference in the coordination number of the GdIII ion (i.e., 9 in Gd⋅1 and Gd⋅3, and 8 in Gd⋅2). 1H-Relaxometric measurements at different pH and in the presence of lactate and oxalate were carried out to get some insight into the formation of ternary complexes from Gd⋅1 and Gd⋅3. Finally, it was found that binding to human-serum albumin (HSA) of Gd⋅1 and Gd⋅2, though weak, yields limited relaxivity enhancements, likely as a consequence of effects on the hydration sphere caused by donor atoms on the surface of the protein.

The intermolecular [3 + 2] annulation of azomethine ylides with 2(2-nitrophenyl)acrylate dienophiles followed by reductive heterocyclization affords the spiro(indole-pyrrolidine) ring system. Hence, this enable us to accomplish a concise and highly enantioselective synthesis of (-)-horsfiline 1, based on chiral auxiliary-directed pi-face discrimination in the 1,3-dipolar cycloaddition of (1S,2R)-2-phenyl-1-cyclohexyl ester 4f with N-methylazomethine ylide.

A practical preparation of the versatile macrocycle 1,4,7,10-tetraazacyclododecane (cyclen) was developed starting from cheap and easily available starting materials as ethylenediamine and glyoxal.

The synthesis of (−)-pyrrolam A starting from (R)-prolinol is described. The key step is the dehydrative alkylation of a conveniently protected (R)-prolinol with triethyl methanetricarboxylate under the conditions of the Mitsunobu reaction.

Enantiomerically pure compounds embodying the 4,6,7,8,8a,9-hexahydropyrrolo[3,2-f]indolizine unit were synthesized via intramolecular iminium ion cyclization. An improved procedure for the preparation of the oxazolidinone 1 is also reported.

Theoretical studies to predict the diastereoselectivity of the electrophilic amination of chiral 1,3,2-oxazaphospholanes led to the design of (1R), (2S)-1,3-diphenyl-2- (N-isopropylamino)-1-propanol 7 as a powerful chiral auxiliary. The experimental results are in good agreement with the calculations. An efficient synthesis of enantiomerically pure 7 is also reported.

The synthesis and characterisation of copper(I) complexes of chiral pyridine-containing macrocyclic ligands (Pc-L*) and their use as catalysts in asymmetric cyclopropanation reactions are reported. All ligands and metal complexes were fully characterised, including crystal structures of some species determined by X-ray diffraction on single crystals. This allowed characterising the very different conformations of the macrocycles which could be induced by different substituents or by metal complexation. The strategy adopted for the ligand synthesis is very flexible allowing several structural modifications. A small library of macrocyclic ligands possessing the same donor properties but with either C(1) or C(2) symmetry was synthesized. Cyclopropane products with both aromatic and aliphatic olefins were obtained in good yields and enantiomeric excesses up to 99%.

A model was developed to rationalize the experimental results of the alkylation of chiral phosphonoglycine equivalents yielding α-amino-α-alkyl-phosphonates. The model studies, carried out using semiempirical calculations, have emphasized the role of the chelating effects in influencing the diastereoselectivity of the alkylation step. Chelation can be optimized by tuning the functionality of the substituent at carbon C-1 of the camphor skeleton. By employing 2d , as suggested by the modelling, a major improvement in the enantiomeric excesses of compounds 5 (R=CH 3 , C 2 H 5 ) was obtained.

The ability to predict the stereochemical outcome of the condensation reaction between a transition metal containing a complex of amino acid derivatives and an aldehyde gives rise to the possibility of directing synthetic efforts toward the synthesis β,3-hydroxy-α-amino acids of known configuration. Four models for studying the role played by the complex were reported previously. In this paper we describe application of the models and the results obtained. The possibility of using both a monomeric and a trimeric model with metal intervention is suggested. The calculated data were compared with some experimental results and good agreement was found.

The eight-membered 3,7-dihydroxy-3,7-dioxoperhydro-1,5,3,7-diazadiphosphocine-1,5-diacetic acid was obtained with a one-step reaction of glycine, formaldehyde and hypophosphorous acid in acidic aqueous medium. A preliminary investigation of its coordination properties is reported.

The dicyclopenta[a,d]cyclooctane skeleton is obtained by a very mild Cope arrangement of the highly functionalized divinylcyclobutane derivative 10 .

Diethyl α-amino-α-alkyl-phosphonates are obtained in good to high enantiomeric excesses by alkylation of chiral phosphonoglycine equivalents embodying the camphor skeleton. The chelating effects in the alkylation step play an important role in enhancing the diastereoselectivity of the reaction as substantiated by semiempirical calculations (AM1).

