Georges Dupas

Deracemization of diarylmethanes via lateral lithiation–protonation sequences by means of sparteine

Abstract Deracemization of diarylmethane derivatives was investigated by lateral lithiation–protonation mediated by (−)-sparteine. Treatment of racemic 4-phenyltetrahydroisoquinoline 1 with s-butyllithium–(−)-sparteine followed by protonation of the resulting anion afforded (R)-phenyltetrahydroisoquinoline 1 in up to 88% e.e. Following the same procedure, racemic 2-(1-phenylethyl)pyridine 2 was subjected to the lithiation–protonation sequence. The stereochemical outcome of the sequence proved to be highly dependent on the proton sources giving either (S)- or (R)-2-(1-phenylethyl)pyridine 2 with EtOH or t-BuOH respectively in up to 50% e.e.

REGIOSELECTIVE REDUCTIONS OF VARIOUS 3-AMINOSUCCINIMIDES ; APPLICATION TO THE SYNTHESIS OF TWO HETEROCYCLIC SYSTEMS

Abstract The synthesis of novel pyrrolo[3,2-c]isoquinolines is investigated starting from 3-aminosuccinimides. Various known routes leading to 3-aminosuccinimides were tested but a new approach via nucleophilic addition of arylalkylamines on maleimide gave better results. The regioselectivity of the reduction of these compounds was shown to depend on the degree of substitution of the concerned 3-aminosuccinimide. The hydroxylactams are formed in-situ, then converted into the ethoxylactams. The latter, after generation of an iminium salt, afforded the target pyrroloisoquinolines and two further derivatives of another new heterocyclic system: the 3,6-methano-2,5-benzodiazocine.

Metalation of pi-deficient heterocycles a facile synthesis of cerpegin

Abstract The first total synthesis of the naturally occuring cerpegin is described. Metalation of a pyridine derivative has been used in the key step.

Diastereoselective alkylation of homochiral 1,2,3,4-tetrahydroisoquinolin-3-one. A potential route to enantiomerically pure 4-substituted tetrahydroisoquinolines

Abstract Enantiomerically pure 1,4-dihydroisoquinolin-3-one 1 was prepared in four steps with an overall yield of 60%. Alkylation of the corresponding lactam enolate has been studied and has proven to be highly diastereoselective. Thus, 4-substituted-1,4-dihydroisoquinolin-3-ones 7a-d were obtained in high chemical yields with up to 97% diastereoisomeric excesses.

DESIGN AND SYNTHESIS OF A HETEROCYCLIC AMINE RECEPTOR

Abstract After a short review on the amine receptors already published in the literature, the design of a new host 1 is described. This new host possesses two heterocyclic parts (isoquinoline and pyridine) separated by a flexible arm. The synthesis of receptor 1 involves regioselective acylation or halogenoacylation at the C-7 of isoquinoline followed by a Willgerodt-Kindler reaction affording the isoquinoline-7-acetic acid derivatives 4b,c . Coupling of 4c with 2-aminopyridine gives the required host 1 . The association constants of this latter compound with some amine guests are determined using the classical NMR titration method.

Study of the mechanism of the hydride transfer with a highly reactive and stereoselective NADH model

Abstract The 1 H and 13 C NMR spectra of the chiral NADH models 3 and 4 were studied both in the presence or absence of Mg 2+ ions. These two compounds have a chiral carboxamide part derived from (S)-phenylalaninol but contrary to 3 , compound 4 has the ability to free-rotate about the C 3 CO bond. Careful analysis of the spectral results and comparison with some other studies recently published in the literature allowed the following assumptions: 1-the 1,4-dihydropyridine structure is planar both in the absence or presence of magnesium ions. 2-in the case of the rigid model 3 , the CO is out of the plane of the dihydropyridine structure. 3-with Mg 2+ the chiral amino alcohol moiety adopts a quasi-cyclic conformation in the case of 4 but not in the case of 3 . The observed enantioselectivities are explained by the mean of ternary complexes between the model, Mg 2+ and the substrate.

Study of the lithiation of 3-substituted α-carbolines a new route to 3,4-disubstituted derivatives

Abstract The synthesis of new 3-substituted α-carbolines is described and these products were subjected to ortho-lithiation experiments. 3-pivalamido and 3-carboxamido derivatives are cleanly lithiated at 4-position. The results are correlated with MNDO calculations. Various 3,4-disubstituted α-carbolines are obtained in excellent yields.

Reduction of new substrates with a NADH model reduction of N-acyl-enamines: Mechanism and scope

Abstract Several examples of the successful reduction of N-acyl-enamine derivatives with a NADH model in the pyrrolo[2,3-b]pyridine series are given. It is shown, that the reduction is strongly dependent on electronic and geometrical factors. It appears that in general, the success of the reduction can be related to the ability of the magnesium ions to form a complex with the acyl group and with the enamine function. Herein the reduction of the enamine function in α-acetylaminoacrylate derivatives is discussed from this point of view and the influence of the enamine imine equilibrium is discussed.

Solid phase synthesis of a redox delivery system with the aim of targeting peptides into the brain

A solid phase approach for the preparation of peptides attached to a redox chemical delivery system derived from stable annulated NADH models is reported. The synthesis starts with the grafting on a Merrifield resin of quinoline 4b, precursor of the redox carrier. From the resulting quinoline supported resin 4d, the stepwise SPPS of both octapeptide OP (RPGLLDLK) and octadecaneuropeptide ODN (QATVGDVNTDRPGLLDLK), two neuropeptides exhibiting anorexigenic effects, was successfully achieved by conventional methods. Quaternization of the quinoline moiety prior to cleavage of the modified OP and ODN peptides from the resin, led to the expected quinolinium salt 8a and 8b respectively linked to OP or ODN peptides. Finally, the reduction with NaBH4 monitored by UV-vis, provided the desired annulated NADH models as peptides carriers with either the OP (11a,b) or ODN (12a,b) moiety.

Synthesis of a Heterocyclic Amine and Acid Receptor

Abstract The synthesis of a molecule able to bind both with an amine and a carboxylic acid is described. This new host consists in a pyrroloisoquinoline structure possessing a side arm with an acetamidopyridine moiety. The pyrroloisoquinoline part was obtained after improvement of the previously published route involving regioselective reduction of appropriate 3-arylalkylaminosuccinimides followed by ring closure using iminium chemistry. The tricyclic structure was then functionalized by cross-coupling reaction under Pd0 catalysis of its triflate derivative with the trimethylsilyl ketene acetal of methyl acetate. The so-obtained ester was then reacted with 2-amino-4,6-dimethylpyridine leading to the targeted host. The association constants of this latter compound with some carboxylic acids and amines were determined by 1H NMR titration. NOESY experiments and molecular modeling calculations were performed in order to precise the actual host–guest interactions.