High-performance liquid chromatographic determination of 3,5-dimethylhippuric acid in the occupational exposure to trimethylbenzenes.

A high-performance liquid chromatographic method for the measurement of urinary 3,5-dimethylhippuric acid (3,5-DMHA) in the human biological monitoring of the occupational exposure to trimethylbenzenes has been developed. 3,5-DMHA was extracted from urine with ethyl acetate. The organic phase was dried under vacuum and the resultant product, dissolved in the mobile phase, was analysed by an isocratic system and a programmable photodiode-array detector adjusted to 205 nm. The mobile phase was water-acetonitrile (80:20, v/v) containing 0.1% acetic acid. 3,5-DMHA was chromatographed on a reversed-phase Supelco C18 column (3 microns; 15 cm x 0.46 cm I.D.), and identified by its retention time and ultraviolet spectrum. Quantitation was performed by peak area. The detection limit of the method is 30 ng/ml and the recovery and the accuracy are 96%.     

Stereoselective synthesis of spirocyclic ketones by Nazarov reaction

[reaction: see text] The Suzuki-Miyaura cross-coupling reaction between alpha-ethoxydienyl boronates and lactone-derived vinyl triflates affords functionalized 6-(1-ethoxy-1,3-butadienyl)dihydropyran derivatives that undergo a Nazarov electrocyclic reaction under mild acidic conditions to give functionalized spirocyclic ketones. The product distribution and the stereoselectivity of the process are strongly dependent on the substitution of both the alpha-ethoxydiene and dihydropyran moieties. High stereoselectivity is observed in the presence of a C2-substituent on the dihydropyran moiety. The results are explained in terms of transition state geometries.     

Remote stereocontrol in the Nazarov reaction: a new approach to the core of roseophilin

Three different procedures are compared to obtain properly substituted divinyl ketones in which one of the double bonds is embedded in a five-membered heterocyclic structure and therefore suitable to produce cyclopenta-fused pyrrole derivatives by the acid-catalyzed Nazarov reaction. These, on treatment with TFA, afforded 2,4-cis-disubstituted 2,3,4,5-tetrahydro-1H-cyclopenta[b]pyrrol-6-ones with high stereocontrol. One of these Nazarov products was oxidized to the corresponding 4,5-dihydro-1H-cyclopenta[b]pyrrol-6-one derivative, thus obtaining an enantiopure key intermediate in the total synthesis of roseophilin.     

Pentannulation of Heterocycles by Virtue of Precious Metal Catalysis

Pentannulated heterocycles are the key structural subunit of many natural and biologically active compounds. Over the last decades, many precious metal‐assisted pentannulations have been described as a consequence of an extensive research. This Focus Review gives an overview of precious metal‐catalyzed reactions applied to the synthesis of cyclopenta‐fused heterocycles in the last five years.     

Density functional studies on the Nazarov reaction involving cyclic systems

Density functional theory (DFT) has been used to define the energy profiles of the Nazarov reaction involving cyclic systems. The calculations were carried out at the B3LYP/6-311G** level of theory and the solvent (dichloromethane) contribution was estimated by using the recently developed SM5.43R solvation model. DFT calculations were first carried out to determine the energy profiles associated with the electrocyclization reactions of 3-hydroxy- and 3-ethoxypentadienyl cations in which one of the double bonds is embedded in O-heterocyclic and carbocyclic systems. In particular, the effects on the reaction rate of modifications to the substrate, as well as the presence of the heteroatom in the cycle, have been investigated. The torquoselectivity of the electrocyclization reaction was then explored with substituted O-heterocycles to understand the factors that control the stereochemical outcome of the process that preferentially provides 2,5-trans-disubstituted products. These DFT-based results rationally explain most of the experimental observations related to the Nazarov reaction of the substrates herein investigated and could be useful in the rational interpretation, and likely in the prediction, of the outcome of Nazarov reactions involving other cyclic systems.     