A model was developed to rationalize the experimental results of the alkylation of chiral phosphonoglycine equivalents yielding α-amino-α-alkyl-phosphonates. The model studies, carried out using semiempirical calculations, have emphasized the role of the chelating effects in influencing the diastereoselectivity of the alkylation step. Chelation can be optimized by tuning the functionality of the substituent at carbon C-1 of the camphor skeleton. By employing 2d , as suggested by the modelling, a major improvement in the enantiomeric excesses of compounds 5 (R=CH 3 , C 2 H 5 ) was obtained.

A novel non-biomimetic synthesis of horsfiline has been developed. The key pyrrolidine forming reaction is the 1,3-dipolar cycloaddition of the thermally generated N -methylazomethine ylide to a suitable 3-alkylidene-indolin-2(3 H )one. The same strategy was also applied to the synthesis of pure ( R )-(−)-enantiomer.

Triethyl methanetricarboxylate (TEMT) can be mildly alkylated by primary, benzylic and allylic alcohols under classical Mitsunobu conditions, in fair to good yields. The utility of TEMT in organic synthesis as a diethyl malonate surrogate is reported.

Theoretical studies to predict the diastereoselectivity of the electrophilic amination of chiral 1,3,2-oxazaphospholanes led to the design of (1R), (2S)-1,3-diphenyl-2- (N-isopropylamino)-1-propanol 7 as a powerful chiral auxiliary. The experimental results are in good agreement with the calculations. An efficient synthesis of enantiomerically pure 7 is also reported.

Constrained camphor-derived oxazaphospholanes have provided an efficient entry for the preparation of enantiomerically enriched α-chlorophosphonic acids.

The reaction of cyclen 1 with chloral hydrate afforded exclusively 1,4,7-triformylcyclen 2 in high yield; the triprotected macrocycle was easily alkylated with various electrophiles in good to excellent yields. The alkaline removal of the formyl groups provided a selective entry into N-monosubstituted cyclen derivatives.

The intermolecular [3 + 2] annulation of azomethine ylides with 2(2-nitrophenyl)acrylate dienophiles followed by reductive heterocyclization affords the spiro(indole-pyrrolidine) ring system. Hence, this enable us to accomplish a concise and highly enantioselective synthesis of (-)-horsfiline 1, based on chiral auxiliary-directed pi-face discrimination in the 1,3-dipolar cycloaddition of (1S,2R)-2-phenyl-1-cyclohexyl ester 4f with N-methylazomethine ylide.

Diethyl α-amino-α-alkyl-phosphonates are obtained in good to high enantiomeric excesses by alkylation of chiral phosphonoglycine equivalents embodying the camphor skeleton. The chelating effects in the alkylation step play an important role in enhancing the diastereoselectivity of the reaction as substantiated by semiempirical calculations (AM1).

The alkylation of the chiral Schiff base derived from the condensation of (+)-ketopinic acid and diethyl aminomethylphosphonate followed by hydrolysis affords diethyl (S)-α-amino-α-alkyl phosphonates with high enantiomeric excesses when benzyl or allyl halides are used in the alkylation step. An improved procedure for the preparation of diethyl aminomethylphosphonate is also reported.

The dicyclopenta[a,d]cyclooctane skeleton is obtained by a very mild Cope arrangement of the highly functionalized divinylcyclobutane derivative 10 .

The synthesis and characterisation of copper(I) complexes, including two crystal structures of the new chiral pyridine-containing macrocyclic ligands (PC-type), and their use as catalysts in asymmetric cyclopropanation reactions are reported.

The condensation between benzaldehyde and the zinc(II) and copper(II) complexes of the glycine imines of (1R)-3-hydroxymethylenebornan-2-one in the presence of strong bases has been studied. The diastereo- and enantio-selectivity of the reaction together with the spectroscopic characterization of the metal complexes and the corresponding enolate intermediates are reported.

We report the synthesis and the properties of the Gd(III) complex with 4 (H 4 dotetra), a novel mixed pendant-arm macrocyclic ligand embodying a tetrazole subunit in a N 5 O 3 donor set as a potential magnetic resonance imaging (MRI) contrast agent.

PTC-alkylation of a chiral non-racemic cyanomethyl phosphonic acid equivalent embodying the camphor skeleton gave rise to a formal entry into enantiomerically enriched β-amino-α-substituted phosphonic acids.

PTC-alkylation of a chiral non-racemic cyanomethyl phosphonic acid equivalent embodying the camphor skeleton gave rise to a formal entry into enantiomerically enriched β-amino-α-substituted phosphonic acids.

