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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.

Mn(II)-complexes are experiencing renewed interest as MRI contrast agents due to safety concerns related to the use of Gd(III)-chelates. While the preparation of oligomeric and polymeric Gd(III)-chelates is widely employed to multiply their efficiency, scarce examples of this strategy are reported for the corresponding Mn(II)-complexes. Two novel ditopic DO3A-based ligands were designed and synthesized and their Mn(II)-complexes evaluated in order to shed more light on the correlation of the paramagnetic properties of the resultant dinuclear complexes with their structural features. The stability of these complexes was assessed by potentiometric titration, while modelling was adopted to gain the structural features. A detailed relaxometric characterization provided a defined picture of the paramagnetic properties of these dinuclear chelates, paving the way for the design of Mn(II)-based multimeric MRI contrast agents.

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.

The present review is devoted to illustrate the state of the art of the syntheses of indoles, focusing particularly on the most recent developments of new synthetic approaches. Emphasis is given to the preparation of natural products or bioactive compounds containing the indole unit. We present a historical perspective of indole synthesis showing the strategies by choosing the nitrogen precursors. The review is organized sharing the indole synthetic approaches by using different nitrogen-containing functional groups in aromatic substrates used as source of the nitrogen of the indole moiety. Some functional groups and some typical reactions are particularly stressed and highlighted because of the limited coverage given in previous reviews published on this topic. Other synthetic approaches more used and discussed in recent, complete and excellent reviews on the topic are summarized but the most recent published results are highlighted. Our interest is particularly focused on the indolization procedures and on the different methods used for the ring closure and no attention is given to modification of indole structures starting from molecules with a preformed indole unit. Intriguing indole syntheses are continually discovered and the importance that the scientific community gives to these new developments is connected with the strategic role of molecules containing the indole unit. Indoles are the class of heterocycles with more applications and extensive interest due to their biological and pharmacological activity.

We have developed a three-component, one-pot domino reaction that combines the allylindation of 1H-indole-3-carbaldehyde with the dehydrative alkylation of stabilized Cnucleophiles (e.g., electron-rich heteroarenes, electron-rich aromatics, and stabilized enols) or N nucleophiles (e.g., azoles). (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

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 formation of a macromolecular adduct between a suitably functionalized GdIII complex and an exogeneous substance such as a poly-β-cyclodextrin (see picture) forms the basis of the novel route to contrast agents for magnetic resonance imaging endowed with high relaxivity discussed herein.

The asymmetric aminohydroxylation (AA) reaction of β-substituted vinylphosphonates under Sharpless protocol followed by hydrolysis afforded β-amino-α-hydroxyphosphonic acids in moderate to good ee.

Triethyl methanetricarboxylate (TEMT) is allylated by allylic carbonates in the presence of catalytic amounts of Pd(0) complexes; the reaction, conducted in very mild conditions, is fast and gives high yields of the title products.

A novel heptacoordinating ligand consisting of a thirteen-membered tetraazamacrocycle containing the pyridine ring and bearing three methylenephosphonate groups (PCTP-[13]) has been synthesized. Its Gd(III) complex displays a remarkably high longitudinal water proton relaxivity (7.7 mM–1 s–1 at 25 °C, 20 MHz and pH 7.5) which has been accounted for in terms of contributions arising from (1) one water molecule bound to the metal ion, (2) hydrogen-bonded water molecules in the second coordination sphere, or (3) water molecules diffusing near the paramagnetic chelate. Variable-temperature 17O-NMR transverse relaxation data indicate that the residence lifetime of the metal-bound water molecule is very short (8.0 ns at 25 °C) with respect to the Gd(III) complexes currently considered as contrast agents for magnetic resonance imaging. Furthermore, GdPCTP-[13] interacts with human serum albumin (HSA), likely through electrostatic forces. By comparing water proton relaxivity data for the GdPCTP-[13]-HSA adduct, measured as a function of temperature and magnetic field strength, with those for the analogous adduct with GdDOTP (a twelve-membered tetraaza macrocyclic tetramethylenephosphonate complex lacking a metal-bound water molecule), it has been possible to propose a general picture accounting for the main determinants of the relaxation enhancement observed when a paramagnetic Gd(III) complex is bound to HSA. Basically, the relaxation enhancement in these systems arises from (1) water molecules in the hydration shell of the macromolecule and protein exchangeable protons which lie close to the interaction site of the paramagnetic complex and (2) the metal bound water molecule(s). As far as the latter contribution is concerned, the interaction with the protein causes an elongation of the residence lifetime of the metal-bound water molecule, which limits, to some extent, the potential relaxivity enhancement expected upon the binding of the paramagnetic complex to HSA.