Preparation and Suzuki-Miyaura coupling reactions of tetrahydropyridine-2-boronic acid pinacol esters

[reaction: see text] A study on the conversion of lactam-derived vinyl triflates and phosphates into the corresponding vinyl boronates was carried out. While delta-valerolactam-derived vinyl triflates were successfully converted into 1,4,5,6-tetrahydropyridine-2-boronic acid pinacol ester derivatives by Pd-catalyzed coupling reaction with both bis(pinacolato)diboron and pinacolborane, pyrrolidinone and epsilon-caprolactam derivatives either did not react or were readily reduced. The delta-valerolactam-derived vinyl boronates are thermally stable compounds that efficiently coupled, under Pd catalysis, with structurally diverse aryl and heteroaryl bromides and triflates, vinyl iodides and bromides, and aromatic acid chlorides, to give the corresponding 2-substituted piperidines in good to excellent yields. The number of electrophiles that can virtually be coupled with these new boronic esters makes them very useful reagents for the synthesis of N-heterocyclic compounds.     

Synthesis of alpha-acyl-functionalized azacycles by Pd-catalyzed cross-coupling reactions of alpha-alkoxyboronates with lactam-derived vinyl triflates

Alkoxydienyl- and alkoxystyrylboronates were used for Pd-catalyzed cross-coupling reactions with lactam-derived vinyl triflates. The hydrolysis of the coupling products with alkoxystyrylboronates provided the corresponding alpha-acyl-substituted 3,4-dihydro-(2H)-pyridines and 2,3,4,5-tetrahydroazepines in good to high yields. The hydrolysis of the coupling products with alkoxydienylboronates, performed in the presence of Amberlyst 15, resulted in a Nazarov-type cyclization that afforded hexahydro[1]pyrindin-7-ones and 3,4,5,6,7,8-hexahydro-(2H)-cyclopenta[b]azepin-8-ones. This methodology represents a novel and efficient procedure for the preparation of these classes of azacyclic compounds.     

The Lewis acid-catalyzed nazarov reaction of 2-(n-methoxycarbonylamino)-1,4-pentadien-3-ones

[reaction: see text] A highly efficient carbonylative Suzuki-Miyaura coupling reaction of lactam-derived vinyl triflates and alkenylboronic acids afforded 2-(N-methoxycarbonylamino)-1,4-pentadien-3-ones as suitable substrates for the Nazarov reaction. The most competent Lewis acids for the Nazarov reaction were Cu(OTf)(2) (2 mol %) and Sc(OTf)(3) (3 mol %) in DCE, which provided the Nazarov products in excellent yield. As both the carbonylative coupling and the subsequent Nazarov reaction were high yielding, the overall methodology is a concise and efficient route to [1]pyrindine systems.     

Predicting reactivity and stereoselectivity in the Nazarov reaction: a combined computational and experimental study

The Nazarov reaction of pentadienyl cations generated by protonation of either dienones or alkoxytrienes has been examined in detail both experimentally and by DFT calculations. In particular, calculations at the B3LYP/6‐311G** level of theory accurately predicted, and accounted for, the outcome of the Brønsted acid catalyzed electrocyclization of 4π‐electron systems in which one of the double bonds involved in the process was embedded in N‐ and S‐heterocyclic rings. Calculations showed that both heteroatoms are capable of accelerating the ring closure by stabilizing the partial positive charge which develops at C‐6 (C‐2) in the transition state, with S‐heterocyclic derivatives being more reactive than the corresponding N‐containing compounds. In general, pentadienyl cations generated by protonation of alkoxytrienes were expected to react faster than those obtained by protonation of the corresponding dienones, as the latter were stabilized by a hydrogen bond. The presence of a substituent on the heterocyclic ring significantly affects the stereoselectivity (torquoselectivity) only in the case of the N‐heterocyclic derivatives, in which a 2‐alkyl group is axially oriented, providing the cis‐2,5‐disubstituted isomer only. Instead, with substituted S‐heterocyclic compounds, the anticipated torquoselectivity was very low and, in fact, a 3:1 diastereomeric mixture between the trans and cis products was experimentally found after ring closure. For this study, the synthesis of the appropriate N‐ and S‐containing dienones and alkoxytrienes was realized to evaluate the predictivity power of the DFT computations, which was very good in all of the cases examined, both in terms of reactivity and stereoselectivity. The consistency observed between computational and experimental results, therefore, shows the usefulness of DFT calculations at the B3LYP/6‐311G** level of theory as a robust instrument for the prediction of reactivity and stereoselectivity in the Nazarov electrocyclic reaction.