The fully diethoxyphosphoryl(Dep)-protected polyamines 1b – 3b were prepared from the corresponding polyamines with `diethyl phosphite' (=diethyl phosphonate) and CCl4 in a solid base/organic liquid two-phase system in the presence of Bu4NBr as phase-transfer catalyst. Subsequent phase-transfer-catalyzed alkylation of phosphoramidates 1b – 3b with bis(chloromethyl)arenes 5 – 8 in the presence of Bu4N(HSO4) followed by deprotection gave good yields of polyazacyclophanes 9a – 16a.

Constrained camphor-derived oxazaphospholanes have provided an efficient entry for the preparation of enantiomerically enriched α-chlorophosphonic acids.

The water 1H and 17O NMR relaxation properties of solutions containing Gd(III) chelates of the heptadentate DO3A, PCTA[12] and PCTP[12] ligands were thoroughly investigated and the results obtained are compared with those previously reported for other Gd(III) complexes with octadentate ligands {H3DO3A=1,4,7,10-tetraazacyclododecane 1,4,7-triacetic acid; H3PCTA[12]=3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-triacetic acid; H6PCTP[12]=3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(15),11,13-triene-3,6,9-tris(methanephosphonic) acid}. The observed behaviour is consistent with a hydration number q=2 in the case of GdDO3A and GdPCTA[12] and q=1 in the case of PCTP[12]. The high relaxivity of the latter complex is accounted for in terms of the occurrence of an additional contribution arising from water molecules tightly bound to the phosphonate moieties on the surface of the paramagnetic chelate. Furthermore, it was found that the decreased relaxation rates observed at basic pH in the case of GdDO3A and GdPCTA[12] can probably be ascribed to a partial decrease in their hydration. The measurement of 17O NMR transverse relaxation rates, in the temperature range 273–342 K, allowed the assessment of the water exchange rate between the coordination site and the bulk solvent. A particularly short exchange lifetime was measured for the octacoordinate GdPCTP[12], which suggests the occurrence of an associative exchange mechanism. Further insights into the understanding of the structural properties of the three complexes were gained by measuring the magnetic field dependence (NMRD profiles) of the proton relaxivity on a Koenig–Brown field cycling relaxometer. © 1998 John Wiley & Sons, Ltd.

A novel non-biomimetic synthesis of horsfiline has been developed. The key pyrrolidine forming reaction is the 1,3-dipolar cycloaddition of the thermally generated N -methylazomethine ylide to a suitable 3-alkylidene-indolin-2(3 H )one. The same strategy was also applied to the synthesis of pure ( R )-(−)-enantiomer.

Triethyl methanetricarboxylate (TEMT) can be mildly alkylated by primary, benzylic and allylic alcohols under classical Mitsunobu conditions, in fair to good yields. The utility of TEMT in organic synthesis as a diethyl malonate surrogate is reported.

9-Oxa-4-thia-tetracyclo[5.5.1.02,7.010,13]tridecan-12-one-3-spiro-l'-cyclopentan-3'-ones, which are useful intermediates in the total synthesis of sesterterpenes, display an unusual reactivity towards organometallic reagents in that the tetrahydrofuran ring opening precedes the nucleophilic attack on the carbonyl group in the trans diastereoisomer 5. These experimental results, which are of considerable importance from a synthetic point of view, were rationalized using molecular modelling techniques implemented using the AMPAC package. The different behaviour of the cis and trans diastereoisomers is related to the steric strain of the tetrahydrofuran moiety in the latter compound.

Tetradentate ligands derived from the condensation of (1R)-3-hydroxymethylenebornane-2-thione and symmetric diamines were synthesised together with their zinc(II) complexes. As deduced from cumulative spectral evidence, freshly prepared samples of the free ligands consist exclusively of the thioxoenamine tautomer, while binding to zinc(II) occurs through the enethiolate imine form. The circular dichroism (CD) spectrum of the ligand bearing an ethylene bridging chain shows very intense Cotton effects characteristic of exciton-coupled transitions. The pattern of CD bands associated with the thioxoenamine transitions suggests a gauche structure for the dominant conformer. The NMR spectra of zinc(II) complexes are indicative of the presence of several species resulting from geometric isomerism at the metal atom and conformational mobility of the flexible part of the ligands in the chelates. Lengthening of the carbon chain in the diamine moiety from two to four carbon atoms favours the adoption of tetrahedral structures at zinc(II) as is evidenced by the CD spectral behaviour of the complexes. The absolute configuration of the dominant structure is assigned on the basis of the CD spectrum.