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 asymmetric synthesis of β-hydroxy-α-amino acids with good stereochemical selectivity represents a highly interesting synthetic goal. The possibility of predicting the stereochemical outcome of such preparation gives rise to the opportunity to direct synthetic efforts toward a well-defined objective. A model study on the role played, in this respect, by transition metal containing complexes is described. Four different models are considered and their construction is thoroughly examined.

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 present review is devoted to illustrate the state of the art of the syntheses of indoles, focusing particularly on the most recent developments of new synthetic approaches. Emphasis is given to the preparation of natural products or bioactive compounds containing the indole unit. We present a historical perspective of indole synthesis showing the strategies by choosing the nitrogen precursors. The review is organized sharing the indole synthetic approaches by using different nitrogen-containing functional groups in aromatic substrates used as source of the nitrogen of the indole moiety. Some functional groups and some typical reactions are particularly stressed and highlighted because of the limited coverage given in previous reviews published on this topic. Other synthetic approaches more used and discussed in recent, complete and excellent reviews on the topic are summarized but the most recent published results are highlighted. Our interest is particularly focused on the indolization procedures and on the different methods used for the ring closure and no attention is given to modification of indole structures starting from molecules with a preformed indole unit. Intriguing indole syntheses are continually discovered and the importance that the scientific community gives to these new developments is connected with the strategic role of molecules containing the indole unit. Indoles are the class of heterocycles with more applications and extensive interest due to their biological and pharmacological activity.

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).

Lipase-catalyzed transesterification of 2-bromo-2-cyclopenten-1-ol has been utilized in the asymmetric synthesis and consequent configurational assignment of the title compound.

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.

The asymmetric aminohydroxylation (AA) reaction of β-substituted vinylphosphonates under Sharpless protocol followed by hydrolysis afforded β-amino-α-hydroxyphosphonic acids in moderate to good ee.

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 .

We have developed a three-component, one-pot domino reaction that combines the allylindation of 1H-indole-3-carbaldehyde with the dehydrative alkylation of stabilized Cnucleophiles (e.g., electron-rich heteroarenes, electron-rich aromatics, and stabilized enols) or N nucleophiles (e.g., azoles). (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

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.

The absolute configuration of (+)-convolutamydine A 1 isolated from Amathia convoluta has been unambiguously established as (R) by enantioselective synthesis, based on chiral auxiliary-directed π-face discrimination in an allyl metal addition to (1R,2S,5R)-8-phenylmenthyl ester 7. For an independent and unequivocal proof, the absolute stereochemistry of synthetic precursor 11 en route to 1 was determined by X-ray crystallography.

An innovative MRI contrast agent based on the unprecedented and easily obtained ligand AAZTA is described. The simple and straightforward synthesis of the ligand, together with the potentiometric and relaxometric behavior of the corresponding Gd(III) chelate, is reported. The complex [Gd(AAZTA)]- shows outstanding magnetic properties connected with high thermodynamic stability in aqueous solution and a nearly complete inertness toward the influence of bidentate endogenous anions, placing this compound as one of the most promising candidates for the development of high performance MRI contrast agents.

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.