A novel pyridine-containing DTPA-like ligand, carrying additional hydroxymethyl groups on the pyridine side-arms, was synthesized in 5 steps. The corresponding Gd(III) complex, potentially useful as an MRI contrast agent, was prepared and characterized in detail by relaxometric methods and its structure modeled by computational methods.

A series of tetradentate ligands derived from the condensation of (1R)-3-hydroxymethylenebornane-2-thione and several 2-aminothia-alkylbenzimidazoles were synthesized together with their cationic zinc(II) and copper(II) complexes. While the free ligands exist in the thioxoenamine tautomeric form, binding to the metals occurs in their enethiolateimine form, as deduced from cumulative spectral evidence. The copper(II) complexes exhibit medium-intensity absorptions between 410 and 435 (Iµ≳ 3 500) and between 520 and 535 nm (Iµ≳ 1 200 dm3 mol–1 cm–1) attributable to enethiolate σ(S–)→ CuII and π(S–)→ CuII ligand-to-metal charge transfer (I.m.c.t.) transitions, respectively, and relatively intense ligand-field transitions in the range 610–650 nm (Iµ≳ 1 500 dm3 mol–1 cm–1). All the bands undergo progressive red shifts as the length of the carbon chain connecting the imine and thioether functions increases from two to four atoms. The frozen-solution e.p.r. spectra are indicative of progressive distortion towards a pseudo-tetrahedral geometry for copper(II) as the carbon chain length increases. A series of neutral copper(II) complexes derived from the condensation of (1R)-3-hydroxymethylenebornane-2-thione and symmetric diamines was also synthesized for comparison. Here too the length of the carbon chain connecting the imine nitrogen atoms was varied from two to four atoms. These complexes exhibit the same spectroscopic trends but with less marked distortion of the copper(II) chromophores as the length of the carbon chain increases. The cationic copper(II) complexes from (1R)-3-hydroxy-methylenebornane-2-thione and 2-aminothia-alkylbenzimidazoles display, in acetonitrile solution at –15 °C, easy access to the corresponding copper(I) congeners (E0=–0.02 V vs. s.c.e.). By contrast, the neutral copper(II) species derived from (1R)-3-hydroxymethylenebornane-2-thione and diamines are reduced to the corresponding copper(I) complexes at potentials more negative by 0.7–1.0 V, depending upon the extent of stereochemical distortion around the copper(II) centre induced by the length of the imine-nitrogen-linking carbon chain. The planar complex bearing an ethylene bridging chain can be reversibly oxidized to the corresponding copper(III) species (E0=+0.37 V).

The enolates from 1,4 addition of lithium dimethylcuprate to 2-cyclohexenone, 2-cyclopentenone and methyl vinyl ketone, with acetyl chloride, give only C-acylated products and not O-acylated products as previously reported in literature.

Reactions of aliphatic branched aldehydes with proline in dimethyl sulfoxide or acetonitrile solution afford oxazolidin-5-ones with high diastereoselection. Linear aldehydes afford aldolic/crotonic condensation products; with short reaction times, the presence of Oxazolidinones can be detected in the pmr spectra. Acyclic aminoacids and branched aldehydes yield a reaction mixture the pmr and ir spectra of which give evidence for iminic-oxazolidinone equilibria. The structure of (2R,5S)-2-trichloromethyl-1-aza-3-oxabiciclo-[3.3.0]octan-4-one has been confirmed by X-ray diffraction analysis.

A new entry to the drimane-related sesquiterpene Confertifolin is reported. The key step involves the conversion of a β-phenylthio-α, β-unsaturated ketone into the corresponding silylcyanohydrin followed by diisobutylaluminum hydride reduction to the homologous α,β-unsaturated aldehyde.

Ozonolysis of the ethylene acetals of 2-substituted 2-cyclohexenones followed by cyclization of the intermediate 1,6-dicarbonyl compounds affords 6-substituted 7-formyl-1,4-dioxaspiro[4,4]non-6-enes in modest yields. The same procedure applied to protected 2-substituted 2-cyclohexenols gives 2-substituted 3-formyl-2-cyclopentenyl 2-methoxyethoxymethyl ethers in satisfactory yields

Substituted pyrrolizidines have been synthesized by 1,3-dipolar cycloaddition of various dipolarophiles with the azomethine ylide generated by treatment of proline with benzaldehyde in dimethylsulfoxide. The regio- and stereochemical outcome of the reaction as well as the stability of the isomers obtained are discussed.

A new and efficient synthesis of indazole-3-carboxylic acid is reported. The method consists in reacting β-acetylphenylhydrazine with chloral hydrate and hydroxylamine hydrochloride in acidic medium to afford N-acetylaminoisonitrosoacetanilide which, in turn, is converted into the title compound by treatment with sulphuric acid.